thrombophilia & cardiovascular diseasedeep vein thrombosis – dvt . pulmonary embolism pe –...
TRANSCRIPT
VenousThromboEmbolism (VTE)
Deep Vein Thrombosis ndash DVT Pulmonary Embolism ndash PE
Dr Mudi Misgav
The National Hemophilia amp Thrombosis center
Topics
Treatment options
Treatment duration
Cancer associated VTE (CAT)
Medical patients
VTE treatment
AC Thrombolysis PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
תיאור מקרה בריא 25בן
כאב שמתחיל בסובך שמאל
והרגל מתנפחת לכל אורכהמתגבר ימים הכאב 5במהלך של
-פנייה לחדר מיון
Fem-Pop DVT
The probability of DVT (DVT in 3months FU)
ge 3 High (49)
1 2 Intermediate (143)
le 0 low (32)
Modified Wellrsquos criteria
Wells Anderson et al Lancet 1997 Anderson DR et al Arch Intern Med 1999
Previously documented DVT 1
The probability of DVT ge 2 DVT likely
le 1 DVT Unlikely
Recurrent VTE
NEJM 1992
Topics
Treatment options
Treatment duration
Cancer associated VTE (CAT)
Medical patients
VTE treatment
AC Thrombolysis PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
תיאור מקרה בריא 25בן
כאב שמתחיל בסובך שמאל
והרגל מתנפחת לכל אורכהמתגבר ימים הכאב 5במהלך של
-פנייה לחדר מיון
Fem-Pop DVT
The probability of DVT (DVT in 3months FU)
ge 3 High (49)
1 2 Intermediate (143)
le 0 low (32)
Modified Wellrsquos criteria
Wells Anderson et al Lancet 1997 Anderson DR et al Arch Intern Med 1999
Previously documented DVT 1
The probability of DVT ge 2 DVT likely
le 1 DVT Unlikely
Recurrent VTE
NEJM 1992
VTE treatment
AC Thrombolysis PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
תיאור מקרה בריא 25בן
כאב שמתחיל בסובך שמאל
והרגל מתנפחת לכל אורכהמתגבר ימים הכאב 5במהלך של
-פנייה לחדר מיון
Fem-Pop DVT
The probability of DVT (DVT in 3months FU)
ge 3 High (49)
1 2 Intermediate (143)
le 0 low (32)
Modified Wellrsquos criteria
Wells Anderson et al Lancet 1997 Anderson DR et al Arch Intern Med 1999
Previously documented DVT 1
The probability of DVT ge 2 DVT likely
le 1 DVT Unlikely
Recurrent VTE
NEJM 1992
תיאור מקרה בריא 25בן
כאב שמתחיל בסובך שמאל
והרגל מתנפחת לכל אורכהמתגבר ימים הכאב 5במהלך של
-פנייה לחדר מיון
Fem-Pop DVT
The probability of DVT (DVT in 3months FU)
ge 3 High (49)
1 2 Intermediate (143)
le 0 low (32)
Modified Wellrsquos criteria
Wells Anderson et al Lancet 1997 Anderson DR et al Arch Intern Med 1999
Previously documented DVT 1
The probability of DVT ge 2 DVT likely
le 1 DVT Unlikely
Recurrent VTE
NEJM 1992
The probability of DVT (DVT in 3months FU)
ge 3 High (49)
1 2 Intermediate (143)
le 0 low (32)
Modified Wellrsquos criteria
Wells Anderson et al Lancet 1997 Anderson DR et al Arch Intern Med 1999
Previously documented DVT 1
The probability of DVT ge 2 DVT likely
le 1 DVT Unlikely
Recurrent VTE
NEJM 1992
Recurrent VTE
NEJM 1992
Chart1
Sheet1
Chest 2010
Chest 2010
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Prothrombin
Fibrinogen Fibrin
Va
TF
Extrinsic pathway
Intrinsic pathway
Xa
VIIa
Oral DXa Inhibitor
Rivaroxaban (Xarelto)
Apixaban (Eliquis)
Thrombin (IIa)
Oral DTI Dabigatran (Pradaxa)
Acute VTE treatment studies
RE-COVER (I+II) (dabigatran)
bull DVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bull DVT (2010) bull PE (2012)
AMPLIFY (apixaban)
bull DVT-PE (2013)
HOKUSAI VTE (edoxaban)
bull DVT-PE (2013)
27023 patients
DOAC
Pradaxa (Dabigatran)
Re-Cover UFHLMWH for ~10d
Pradaxa 150mg BID
Xarelto (rivaroxaban)
Einstein Dosing 15mg BID
for 21d follow by 20mg OD
Eliquis (Apixaban
Amplify Dosing 10mg BID for 7 days follow by
5mg BID
The comparator warfarin
Events DOAC ENX-VKA
Rec VTE 204 226
MB+CRNMB 734 977
Main outcomes
Odds ratio meta-analysis plot [fixed effects]
02 05 1 2
HOKUSAI 082 (058 116)
AMPLIFY 083 (058 120)
EINSTEIN PE 114 (074 175)
EINSTEIN DVT 069 (044 109)
RECOVER II 108 (062 189)
RECOVER I 106 (063 178)
combined [fixed] 090 (076 106)
odds ratio (95 confidence interval)
Rec Symptomatic adjudicated VTE
OR = 089 (076 ndash 106) FIXED MODEL
= Non-inferiorityיעילות זהה
MB+CRNMB
OR = 070 (054 ndash 090) RANDOM MODEL
Odds ratio meta-analysis plot [random effects]
02 05 1 2
HOKUSAI 080 (069 093)
AMPLIFY 042 (033 053)
EINSTEIN PE 090 (074 108)
EINSTEIN DVT 100 (078 129)
RECOVER II 061 (044 086)
RECOVER I 061 (044 085)
combined [random] 070 (054 090)
odds ratio (95 confidence interval)
בטיחות עדיפה
VTE - Treatment
Vitamin K antagonist
UFH or LMWH
Initial (0 to ~7days)
Extended (~3 months to indefinite)
Long-term (~7 days to ~3 months)
Phases of anticoagulation
LMWH Dabigatran Rivaroxaban Apixaban Edoxaban
Rivaroxaban Apixaban
Kearon C et al Chest 2012
VTE - Treatment
AHJ 2018
VTE - Treatment
AHJ 2018
תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת
-לחדר מיון פנייה לכל אורכה
Ilio-Fem DVT
Treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
Thrombolysis for Deep vein Thrombosis
Not to decrease mortality
Not to prevent recurrence
To prevent Post-thrombotic syndrome
Post Thrombotic Syndrome
209 pt randomly assigned to control 108 or CDT 101
iliofemoral DVT within 21 days
FU for 24 months gtgt
Lancet 2012
NNT = 87 NNH = 112
Events CDT Standard Rx P
Ilio-femoral V (6m) 659 474 0012
PTS - 6m 303 322 077
PTS ndash 24m 411 556 0047
Bleeding M+CRNM 89 0
CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)
No better QOL
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
The rationale for the use of thrombolysis for DVT is
to prevent long-term complications related to poor
venus function including PTS and ulceration
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results (long term 6m-5y)
gt PTS significantly less (RR 066 P lt 00001 NNT-4)
gt Complete clot lysis (RR 244 P = 0002)
gt Bleeding complications (RR 223 P = 00006)
IVC-ilio-Fem deep vein thrombosis 10418
Mostly occluded
IVC-ilio-Fem deep vein thrombosis 10418
More than 50 patency
692 pts with acute prox DVT
PCDT N= 337
SOC N=355
bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care
ATTRACT study
Inclusion criteria DVT symptom duration lt 14d
NEJM 2017
Events PCDT Standard Rx P PTS all types 467 482 056
Severe PTS 179 237 0035
Recurrent VTE 125 85 009
All bleeding 45 170 0049
Major bleeding 17 03 0049
Primary outcome ndash PTS (6-24m)
March 2017
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
| AC | UFH+AC | ||
| 20 | 67 |
| AC | |
| UFH+AC |
Sheet1
Chest 2010
Chest 2010
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Prothrombin
Fibrinogen Fibrin
Va
TF
Extrinsic pathway
Intrinsic pathway
Xa
VIIa
Oral DXa Inhibitor
Rivaroxaban (Xarelto)
Apixaban (Eliquis)
Thrombin (IIa)
Oral DTI Dabigatran (Pradaxa)
Acute VTE treatment studies
RE-COVER (I+II) (dabigatran)
bull DVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bull DVT (2010) bull PE (2012)
AMPLIFY (apixaban)
bull DVT-PE (2013)
HOKUSAI VTE (edoxaban)
bull DVT-PE (2013)
27023 patients
DOAC
Pradaxa (Dabigatran)
Re-Cover UFHLMWH for ~10d
Pradaxa 150mg BID
Xarelto (rivaroxaban)
Einstein Dosing 15mg BID
for 21d follow by 20mg OD
Eliquis (Apixaban
Amplify Dosing 10mg BID for 7 days follow by
5mg BID
The comparator warfarin
Events DOAC ENX-VKA
Rec VTE 204 226
MB+CRNMB 734 977
Main outcomes
Odds ratio meta-analysis plot [fixed effects]
02 05 1 2
HOKUSAI 082 (058 116)
AMPLIFY 083 (058 120)
EINSTEIN PE 114 (074 175)
EINSTEIN DVT 069 (044 109)
RECOVER II 108 (062 189)
RECOVER I 106 (063 178)
combined [fixed] 090 (076 106)
odds ratio (95 confidence interval)
Rec Symptomatic adjudicated VTE
OR = 089 (076 ndash 106) FIXED MODEL
= Non-inferiorityיעילות זהה
MB+CRNMB
OR = 070 (054 ndash 090) RANDOM MODEL
Odds ratio meta-analysis plot [random effects]
02 05 1 2
HOKUSAI 080 (069 093)
AMPLIFY 042 (033 053)
EINSTEIN PE 090 (074 108)
EINSTEIN DVT 100 (078 129)
RECOVER II 061 (044 086)
RECOVER I 061 (044 085)
combined [random] 070 (054 090)
odds ratio (95 confidence interval)
בטיחות עדיפה
VTE - Treatment
Vitamin K antagonist
UFH or LMWH
Initial (0 to ~7days)
Extended (~3 months to indefinite)
Long-term (~7 days to ~3 months)
Phases of anticoagulation
LMWH Dabigatran Rivaroxaban Apixaban Edoxaban
Rivaroxaban Apixaban
Kearon C et al Chest 2012
VTE - Treatment
AHJ 2018
VTE - Treatment
AHJ 2018
תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת
-לחדר מיון פנייה לכל אורכה
Ilio-Fem DVT
Treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
Thrombolysis for Deep vein Thrombosis
Not to decrease mortality
Not to prevent recurrence
To prevent Post-thrombotic syndrome
Post Thrombotic Syndrome
209 pt randomly assigned to control 108 or CDT 101
iliofemoral DVT within 21 days
FU for 24 months gtgt
Lancet 2012
NNT = 87 NNH = 112
Events CDT Standard Rx P
Ilio-femoral V (6m) 659 474 0012
PTS - 6m 303 322 077
PTS ndash 24m 411 556 0047
Bleeding M+CRNM 89 0
CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)
No better QOL
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
The rationale for the use of thrombolysis for DVT is
to prevent long-term complications related to poor
venus function including PTS and ulceration
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results (long term 6m-5y)
gt PTS significantly less (RR 066 P lt 00001 NNT-4)
gt Complete clot lysis (RR 244 P = 0002)
gt Bleeding complications (RR 223 P = 00006)
IVC-ilio-Fem deep vein thrombosis 10418
Mostly occluded
IVC-ilio-Fem deep vein thrombosis 10418
More than 50 patency
692 pts with acute prox DVT
PCDT N= 337
SOC N=355
bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care
ATTRACT study
Inclusion criteria DVT symptom duration lt 14d
NEJM 2017
Events PCDT Standard Rx P PTS all types 467 482 056
Severe PTS 179 237 0035
Recurrent VTE 125 85 009
All bleeding 45 170 0049
Major bleeding 17 03 0049
Primary outcome ndash PTS (6-24m)
March 2017
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
| AC | UFH+AC | ||
| 20 | 67 |
Chest 2010
Chest 2010
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Prothrombin
Fibrinogen Fibrin
Va
TF
Extrinsic pathway
Intrinsic pathway
Xa
VIIa
Oral DXa Inhibitor
Rivaroxaban (Xarelto)
Apixaban (Eliquis)
Thrombin (IIa)
Oral DTI Dabigatran (Pradaxa)
Acute VTE treatment studies
RE-COVER (I+II) (dabigatran)
bull DVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bull DVT (2010) bull PE (2012)
AMPLIFY (apixaban)
bull DVT-PE (2013)
HOKUSAI VTE (edoxaban)
bull DVT-PE (2013)
27023 patients
DOAC
Pradaxa (Dabigatran)
Re-Cover UFHLMWH for ~10d
Pradaxa 150mg BID
Xarelto (rivaroxaban)
Einstein Dosing 15mg BID
for 21d follow by 20mg OD
Eliquis (Apixaban
Amplify Dosing 10mg BID for 7 days follow by
5mg BID
The comparator warfarin
Events DOAC ENX-VKA
Rec VTE 204 226
MB+CRNMB 734 977
Main outcomes
Odds ratio meta-analysis plot [fixed effects]
02 05 1 2
HOKUSAI 082 (058 116)
AMPLIFY 083 (058 120)
EINSTEIN PE 114 (074 175)
EINSTEIN DVT 069 (044 109)
RECOVER II 108 (062 189)
RECOVER I 106 (063 178)
combined [fixed] 090 (076 106)
odds ratio (95 confidence interval)
Rec Symptomatic adjudicated VTE
OR = 089 (076 ndash 106) FIXED MODEL
= Non-inferiorityיעילות זהה
MB+CRNMB
OR = 070 (054 ndash 090) RANDOM MODEL
Odds ratio meta-analysis plot [random effects]
02 05 1 2
HOKUSAI 080 (069 093)
AMPLIFY 042 (033 053)
EINSTEIN PE 090 (074 108)
EINSTEIN DVT 100 (078 129)
RECOVER II 061 (044 086)
RECOVER I 061 (044 085)
combined [random] 070 (054 090)
odds ratio (95 confidence interval)
בטיחות עדיפה
VTE - Treatment
Vitamin K antagonist
UFH or LMWH
Initial (0 to ~7days)
Extended (~3 months to indefinite)
Long-term (~7 days to ~3 months)
Phases of anticoagulation
LMWH Dabigatran Rivaroxaban Apixaban Edoxaban
Rivaroxaban Apixaban
Kearon C et al Chest 2012
VTE - Treatment
AHJ 2018
VTE - Treatment
AHJ 2018
תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת
-לחדר מיון פנייה לכל אורכה
Ilio-Fem DVT
Treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
Thrombolysis for Deep vein Thrombosis
Not to decrease mortality
Not to prevent recurrence
To prevent Post-thrombotic syndrome
Post Thrombotic Syndrome
209 pt randomly assigned to control 108 or CDT 101
iliofemoral DVT within 21 days
FU for 24 months gtgt
Lancet 2012
NNT = 87 NNH = 112
Events CDT Standard Rx P
Ilio-femoral V (6m) 659 474 0012
PTS - 6m 303 322 077
PTS ndash 24m 411 556 0047
Bleeding M+CRNM 89 0
CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)
No better QOL
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
The rationale for the use of thrombolysis for DVT is
to prevent long-term complications related to poor
venus function including PTS and ulceration
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results (long term 6m-5y)
gt PTS significantly less (RR 066 P lt 00001 NNT-4)
gt Complete clot lysis (RR 244 P = 0002)
gt Bleeding complications (RR 223 P = 00006)
IVC-ilio-Fem deep vein thrombosis 10418
Mostly occluded
IVC-ilio-Fem deep vein thrombosis 10418
More than 50 patency
692 pts with acute prox DVT
PCDT N= 337
SOC N=355
bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care
ATTRACT study
Inclusion criteria DVT symptom duration lt 14d
NEJM 2017
Events PCDT Standard Rx P PTS all types 467 482 056
Severe PTS 179 237 0035
Recurrent VTE 125 85 009
All bleeding 45 170 0049
Major bleeding 17 03 0049
Primary outcome ndash PTS (6-24m)
March 2017
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Chest 2010
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Prothrombin
Fibrinogen Fibrin
Va
TF
Extrinsic pathway
Intrinsic pathway
Xa
VIIa
Oral DXa Inhibitor
Rivaroxaban (Xarelto)
Apixaban (Eliquis)
Thrombin (IIa)
Oral DTI Dabigatran (Pradaxa)
Acute VTE treatment studies
RE-COVER (I+II) (dabigatran)
bull DVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bull DVT (2010) bull PE (2012)
AMPLIFY (apixaban)
bull DVT-PE (2013)
HOKUSAI VTE (edoxaban)
bull DVT-PE (2013)
27023 patients
DOAC
Pradaxa (Dabigatran)
Re-Cover UFHLMWH for ~10d
Pradaxa 150mg BID
Xarelto (rivaroxaban)
Einstein Dosing 15mg BID
for 21d follow by 20mg OD
Eliquis (Apixaban
Amplify Dosing 10mg BID for 7 days follow by
5mg BID
The comparator warfarin
Events DOAC ENX-VKA
Rec VTE 204 226
MB+CRNMB 734 977
Main outcomes
Odds ratio meta-analysis plot [fixed effects]
02 05 1 2
HOKUSAI 082 (058 116)
AMPLIFY 083 (058 120)
EINSTEIN PE 114 (074 175)
EINSTEIN DVT 069 (044 109)
RECOVER II 108 (062 189)
RECOVER I 106 (063 178)
combined [fixed] 090 (076 106)
odds ratio (95 confidence interval)
Rec Symptomatic adjudicated VTE
OR = 089 (076 ndash 106) FIXED MODEL
= Non-inferiorityיעילות זהה
MB+CRNMB
OR = 070 (054 ndash 090) RANDOM MODEL
Odds ratio meta-analysis plot [random effects]
02 05 1 2
HOKUSAI 080 (069 093)
AMPLIFY 042 (033 053)
EINSTEIN PE 090 (074 108)
EINSTEIN DVT 100 (078 129)
RECOVER II 061 (044 086)
RECOVER I 061 (044 085)
combined [random] 070 (054 090)
odds ratio (95 confidence interval)
בטיחות עדיפה
VTE - Treatment
Vitamin K antagonist
UFH or LMWH
Initial (0 to ~7days)
Extended (~3 months to indefinite)
Long-term (~7 days to ~3 months)
Phases of anticoagulation
LMWH Dabigatran Rivaroxaban Apixaban Edoxaban
Rivaroxaban Apixaban
Kearon C et al Chest 2012
VTE - Treatment
AHJ 2018
VTE - Treatment
AHJ 2018
תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת
-לחדר מיון פנייה לכל אורכה
Ilio-Fem DVT
Treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
Thrombolysis for Deep vein Thrombosis
Not to decrease mortality
Not to prevent recurrence
To prevent Post-thrombotic syndrome
Post Thrombotic Syndrome
209 pt randomly assigned to control 108 or CDT 101
iliofemoral DVT within 21 days
FU for 24 months gtgt
Lancet 2012
NNT = 87 NNH = 112
Events CDT Standard Rx P
Ilio-femoral V (6m) 659 474 0012
PTS - 6m 303 322 077
PTS ndash 24m 411 556 0047
Bleeding M+CRNM 89 0
CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)
No better QOL
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
The rationale for the use of thrombolysis for DVT is
to prevent long-term complications related to poor
venus function including PTS and ulceration
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results (long term 6m-5y)
gt PTS significantly less (RR 066 P lt 00001 NNT-4)
gt Complete clot lysis (RR 244 P = 0002)
gt Bleeding complications (RR 223 P = 00006)
IVC-ilio-Fem deep vein thrombosis 10418
Mostly occluded
IVC-ilio-Fem deep vein thrombosis 10418
More than 50 patency
692 pts with acute prox DVT
PCDT N= 337
SOC N=355
bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care
ATTRACT study
Inclusion criteria DVT symptom duration lt 14d
NEJM 2017
Events PCDT Standard Rx P PTS all types 467 482 056
Severe PTS 179 237 0035
Recurrent VTE 125 85 009
All bleeding 45 170 0049
Major bleeding 17 03 0049
Primary outcome ndash PTS (6-24m)
March 2017
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Prothrombin
Fibrinogen Fibrin
Va
TF
Extrinsic pathway
Intrinsic pathway
Xa
VIIa
Oral DXa Inhibitor
Rivaroxaban (Xarelto)
Apixaban (Eliquis)
Thrombin (IIa)
Oral DTI Dabigatran (Pradaxa)
Acute VTE treatment studies
RE-COVER (I+II) (dabigatran)
bull DVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bull DVT (2010) bull PE (2012)
AMPLIFY (apixaban)
bull DVT-PE (2013)
HOKUSAI VTE (edoxaban)
bull DVT-PE (2013)
27023 patients
DOAC
Pradaxa (Dabigatran)
Re-Cover UFHLMWH for ~10d
Pradaxa 150mg BID
Xarelto (rivaroxaban)
Einstein Dosing 15mg BID
for 21d follow by 20mg OD
Eliquis (Apixaban
Amplify Dosing 10mg BID for 7 days follow by
5mg BID
The comparator warfarin
Events DOAC ENX-VKA
Rec VTE 204 226
MB+CRNMB 734 977
Main outcomes
Odds ratio meta-analysis plot [fixed effects]
02 05 1 2
HOKUSAI 082 (058 116)
AMPLIFY 083 (058 120)
EINSTEIN PE 114 (074 175)
EINSTEIN DVT 069 (044 109)
RECOVER II 108 (062 189)
RECOVER I 106 (063 178)
combined [fixed] 090 (076 106)
odds ratio (95 confidence interval)
Rec Symptomatic adjudicated VTE
OR = 089 (076 ndash 106) FIXED MODEL
= Non-inferiorityיעילות זהה
MB+CRNMB
OR = 070 (054 ndash 090) RANDOM MODEL
Odds ratio meta-analysis plot [random effects]
02 05 1 2
HOKUSAI 080 (069 093)
AMPLIFY 042 (033 053)
EINSTEIN PE 090 (074 108)
EINSTEIN DVT 100 (078 129)
RECOVER II 061 (044 086)
RECOVER I 061 (044 085)
combined [random] 070 (054 090)
odds ratio (95 confidence interval)
בטיחות עדיפה
VTE - Treatment
Vitamin K antagonist
UFH or LMWH
Initial (0 to ~7days)
Extended (~3 months to indefinite)
Long-term (~7 days to ~3 months)
Phases of anticoagulation
LMWH Dabigatran Rivaroxaban Apixaban Edoxaban
Rivaroxaban Apixaban
Kearon C et al Chest 2012
VTE - Treatment
AHJ 2018
VTE - Treatment
AHJ 2018
תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת
-לחדר מיון פנייה לכל אורכה
Ilio-Fem DVT
Treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
Thrombolysis for Deep vein Thrombosis
Not to decrease mortality
Not to prevent recurrence
To prevent Post-thrombotic syndrome
Post Thrombotic Syndrome
209 pt randomly assigned to control 108 or CDT 101
iliofemoral DVT within 21 days
FU for 24 months gtgt
Lancet 2012
NNT = 87 NNH = 112
Events CDT Standard Rx P
Ilio-femoral V (6m) 659 474 0012
PTS - 6m 303 322 077
PTS ndash 24m 411 556 0047
Bleeding M+CRNM 89 0
CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)
No better QOL
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
The rationale for the use of thrombolysis for DVT is
to prevent long-term complications related to poor
venus function including PTS and ulceration
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results (long term 6m-5y)
gt PTS significantly less (RR 066 P lt 00001 NNT-4)
gt Complete clot lysis (RR 244 P = 0002)
gt Bleeding complications (RR 223 P = 00006)
IVC-ilio-Fem deep vein thrombosis 10418
Mostly occluded
IVC-ilio-Fem deep vein thrombosis 10418
More than 50 patency
692 pts with acute prox DVT
PCDT N= 337
SOC N=355
bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care
ATTRACT study
Inclusion criteria DVT symptom duration lt 14d
NEJM 2017
Events PCDT Standard Rx P PTS all types 467 482 056
Severe PTS 179 237 0035
Recurrent VTE 125 85 009
All bleeding 45 170 0049
Major bleeding 17 03 0049
Primary outcome ndash PTS (6-24m)
March 2017
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Prothrombin
Fibrinogen Fibrin
Va
TF
Extrinsic pathway
Intrinsic pathway
Xa
VIIa
Oral DXa Inhibitor
Rivaroxaban (Xarelto)
Apixaban (Eliquis)
Thrombin (IIa)
Oral DTI Dabigatran (Pradaxa)
Acute VTE treatment studies
RE-COVER (I+II) (dabigatran)
bull DVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bull DVT (2010) bull PE (2012)
AMPLIFY (apixaban)
bull DVT-PE (2013)
HOKUSAI VTE (edoxaban)
bull DVT-PE (2013)
27023 patients
DOAC
Pradaxa (Dabigatran)
Re-Cover UFHLMWH for ~10d
Pradaxa 150mg BID
Xarelto (rivaroxaban)
Einstein Dosing 15mg BID
for 21d follow by 20mg OD
Eliquis (Apixaban
Amplify Dosing 10mg BID for 7 days follow by
5mg BID
The comparator warfarin
Events DOAC ENX-VKA
Rec VTE 204 226
MB+CRNMB 734 977
Main outcomes
Odds ratio meta-analysis plot [fixed effects]
02 05 1 2
HOKUSAI 082 (058 116)
AMPLIFY 083 (058 120)
EINSTEIN PE 114 (074 175)
EINSTEIN DVT 069 (044 109)
RECOVER II 108 (062 189)
RECOVER I 106 (063 178)
combined [fixed] 090 (076 106)
odds ratio (95 confidence interval)
Rec Symptomatic adjudicated VTE
OR = 089 (076 ndash 106) FIXED MODEL
= Non-inferiorityיעילות זהה
MB+CRNMB
OR = 070 (054 ndash 090) RANDOM MODEL
Odds ratio meta-analysis plot [random effects]
02 05 1 2
HOKUSAI 080 (069 093)
AMPLIFY 042 (033 053)
EINSTEIN PE 090 (074 108)
EINSTEIN DVT 100 (078 129)
RECOVER II 061 (044 086)
RECOVER I 061 (044 085)
combined [random] 070 (054 090)
odds ratio (95 confidence interval)
בטיחות עדיפה
VTE - Treatment
Vitamin K antagonist
UFH or LMWH
Initial (0 to ~7days)
Extended (~3 months to indefinite)
Long-term (~7 days to ~3 months)
Phases of anticoagulation
LMWH Dabigatran Rivaroxaban Apixaban Edoxaban
Rivaroxaban Apixaban
Kearon C et al Chest 2012
VTE - Treatment
AHJ 2018
VTE - Treatment
AHJ 2018
תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת
-לחדר מיון פנייה לכל אורכה
Ilio-Fem DVT
Treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
Thrombolysis for Deep vein Thrombosis
Not to decrease mortality
Not to prevent recurrence
To prevent Post-thrombotic syndrome
Post Thrombotic Syndrome
209 pt randomly assigned to control 108 or CDT 101
iliofemoral DVT within 21 days
FU for 24 months gtgt
Lancet 2012
NNT = 87 NNH = 112
Events CDT Standard Rx P
Ilio-femoral V (6m) 659 474 0012
PTS - 6m 303 322 077
PTS ndash 24m 411 556 0047
Bleeding M+CRNM 89 0
CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)
No better QOL
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
The rationale for the use of thrombolysis for DVT is
to prevent long-term complications related to poor
venus function including PTS and ulceration
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results (long term 6m-5y)
gt PTS significantly less (RR 066 P lt 00001 NNT-4)
gt Complete clot lysis (RR 244 P = 0002)
gt Bleeding complications (RR 223 P = 00006)
IVC-ilio-Fem deep vein thrombosis 10418
Mostly occluded
IVC-ilio-Fem deep vein thrombosis 10418
More than 50 patency
692 pts with acute prox DVT
PCDT N= 337
SOC N=355
bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care
ATTRACT study
Inclusion criteria DVT symptom duration lt 14d
NEJM 2017
Events PCDT Standard Rx P PTS all types 467 482 056
Severe PTS 179 237 0035
Recurrent VTE 125 85 009
All bleeding 45 170 0049
Major bleeding 17 03 0049
Primary outcome ndash PTS (6-24m)
March 2017
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Acute VTE treatment studies
RE-COVER (I+II) (dabigatran)
bull DVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bull DVT (2010) bull PE (2012)
AMPLIFY (apixaban)
bull DVT-PE (2013)
HOKUSAI VTE (edoxaban)
bull DVT-PE (2013)
27023 patients
DOAC
Pradaxa (Dabigatran)
Re-Cover UFHLMWH for ~10d
Pradaxa 150mg BID
Xarelto (rivaroxaban)
Einstein Dosing 15mg BID
for 21d follow by 20mg OD
Eliquis (Apixaban
Amplify Dosing 10mg BID for 7 days follow by
5mg BID
The comparator warfarin
Events DOAC ENX-VKA
Rec VTE 204 226
MB+CRNMB 734 977
Main outcomes
Odds ratio meta-analysis plot [fixed effects]
02 05 1 2
HOKUSAI 082 (058 116)
AMPLIFY 083 (058 120)
EINSTEIN PE 114 (074 175)
EINSTEIN DVT 069 (044 109)
RECOVER II 108 (062 189)
RECOVER I 106 (063 178)
combined [fixed] 090 (076 106)
odds ratio (95 confidence interval)
Rec Symptomatic adjudicated VTE
OR = 089 (076 ndash 106) FIXED MODEL
= Non-inferiorityיעילות זהה
MB+CRNMB
OR = 070 (054 ndash 090) RANDOM MODEL
Odds ratio meta-analysis plot [random effects]
02 05 1 2
HOKUSAI 080 (069 093)
AMPLIFY 042 (033 053)
EINSTEIN PE 090 (074 108)
EINSTEIN DVT 100 (078 129)
RECOVER II 061 (044 086)
RECOVER I 061 (044 085)
combined [random] 070 (054 090)
odds ratio (95 confidence interval)
בטיחות עדיפה
VTE - Treatment
Vitamin K antagonist
UFH or LMWH
Initial (0 to ~7days)
Extended (~3 months to indefinite)
Long-term (~7 days to ~3 months)
Phases of anticoagulation
LMWH Dabigatran Rivaroxaban Apixaban Edoxaban
Rivaroxaban Apixaban
Kearon C et al Chest 2012
VTE - Treatment
AHJ 2018
VTE - Treatment
AHJ 2018
תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת
-לחדר מיון פנייה לכל אורכה
Ilio-Fem DVT
Treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
Thrombolysis for Deep vein Thrombosis
Not to decrease mortality
Not to prevent recurrence
To prevent Post-thrombotic syndrome
Post Thrombotic Syndrome
209 pt randomly assigned to control 108 or CDT 101
iliofemoral DVT within 21 days
FU for 24 months gtgt
Lancet 2012
NNT = 87 NNH = 112
Events CDT Standard Rx P
Ilio-femoral V (6m) 659 474 0012
PTS - 6m 303 322 077
PTS ndash 24m 411 556 0047
Bleeding M+CRNM 89 0
CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)
No better QOL
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
The rationale for the use of thrombolysis for DVT is
to prevent long-term complications related to poor
venus function including PTS and ulceration
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results (long term 6m-5y)
gt PTS significantly less (RR 066 P lt 00001 NNT-4)
gt Complete clot lysis (RR 244 P = 0002)
gt Bleeding complications (RR 223 P = 00006)
IVC-ilio-Fem deep vein thrombosis 10418
Mostly occluded
IVC-ilio-Fem deep vein thrombosis 10418
More than 50 patency
692 pts with acute prox DVT
PCDT N= 337
SOC N=355
bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care
ATTRACT study
Inclusion criteria DVT symptom duration lt 14d
NEJM 2017
Events PCDT Standard Rx P PTS all types 467 482 056
Severe PTS 179 237 0035
Recurrent VTE 125 85 009
All bleeding 45 170 0049
Major bleeding 17 03 0049
Primary outcome ndash PTS (6-24m)
March 2017
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
DOAC
Pradaxa (Dabigatran)
Re-Cover UFHLMWH for ~10d
Pradaxa 150mg BID
Xarelto (rivaroxaban)
Einstein Dosing 15mg BID
for 21d follow by 20mg OD
Eliquis (Apixaban
Amplify Dosing 10mg BID for 7 days follow by
5mg BID
The comparator warfarin
Events DOAC ENX-VKA
Rec VTE 204 226
MB+CRNMB 734 977
Main outcomes
Odds ratio meta-analysis plot [fixed effects]
02 05 1 2
HOKUSAI 082 (058 116)
AMPLIFY 083 (058 120)
EINSTEIN PE 114 (074 175)
EINSTEIN DVT 069 (044 109)
RECOVER II 108 (062 189)
RECOVER I 106 (063 178)
combined [fixed] 090 (076 106)
odds ratio (95 confidence interval)
Rec Symptomatic adjudicated VTE
OR = 089 (076 ndash 106) FIXED MODEL
= Non-inferiorityיעילות זהה
MB+CRNMB
OR = 070 (054 ndash 090) RANDOM MODEL
Odds ratio meta-analysis plot [random effects]
02 05 1 2
HOKUSAI 080 (069 093)
AMPLIFY 042 (033 053)
EINSTEIN PE 090 (074 108)
EINSTEIN DVT 100 (078 129)
RECOVER II 061 (044 086)
RECOVER I 061 (044 085)
combined [random] 070 (054 090)
odds ratio (95 confidence interval)
בטיחות עדיפה
VTE - Treatment
Vitamin K antagonist
UFH or LMWH
Initial (0 to ~7days)
Extended (~3 months to indefinite)
Long-term (~7 days to ~3 months)
Phases of anticoagulation
LMWH Dabigatran Rivaroxaban Apixaban Edoxaban
Rivaroxaban Apixaban
Kearon C et al Chest 2012
VTE - Treatment
AHJ 2018
VTE - Treatment
AHJ 2018
תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת
-לחדר מיון פנייה לכל אורכה
Ilio-Fem DVT
Treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
Thrombolysis for Deep vein Thrombosis
Not to decrease mortality
Not to prevent recurrence
To prevent Post-thrombotic syndrome
Post Thrombotic Syndrome
209 pt randomly assigned to control 108 or CDT 101
iliofemoral DVT within 21 days
FU for 24 months gtgt
Lancet 2012
NNT = 87 NNH = 112
Events CDT Standard Rx P
Ilio-femoral V (6m) 659 474 0012
PTS - 6m 303 322 077
PTS ndash 24m 411 556 0047
Bleeding M+CRNM 89 0
CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)
No better QOL
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
The rationale for the use of thrombolysis for DVT is
to prevent long-term complications related to poor
venus function including PTS and ulceration
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results (long term 6m-5y)
gt PTS significantly less (RR 066 P lt 00001 NNT-4)
gt Complete clot lysis (RR 244 P = 0002)
gt Bleeding complications (RR 223 P = 00006)
IVC-ilio-Fem deep vein thrombosis 10418
Mostly occluded
IVC-ilio-Fem deep vein thrombosis 10418
More than 50 patency
692 pts with acute prox DVT
PCDT N= 337
SOC N=355
bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care
ATTRACT study
Inclusion criteria DVT symptom duration lt 14d
NEJM 2017
Events PCDT Standard Rx P PTS all types 467 482 056
Severe PTS 179 237 0035
Recurrent VTE 125 85 009
All bleeding 45 170 0049
Major bleeding 17 03 0049
Primary outcome ndash PTS (6-24m)
March 2017
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Events DOAC ENX-VKA
Rec VTE 204 226
MB+CRNMB 734 977
Main outcomes
Odds ratio meta-analysis plot [fixed effects]
02 05 1 2
HOKUSAI 082 (058 116)
AMPLIFY 083 (058 120)
EINSTEIN PE 114 (074 175)
EINSTEIN DVT 069 (044 109)
RECOVER II 108 (062 189)
RECOVER I 106 (063 178)
combined [fixed] 090 (076 106)
odds ratio (95 confidence interval)
Rec Symptomatic adjudicated VTE
OR = 089 (076 ndash 106) FIXED MODEL
= Non-inferiorityיעילות זהה
MB+CRNMB
OR = 070 (054 ndash 090) RANDOM MODEL
Odds ratio meta-analysis plot [random effects]
02 05 1 2
HOKUSAI 080 (069 093)
AMPLIFY 042 (033 053)
EINSTEIN PE 090 (074 108)
EINSTEIN DVT 100 (078 129)
RECOVER II 061 (044 086)
RECOVER I 061 (044 085)
combined [random] 070 (054 090)
odds ratio (95 confidence interval)
בטיחות עדיפה
VTE - Treatment
Vitamin K antagonist
UFH or LMWH
Initial (0 to ~7days)
Extended (~3 months to indefinite)
Long-term (~7 days to ~3 months)
Phases of anticoagulation
LMWH Dabigatran Rivaroxaban Apixaban Edoxaban
Rivaroxaban Apixaban
Kearon C et al Chest 2012
VTE - Treatment
AHJ 2018
VTE - Treatment
AHJ 2018
תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת
-לחדר מיון פנייה לכל אורכה
Ilio-Fem DVT
Treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
Thrombolysis for Deep vein Thrombosis
Not to decrease mortality
Not to prevent recurrence
To prevent Post-thrombotic syndrome
Post Thrombotic Syndrome
209 pt randomly assigned to control 108 or CDT 101
iliofemoral DVT within 21 days
FU for 24 months gtgt
Lancet 2012
NNT = 87 NNH = 112
Events CDT Standard Rx P
Ilio-femoral V (6m) 659 474 0012
PTS - 6m 303 322 077
PTS ndash 24m 411 556 0047
Bleeding M+CRNM 89 0
CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)
No better QOL
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
The rationale for the use of thrombolysis for DVT is
to prevent long-term complications related to poor
venus function including PTS and ulceration
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results (long term 6m-5y)
gt PTS significantly less (RR 066 P lt 00001 NNT-4)
gt Complete clot lysis (RR 244 P = 0002)
gt Bleeding complications (RR 223 P = 00006)
IVC-ilio-Fem deep vein thrombosis 10418
Mostly occluded
IVC-ilio-Fem deep vein thrombosis 10418
More than 50 patency
692 pts with acute prox DVT
PCDT N= 337
SOC N=355
bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care
ATTRACT study
Inclusion criteria DVT symptom duration lt 14d
NEJM 2017
Events PCDT Standard Rx P PTS all types 467 482 056
Severe PTS 179 237 0035
Recurrent VTE 125 85 009
All bleeding 45 170 0049
Major bleeding 17 03 0049
Primary outcome ndash PTS (6-24m)
March 2017
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Odds ratio meta-analysis plot [fixed effects]
02 05 1 2
HOKUSAI 082 (058 116)
AMPLIFY 083 (058 120)
EINSTEIN PE 114 (074 175)
EINSTEIN DVT 069 (044 109)
RECOVER II 108 (062 189)
RECOVER I 106 (063 178)
combined [fixed] 090 (076 106)
odds ratio (95 confidence interval)
Rec Symptomatic adjudicated VTE
OR = 089 (076 ndash 106) FIXED MODEL
= Non-inferiorityיעילות זהה
MB+CRNMB
OR = 070 (054 ndash 090) RANDOM MODEL
Odds ratio meta-analysis plot [random effects]
02 05 1 2
HOKUSAI 080 (069 093)
AMPLIFY 042 (033 053)
EINSTEIN PE 090 (074 108)
EINSTEIN DVT 100 (078 129)
RECOVER II 061 (044 086)
RECOVER I 061 (044 085)
combined [random] 070 (054 090)
odds ratio (95 confidence interval)
בטיחות עדיפה
VTE - Treatment
Vitamin K antagonist
UFH or LMWH
Initial (0 to ~7days)
Extended (~3 months to indefinite)
Long-term (~7 days to ~3 months)
Phases of anticoagulation
LMWH Dabigatran Rivaroxaban Apixaban Edoxaban
Rivaroxaban Apixaban
Kearon C et al Chest 2012
VTE - Treatment
AHJ 2018
VTE - Treatment
AHJ 2018
תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת
-לחדר מיון פנייה לכל אורכה
Ilio-Fem DVT
Treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
Thrombolysis for Deep vein Thrombosis
Not to decrease mortality
Not to prevent recurrence
To prevent Post-thrombotic syndrome
Post Thrombotic Syndrome
209 pt randomly assigned to control 108 or CDT 101
iliofemoral DVT within 21 days
FU for 24 months gtgt
Lancet 2012
NNT = 87 NNH = 112
Events CDT Standard Rx P
Ilio-femoral V (6m) 659 474 0012
PTS - 6m 303 322 077
PTS ndash 24m 411 556 0047
Bleeding M+CRNM 89 0
CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)
No better QOL
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
The rationale for the use of thrombolysis for DVT is
to prevent long-term complications related to poor
venus function including PTS and ulceration
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results (long term 6m-5y)
gt PTS significantly less (RR 066 P lt 00001 NNT-4)
gt Complete clot lysis (RR 244 P = 0002)
gt Bleeding complications (RR 223 P = 00006)
IVC-ilio-Fem deep vein thrombosis 10418
Mostly occluded
IVC-ilio-Fem deep vein thrombosis 10418
More than 50 patency
692 pts with acute prox DVT
PCDT N= 337
SOC N=355
bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care
ATTRACT study
Inclusion criteria DVT symptom duration lt 14d
NEJM 2017
Events PCDT Standard Rx P PTS all types 467 482 056
Severe PTS 179 237 0035
Recurrent VTE 125 85 009
All bleeding 45 170 0049
Major bleeding 17 03 0049
Primary outcome ndash PTS (6-24m)
March 2017
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
MB+CRNMB
OR = 070 (054 ndash 090) RANDOM MODEL
Odds ratio meta-analysis plot [random effects]
02 05 1 2
HOKUSAI 080 (069 093)
AMPLIFY 042 (033 053)
EINSTEIN PE 090 (074 108)
EINSTEIN DVT 100 (078 129)
RECOVER II 061 (044 086)
RECOVER I 061 (044 085)
combined [random] 070 (054 090)
odds ratio (95 confidence interval)
בטיחות עדיפה
VTE - Treatment
Vitamin K antagonist
UFH or LMWH
Initial (0 to ~7days)
Extended (~3 months to indefinite)
Long-term (~7 days to ~3 months)
Phases of anticoagulation
LMWH Dabigatran Rivaroxaban Apixaban Edoxaban
Rivaroxaban Apixaban
Kearon C et al Chest 2012
VTE - Treatment
AHJ 2018
VTE - Treatment
AHJ 2018
תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת
-לחדר מיון פנייה לכל אורכה
Ilio-Fem DVT
Treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
Thrombolysis for Deep vein Thrombosis
Not to decrease mortality
Not to prevent recurrence
To prevent Post-thrombotic syndrome
Post Thrombotic Syndrome
209 pt randomly assigned to control 108 or CDT 101
iliofemoral DVT within 21 days
FU for 24 months gtgt
Lancet 2012
NNT = 87 NNH = 112
Events CDT Standard Rx P
Ilio-femoral V (6m) 659 474 0012
PTS - 6m 303 322 077
PTS ndash 24m 411 556 0047
Bleeding M+CRNM 89 0
CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)
No better QOL
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
The rationale for the use of thrombolysis for DVT is
to prevent long-term complications related to poor
venus function including PTS and ulceration
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results (long term 6m-5y)
gt PTS significantly less (RR 066 P lt 00001 NNT-4)
gt Complete clot lysis (RR 244 P = 0002)
gt Bleeding complications (RR 223 P = 00006)
IVC-ilio-Fem deep vein thrombosis 10418
Mostly occluded
IVC-ilio-Fem deep vein thrombosis 10418
More than 50 patency
692 pts with acute prox DVT
PCDT N= 337
SOC N=355
bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care
ATTRACT study
Inclusion criteria DVT symptom duration lt 14d
NEJM 2017
Events PCDT Standard Rx P PTS all types 467 482 056
Severe PTS 179 237 0035
Recurrent VTE 125 85 009
All bleeding 45 170 0049
Major bleeding 17 03 0049
Primary outcome ndash PTS (6-24m)
March 2017
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
VTE - Treatment
Vitamin K antagonist
UFH or LMWH
Initial (0 to ~7days)
Extended (~3 months to indefinite)
Long-term (~7 days to ~3 months)
Phases of anticoagulation
LMWH Dabigatran Rivaroxaban Apixaban Edoxaban
Rivaroxaban Apixaban
Kearon C et al Chest 2012
VTE - Treatment
AHJ 2018
VTE - Treatment
AHJ 2018
תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת
-לחדר מיון פנייה לכל אורכה
Ilio-Fem DVT
Treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
Thrombolysis for Deep vein Thrombosis
Not to decrease mortality
Not to prevent recurrence
To prevent Post-thrombotic syndrome
Post Thrombotic Syndrome
209 pt randomly assigned to control 108 or CDT 101
iliofemoral DVT within 21 days
FU for 24 months gtgt
Lancet 2012
NNT = 87 NNH = 112
Events CDT Standard Rx P
Ilio-femoral V (6m) 659 474 0012
PTS - 6m 303 322 077
PTS ndash 24m 411 556 0047
Bleeding M+CRNM 89 0
CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)
No better QOL
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
The rationale for the use of thrombolysis for DVT is
to prevent long-term complications related to poor
venus function including PTS and ulceration
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results (long term 6m-5y)
gt PTS significantly less (RR 066 P lt 00001 NNT-4)
gt Complete clot lysis (RR 244 P = 0002)
gt Bleeding complications (RR 223 P = 00006)
IVC-ilio-Fem deep vein thrombosis 10418
Mostly occluded
IVC-ilio-Fem deep vein thrombosis 10418
More than 50 patency
692 pts with acute prox DVT
PCDT N= 337
SOC N=355
bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care
ATTRACT study
Inclusion criteria DVT symptom duration lt 14d
NEJM 2017
Events PCDT Standard Rx P PTS all types 467 482 056
Severe PTS 179 237 0035
Recurrent VTE 125 85 009
All bleeding 45 170 0049
Major bleeding 17 03 0049
Primary outcome ndash PTS (6-24m)
March 2017
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
VTE - Treatment
AHJ 2018
VTE - Treatment
AHJ 2018
תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת
-לחדר מיון פנייה לכל אורכה
Ilio-Fem DVT
Treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
Thrombolysis for Deep vein Thrombosis
Not to decrease mortality
Not to prevent recurrence
To prevent Post-thrombotic syndrome
Post Thrombotic Syndrome
209 pt randomly assigned to control 108 or CDT 101
iliofemoral DVT within 21 days
FU for 24 months gtgt
Lancet 2012
NNT = 87 NNH = 112
Events CDT Standard Rx P
Ilio-femoral V (6m) 659 474 0012
PTS - 6m 303 322 077
PTS ndash 24m 411 556 0047
Bleeding M+CRNM 89 0
CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)
No better QOL
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
The rationale for the use of thrombolysis for DVT is
to prevent long-term complications related to poor
venus function including PTS and ulceration
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results (long term 6m-5y)
gt PTS significantly less (RR 066 P lt 00001 NNT-4)
gt Complete clot lysis (RR 244 P = 0002)
gt Bleeding complications (RR 223 P = 00006)
IVC-ilio-Fem deep vein thrombosis 10418
Mostly occluded
IVC-ilio-Fem deep vein thrombosis 10418
More than 50 patency
692 pts with acute prox DVT
PCDT N= 337
SOC N=355
bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care
ATTRACT study
Inclusion criteria DVT symptom duration lt 14d
NEJM 2017
Events PCDT Standard Rx P PTS all types 467 482 056
Severe PTS 179 237 0035
Recurrent VTE 125 85 009
All bleeding 45 170 0049
Major bleeding 17 03 0049
Primary outcome ndash PTS (6-24m)
March 2017
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
VTE - Treatment
AHJ 2018
תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת
-לחדר מיון פנייה לכל אורכה
Ilio-Fem DVT
Treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
Thrombolysis for Deep vein Thrombosis
Not to decrease mortality
Not to prevent recurrence
To prevent Post-thrombotic syndrome
Post Thrombotic Syndrome
209 pt randomly assigned to control 108 or CDT 101
iliofemoral DVT within 21 days
FU for 24 months gtgt
Lancet 2012
NNT = 87 NNH = 112
Events CDT Standard Rx P
Ilio-femoral V (6m) 659 474 0012
PTS - 6m 303 322 077
PTS ndash 24m 411 556 0047
Bleeding M+CRNM 89 0
CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)
No better QOL
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
The rationale for the use of thrombolysis for DVT is
to prevent long-term complications related to poor
venus function including PTS and ulceration
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results (long term 6m-5y)
gt PTS significantly less (RR 066 P lt 00001 NNT-4)
gt Complete clot lysis (RR 244 P = 0002)
gt Bleeding complications (RR 223 P = 00006)
IVC-ilio-Fem deep vein thrombosis 10418
Mostly occluded
IVC-ilio-Fem deep vein thrombosis 10418
More than 50 patency
692 pts with acute prox DVT
PCDT N= 337
SOC N=355
bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care
ATTRACT study
Inclusion criteria DVT symptom duration lt 14d
NEJM 2017
Events PCDT Standard Rx P PTS all types 467 482 056
Severe PTS 179 237 0035
Recurrent VTE 125 85 009
All bleeding 45 170 0049
Major bleeding 17 03 0049
Primary outcome ndash PTS (6-24m)
March 2017
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
תיאור מקרה כאב שמתחיל בסובך שמאל ותוך יומיים והרגל מתנפחת 28בת
-לחדר מיון פנייה לכל אורכה
Ilio-Fem DVT
Treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
Thrombolysis for Deep vein Thrombosis
Not to decrease mortality
Not to prevent recurrence
To prevent Post-thrombotic syndrome
Post Thrombotic Syndrome
209 pt randomly assigned to control 108 or CDT 101
iliofemoral DVT within 21 days
FU for 24 months gtgt
Lancet 2012
NNT = 87 NNH = 112
Events CDT Standard Rx P
Ilio-femoral V (6m) 659 474 0012
PTS - 6m 303 322 077
PTS ndash 24m 411 556 0047
Bleeding M+CRNM 89 0
CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)
No better QOL
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
The rationale for the use of thrombolysis for DVT is
to prevent long-term complications related to poor
venus function including PTS and ulceration
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results (long term 6m-5y)
gt PTS significantly less (RR 066 P lt 00001 NNT-4)
gt Complete clot lysis (RR 244 P = 0002)
gt Bleeding complications (RR 223 P = 00006)
IVC-ilio-Fem deep vein thrombosis 10418
Mostly occluded
IVC-ilio-Fem deep vein thrombosis 10418
More than 50 patency
692 pts with acute prox DVT
PCDT N= 337
SOC N=355
bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care
ATTRACT study
Inclusion criteria DVT symptom duration lt 14d
NEJM 2017
Events PCDT Standard Rx P PTS all types 467 482 056
Severe PTS 179 237 0035
Recurrent VTE 125 85 009
All bleeding 45 170 0049
Major bleeding 17 03 0049
Primary outcome ndash PTS (6-24m)
March 2017
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
Thrombolysis for Deep vein Thrombosis
Not to decrease mortality
Not to prevent recurrence
To prevent Post-thrombotic syndrome
Post Thrombotic Syndrome
209 pt randomly assigned to control 108 or CDT 101
iliofemoral DVT within 21 days
FU for 24 months gtgt
Lancet 2012
NNT = 87 NNH = 112
Events CDT Standard Rx P
Ilio-femoral V (6m) 659 474 0012
PTS - 6m 303 322 077
PTS ndash 24m 411 556 0047
Bleeding M+CRNM 89 0
CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)
No better QOL
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
The rationale for the use of thrombolysis for DVT is
to prevent long-term complications related to poor
venus function including PTS and ulceration
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results (long term 6m-5y)
gt PTS significantly less (RR 066 P lt 00001 NNT-4)
gt Complete clot lysis (RR 244 P = 0002)
gt Bleeding complications (RR 223 P = 00006)
IVC-ilio-Fem deep vein thrombosis 10418
Mostly occluded
IVC-ilio-Fem deep vein thrombosis 10418
More than 50 patency
692 pts with acute prox DVT
PCDT N= 337
SOC N=355
bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care
ATTRACT study
Inclusion criteria DVT symptom duration lt 14d
NEJM 2017
Events PCDT Standard Rx P PTS all types 467 482 056
Severe PTS 179 237 0035
Recurrent VTE 125 85 009
All bleeding 45 170 0049
Major bleeding 17 03 0049
Primary outcome ndash PTS (6-24m)
March 2017
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Thrombolysis for Deep vein Thrombosis
Not to decrease mortality
Not to prevent recurrence
To prevent Post-thrombotic syndrome
Post Thrombotic Syndrome
209 pt randomly assigned to control 108 or CDT 101
iliofemoral DVT within 21 days
FU for 24 months gtgt
Lancet 2012
NNT = 87 NNH = 112
Events CDT Standard Rx P
Ilio-femoral V (6m) 659 474 0012
PTS - 6m 303 322 077
PTS ndash 24m 411 556 0047
Bleeding M+CRNM 89 0
CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)
No better QOL
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
The rationale for the use of thrombolysis for DVT is
to prevent long-term complications related to poor
venus function including PTS and ulceration
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results (long term 6m-5y)
gt PTS significantly less (RR 066 P lt 00001 NNT-4)
gt Complete clot lysis (RR 244 P = 0002)
gt Bleeding complications (RR 223 P = 00006)
IVC-ilio-Fem deep vein thrombosis 10418
Mostly occluded
IVC-ilio-Fem deep vein thrombosis 10418
More than 50 patency
692 pts with acute prox DVT
PCDT N= 337
SOC N=355
bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care
ATTRACT study
Inclusion criteria DVT symptom duration lt 14d
NEJM 2017
Events PCDT Standard Rx P PTS all types 467 482 056
Severe PTS 179 237 0035
Recurrent VTE 125 85 009
All bleeding 45 170 0049
Major bleeding 17 03 0049
Primary outcome ndash PTS (6-24m)
March 2017
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Post Thrombotic Syndrome
209 pt randomly assigned to control 108 or CDT 101
iliofemoral DVT within 21 days
FU for 24 months gtgt
Lancet 2012
NNT = 87 NNH = 112
Events CDT Standard Rx P
Ilio-femoral V (6m) 659 474 0012
PTS - 6m 303 322 077
PTS ndash 24m 411 556 0047
Bleeding M+CRNM 89 0
CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)
No better QOL
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
The rationale for the use of thrombolysis for DVT is
to prevent long-term complications related to poor
venus function including PTS and ulceration
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results (long term 6m-5y)
gt PTS significantly less (RR 066 P lt 00001 NNT-4)
gt Complete clot lysis (RR 244 P = 0002)
gt Bleeding complications (RR 223 P = 00006)
IVC-ilio-Fem deep vein thrombosis 10418
Mostly occluded
IVC-ilio-Fem deep vein thrombosis 10418
More than 50 patency
692 pts with acute prox DVT
PCDT N= 337
SOC N=355
bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care
ATTRACT study
Inclusion criteria DVT symptom duration lt 14d
NEJM 2017
Events PCDT Standard Rx P PTS all types 467 482 056
Severe PTS 179 237 0035
Recurrent VTE 125 85 009
All bleeding 45 170 0049
Major bleeding 17 03 0049
Primary outcome ndash PTS (6-24m)
March 2017
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
209 pt randomly assigned to control 108 or CDT 101
iliofemoral DVT within 21 days
FU for 24 months gtgt
Lancet 2012
NNT = 87 NNH = 112
Events CDT Standard Rx P
Ilio-femoral V (6m) 659 474 0012
PTS - 6m 303 322 077
PTS ndash 24m 411 556 0047
Bleeding M+CRNM 89 0
CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)
No better QOL
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
The rationale for the use of thrombolysis for DVT is
to prevent long-term complications related to poor
venus function including PTS and ulceration
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results (long term 6m-5y)
gt PTS significantly less (RR 066 P lt 00001 NNT-4)
gt Complete clot lysis (RR 244 P = 0002)
gt Bleeding complications (RR 223 P = 00006)
IVC-ilio-Fem deep vein thrombosis 10418
Mostly occluded
IVC-ilio-Fem deep vein thrombosis 10418
More than 50 patency
692 pts with acute prox DVT
PCDT N= 337
SOC N=355
bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care
ATTRACT study
Inclusion criteria DVT symptom duration lt 14d
NEJM 2017
Events PCDT Standard Rx P PTS all types 467 482 056
Severe PTS 179 237 0035
Recurrent VTE 125 85 009
All bleeding 45 170 0049
Major bleeding 17 03 0049
Primary outcome ndash PTS (6-24m)
March 2017
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
NNT = 87 NNH = 112
Events CDT Standard Rx P
Ilio-femoral V (6m) 659 474 0012
PTS - 6m 303 322 077
PTS ndash 24m 411 556 0047
Bleeding M+CRNM 89 0
CaVenT 5 years follow-up 37 CDT Vs 63 of control had PTS (Plt00001 NNT4)
No better QOL
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
The rationale for the use of thrombolysis for DVT is
to prevent long-term complications related to poor
venus function including PTS and ulceration
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results (long term 6m-5y)
gt PTS significantly less (RR 066 P lt 00001 NNT-4)
gt Complete clot lysis (RR 244 P = 0002)
gt Bleeding complications (RR 223 P = 00006)
IVC-ilio-Fem deep vein thrombosis 10418
Mostly occluded
IVC-ilio-Fem deep vein thrombosis 10418
More than 50 patency
692 pts with acute prox DVT
PCDT N= 337
SOC N=355
bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care
ATTRACT study
Inclusion criteria DVT symptom duration lt 14d
NEJM 2017
Events PCDT Standard Rx P PTS all types 467 482 056
Severe PTS 179 237 0035
Recurrent VTE 125 85 009
All bleeding 45 170 0049
Major bleeding 17 03 0049
Primary outcome ndash PTS (6-24m)
March 2017
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
The rationale for the use of thrombolysis for DVT is
to prevent long-term complications related to poor
venus function including PTS and ulceration
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results (long term 6m-5y)
gt PTS significantly less (RR 066 P lt 00001 NNT-4)
gt Complete clot lysis (RR 244 P = 0002)
gt Bleeding complications (RR 223 P = 00006)
IVC-ilio-Fem deep vein thrombosis 10418
Mostly occluded
IVC-ilio-Fem deep vein thrombosis 10418
More than 50 patency
692 pts with acute prox DVT
PCDT N= 337
SOC N=355
bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care
ATTRACT study
Inclusion criteria DVT symptom duration lt 14d
NEJM 2017
Events PCDT Standard Rx P PTS all types 467 482 056
Severe PTS 179 237 0035
Recurrent VTE 125 85 009
All bleeding 45 170 0049
Major bleeding 17 03 0049
Primary outcome ndash PTS (6-24m)
March 2017
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results gt Seventeen RCTs with 1103 Pt gt There was no significant effect on mortality gt Systemic thrombolysis and CDT had similar effectiveness
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results (long term 6m-5y)
gt PTS significantly less (RR 066 P lt 00001 NNT-4)
gt Complete clot lysis (RR 244 P = 0002)
gt Bleeding complications (RR 223 P = 00006)
IVC-ilio-Fem deep vein thrombosis 10418
Mostly occluded
IVC-ilio-Fem deep vein thrombosis 10418
More than 50 patency
692 pts with acute prox DVT
PCDT N= 337
SOC N=355
bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care
ATTRACT study
Inclusion criteria DVT symptom duration lt 14d
NEJM 2017
Events PCDT Standard Rx P PTS all types 467 482 056
Severe PTS 179 237 0035
Recurrent VTE 125 85 009
All bleeding 45 170 0049
Major bleeding 17 03 0049
Primary outcome ndash PTS (6-24m)
March 2017
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Thrombolysis for acute deep vein thrombosis -
Cochrane Database Nov-16
Main results (long term 6m-5y)
gt PTS significantly less (RR 066 P lt 00001 NNT-4)
gt Complete clot lysis (RR 244 P = 0002)
gt Bleeding complications (RR 223 P = 00006)
IVC-ilio-Fem deep vein thrombosis 10418
Mostly occluded
IVC-ilio-Fem deep vein thrombosis 10418
More than 50 patency
692 pts with acute prox DVT
PCDT N= 337
SOC N=355
bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care
ATTRACT study
Inclusion criteria DVT symptom duration lt 14d
NEJM 2017
Events PCDT Standard Rx P PTS all types 467 482 056
Severe PTS 179 237 0035
Recurrent VTE 125 85 009
All bleeding 45 170 0049
Major bleeding 17 03 0049
Primary outcome ndash PTS (6-24m)
March 2017
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
IVC-ilio-Fem deep vein thrombosis 10418
Mostly occluded
IVC-ilio-Fem deep vein thrombosis 10418
More than 50 patency
692 pts with acute prox DVT
PCDT N= 337
SOC N=355
bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care
ATTRACT study
Inclusion criteria DVT symptom duration lt 14d
NEJM 2017
Events PCDT Standard Rx P PTS all types 467 482 056
Severe PTS 179 237 0035
Recurrent VTE 125 85 009
All bleeding 45 170 0049
Major bleeding 17 03 0049
Primary outcome ndash PTS (6-24m)
March 2017
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
IVC-ilio-Fem deep vein thrombosis 10418
More than 50 patency
692 pts with acute prox DVT
PCDT N= 337
SOC N=355
bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care
ATTRACT study
Inclusion criteria DVT symptom duration lt 14d
NEJM 2017
Events PCDT Standard Rx P PTS all types 467 482 056
Severe PTS 179 237 0035
Recurrent VTE 125 85 009
All bleeding 45 170 0049
Major bleeding 17 03 0049
Primary outcome ndash PTS (6-24m)
March 2017
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
692 pts with acute prox DVT
PCDT N= 337
SOC N=355
bull Pharmaco-mechanic catheter directed thrombolysis bull Standard of care
ATTRACT study
Inclusion criteria DVT symptom duration lt 14d
NEJM 2017
Events PCDT Standard Rx P PTS all types 467 482 056
Severe PTS 179 237 0035
Recurrent VTE 125 85 009
All bleeding 45 170 0049
Major bleeding 17 03 0049
Primary outcome ndash PTS (6-24m)
March 2017
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Events PCDT Standard Rx P PTS all types 467 482 056
Severe PTS 179 237 0035
Recurrent VTE 125 85 009
All bleeding 45 170 0049
Major bleeding 17 03 0049
Primary outcome ndash PTS (6-24m)
March 2017
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
March 2017
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Events PCDT Standard Rx P
Severe PTS 179 237 0035
- Ileo-femoral DVT 184 282
- femoro-popliteal DVT 171 181
Results Summary
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Compared with MB rates
Events NNT NNH
Severe PTS 172 714
- Ileo-femoral DVT 102 714
- femoro-popliteal DVT 100 714
Risk-Benefit ratio
High NNT - The average number of patients who need to be treated to prevent one bad outcome
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Plegmasia cerulea Dolens Painful Blue edema
Venous gangrena
Thrombolysis
65ltפקקת אילאופמורלית בסיכון דמם רגיל בגיל
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
תיאור מקרה
שלושה חודשים לאחר התחלת גלולות 29בת
מתארת כאב פליאוריטי וקוצר נשימה
BP - 120 85
HR - 125min
RR - 34 min
Temp - 37cdeg
Arterial O2 - 96
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Diagnosis of PE Modified Wellrsquos criteria for Pulmonary Embolism (PE)
le 4 PE Unlikely gt 4 PE likely
TampH 2000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Fibrinolysis
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Positive predictive value 40-80 Elevated D-dimer levels are not specific for VTE bull Hospitalized patients
bull Elderly
bull Malignancy
bull Recent surgery
bull Renal insufficiency
bull Inflammation
bull Second and third trimester of a normal pregnancy
D-dimer test
dDimer negative predictive value of gt 95
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Suspected PE ndash Hemodynamically stable patients
le 4 PE Unlikely gt 4 PE likely
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Treatment
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
VTE treatment
AC PMCDT
Pharmaco-mechanical catheter directed thrombolysis
AC ndash Anticoagulation
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Low risk Class I lt 66 class II 66-85 gtgt 30d mortality 1-2
High risk Class III 86-105 IV 106 -125 V 125 gtgt 30d mortality 3-15
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Anti-coagulation
LMWH vitK antagonist DOAC
ldquoTraditionalrdquo treatment
Or
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
תיאור מקרה
שבוע לאחר טיסה מיפן 50בן
גוש בריאה אובחן לפני כחודש נמצא בבירור רקע רפואי
קוצר נשימה חולשה מתאר כאב פליאוריטי BP - 95 65
HR - 125min
RR - 34min
Temp - 37cdeg
Arterial O2 - 93
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Suspected PE with shock or Hypotension
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Suspected PE with shock or Hypotension
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Echocardiography
Diagnosis of PE
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Chest CTA ( Computed tomography angiography)
Diagnosis of PE
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Low risk gtgt Class I lt 66 class II 66-85
High risk gtgt Class III 86-105 Class IV 106 -125 Class V gt 125
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Eur Heart J (2014)
Classification of patients with acute PE based on early mortality risk
RV dysfunction
Echo RV dilatation or an increase end-diastolic RV or Hypokinesia Increased EDRV EDLV diameter ratio 09 CTA Increased end-diastolic RV LV diameter ratio 09
Markers of myocardial injury
Elevated cardiac troponin I or T Elevated BNP
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Eur Heart J 2014
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
Methods RCT - Tenecteplase plus heparin with placebo plus heparin Normotensive patients with intermediate-risk pulmonary embolism RV dysfunction on Echo or CT + positive cardiac troponin I or T The primary outcome Death or hemodynamic decompensation within 7 days
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
NEJM 2014
PE with RV dysfunction
Randomization to standard treatment or thrombolysis
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
NNT = 33 NNH = 20
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
NEJM 2014
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Guidelines
Thrombosis Canada
Harm with thrombolysis outweighs the benefit in most patients with PE except in those who present with massive PE hellip where the short-term mortality is gt15 Thrombolysis is NOT indicated in sub-massive (intermediate-risk) PE (normotensive with right ventricular dysfunction) as it increases major bleeding without survival benefit
American college of chest physician (ACCP)
In patients with acute PE associated with hypotension (eg systolic BP lt90 mm Hg) who do not have a high bleeding risk we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B)
In most patients with acute PE not associated with hypotension we recommend against systemically administered thrombolytic therapy (Grade 1B)
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Thrombolysis
DVT
ilio-Fem DVT
PE
High risk PE
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
VTE - Treatment Aims To prevent short and long-term sequelae
Short term prevent clot extension and PE
Long Term
Post-thrombotic syndrome
Chronic thromboembolic
Pulmonary hypertension
PREVENTION of recurrence
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
For how long
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
How long to treat Transient risk factor
Unprovoked proximal DVT
VTE ndash treatment duration
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
VTE ndash treatment duration How long to treat Proximal DVT of the leg provoked by transient risk factor
Treatment with anticoagulation for 3 months (Grade 2B)
ACCP guidelines CHEST 20122016
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
High Risk
5 Annually
S Shulman NEJM 1995
The Duration of Anticoagulation Trial Study Group (DURAC)
Unprovoked proximal DVT
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
A Comparison of 3 months of AC Vs extended AC for a first episode of idiopathic VTE
17 (27Y)
1 (13Y)
Kearon C NEJM 1999
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Recurrent VTE
Provoked
Surgery
06 Non surgical
3
Unprovoked
Non cancer related
6 Cancer related
15
Blood 2014
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Treatment VTE scenario Number
3 months VTE (prox DVTPE) provoked by surgery 5
3 months (any bleeding risk)
VTE (prox DVTPE) provoked by non surgical transient risk factor
6
3 months VTE (isolated distal) provoked by surgery or non surgical transient risk factor
7
At least 3 months VTE (isolated distal or prox DVTPE) unprovoked 8
Indefinite (when bleeding risk low-moderate) 3 months (high bleeding risk)
VTE (prox DVTPE) ndash unprovoked Second unprovoked VTE
9 10
Indefinite (any bleeding risk)
Any DVT or PE and active cancer 11
ACCP 2016 revised recommendations
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Gender age obesity smoking
Comorbidity (cancer)
Unprovoked or extensive thrombosis
Recurrent VTE
Residual vein thrombosis post treatment
Thrombophilia
Other predictors (D dimer)
Risk factors for recurrent VTE
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
PROLONG study NEJM 2006
Abnormal D-dimer wo AC - 109 Abnormal D-dimer with AC ndash 2 Normal D-dimer - 44
D-dimer
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
VTE predictors ModelSource
Male D dimer extent VTE Vienna Model Circulation 2010
Male D dimer age (lt50) hormone related VTRE DASH JTH 2012
Gender age (gt65) PTS D dimer BMI (gt30) HERDOTOO CMAJ 2008
VTE prediction models
bull Thrombophilia and residual vein thrombosis also studied
bull NO clear consensus about any of the above
httpwwwmeduniwienacatusergeorgheinzedvpm
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Aspirin Vs Placebo
The Aspirin for the Prevention of Recurrent Venous Thrombosis
trial (WARFASA for warfarin followed by aspirin or placebo)
The Aspirin to Prevent Venous Thromboembolism (ASPIRE)
WARFASA NEJM 2012 ASPIRE NEJM 2012
VTE ndash Extended Treatment
Combined data 32 Reduction in VTE Recurrence Rate 34 Reduction in Major Vascular Events
Statistically significant
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Apixaban for extended treatment of venous Thromboembolism
NEJM 2013
METHODS
Randomized double-blind
Two doses of apixaban 25 mg and 5 mg with placebo
Patients with VTE who had completed 6 to 12 months of AC
regarding the continuation or cessation of AC Clinical equipoise
The study drugs were administered for 12 months
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
RESULTS - 1
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Placebo (829) 5mg (813) 25mg (840)
73 (88) 14 (17) RR 02
14 (17) RR 019
Rec VTE or VTE-related death
4 (05) 1 (01) 2 (02) Major bleeding
22 (27) 35 (43) 27 (32) M or CRNM
RESULTS - 2
NNT = 14 NNH = 200
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Compared with ASA both 20-mg and 10-mg rivaroxaban reduced
the RR of recurrent VTE by about 70
The rates of M and and CRNMB were low and similar to those with ASA
NEJM 2017
Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism bullJeffrey I Weitz MD the EINSTEIN CHOICE Investigators
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Extended phase
Compared to warfarin
RE-MEDY Dabigatran
Compared to placebo
EINSTEIN EXT Rivaroxaban
AMPLIFY EXT Apixaban
2 doses
RE-SONATE Dabigatran
RE-SONATE RE-MEDY
(dabigatran)
bull N=4199
EXT-EINSTEIN (rivaroxaban)
bull N=1196
AMPLIFY-EXT (apixaban)
bull N=2486
4 trials with 7881 patients
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
vs placebo
vs warfarin 18
13
13 73
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
vs placebo
vs warfarin 101
56
46 20
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Warfarin ASA (100mg) Placebo
25 5 mg
Amplify Ext (Eliquis)
10 20mg 20mg
EINSTEIN EXT EINSTEIN CHOICE (Xarelto)
Less bleeding
150mg
Re-Sonate Re-Medy (Pradaxa)
Secondary prevention of VTE
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Armand Trousseau
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Cancer associated thrombosis (CAT) is unique
VTE is multifactorial
Cancer (more cancer burden ndash more VTE)
Treatment (chemoRx biological Rx)
Hospital (immobilization central lines)
Patient (morbidity thrombophilia)
High rate of recurrent despite treatment
High rate of bleeding events on adequate treatment
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
53336
27336
RR = 048 (030-077)
NEJM 2003
CLOT
Dalteparin Standard therapy
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Cancer patients All patients
335 (66) 5107 RECOVER
1124 (136) 8281 EINSTEIN
534 (99) 5395 AMPLIFY
771 (93) 8292 HOKUSAI
2764 (102) 27075 sum
RE-COVER (I+II) (dabigatran)
bullDVT-PE (2009+2013)
EINSTEIN (rivaroxaban)
bullDVT (2010) bullPE (2012)
AMPLIFY (apixaban)
bullDVT-PE (2013)
HOKUSAI VTE (edoxaban)
bullDVT-PE (2013)
Cancer patients
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10
HOKUSAI 050 (010 205)
EINSTEIN 058 (016 196)
AMPLIFY 056 (008 301)
RECOVER 094 (017 517)
combined [fixed] 061 (032 115)
odds ratio (95 confidence interval)
Rec Symptomatic VTE
OR = 061 (032 ndash 115) FIXED MODEL
Cancer patients
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Major bleeding OR = 066 (036 ndash 121) FIXED MODEL
Odds ratio meta-analysis plot [fixed effects]
001 01 02 05 1 2 5 10 100
HOKUSAI 154 (029 1015)
EINSTEIN 044 (016 112)
AMPLIFY 045 (004 323)
RECOVER 128 (021 896)
combined [fixed] 066 (036 121)
odds ratio (95 confidence interval)
Cancer patients
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Cancer patients Cancer-associated theombosis (CAT)
NEJM 2018
Select-D gt Rivaroxaban Vs Dalteparin JCO 2018
CARAVAGGIO trial gt Apixaban Vs SOC
Edoxaban for the treatment of VTE in patients with Cancer
Apixaban for the prevention of VTE in high-risk ambulatory cancer patients receiving chemotherapy Rational and design of the AVERT trial
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
NEJM 2018
Edoxaban for the treatment of VTE in patients with Cancer
Edoxaban - CAT
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Cancer patients
NEJM 2018
Edoxaban
M + CRNMB HR 14 p-004
Rec VTE HR 071 p-009
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018)
A total of 203 patients randomly assigned to each group 58 of whom had metastases Follow up for 6 months
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
8 4 (HR 043)
18 11
Rec VTE () Rec Rate
6 4 Major Bleeding
13 (HR 376) 4 CRNMB
75 70 Survival
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
DOAC in Cancer patients Rivaroxaban
SELECT D (JCO 2018) - Bleeding
3-fold relative increase in CRNMB with rivaroxaban
Deacrease in reccurent VTE but there was an increase in bleeding
Most bleed in the rivaroxaban arm were from the GI tract
Rivaroxaban (Pt 203)
Dalteparin (Pt 203)
Therapy Outcome
__ Rec VTE ()
Bleeding
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Prophylaxis in medical patients
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Muscle Pump Venous Insufficiency
Venous Function
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Valve Thrombosis
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Circulatory Stasis
ATVB 2012
Blood Flow Oxygen Tension Endothelial Activation
diams Prolonged stasis in the pocket of a venous valve diams Oxidative stress - up-regulation of genes HIF1α P-selectin amp adhesion receptors diams Pro-inflammatory state of the endothelium - monocytes granulocytes platelets MPs diams Local exposure of tissue factor TF
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Formation of Thrombosis
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Padua Score
Score 4 =lt High risk
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
DOAC ndash prophylaxis in medical patients Rivaroxaban
MAGELLAN (NEJM 2013)
Enoxaparin 40mgd for 10d Vs Rivaroxaban 10mgd for 35d
Rivaroxaban (Pt 2938)
Enoxaparin (Pt 2993)
Therapy VTE
78 (27) P = 0003 for non-inferiority 82 (27) Up to 10d ()
131 (44) RR 077 P = 002 175 (57) Up to 35d ()
111 (28 Plt0001)
164 (41 Plt0001)
10d gt 49 (12)
35d gt 67 (17) Major + CRNMB
Asymptomatic proximal or symptomatic VTE up to day 10 (non-inferiority ) and up to day 35 (superiority)
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Enoxaparin 40mgd for 6-14d vs Apixaban 25mg bid d for 30d
Apixaban (Pt 2211)
Enoxaparin (Pt 2284)
Primary outcome
27 306 At 30d
047 RR 258 P=004 019 Major bleeding
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
DOAC ndash prophylaxis in medical patients Apixaban
ADOPT trial (NEJM 2011)
Death related to VTE PE symptomatic DVT or asymptomatic prox DVT
CONCLUSIONS
An extended course of thromboprophylaxiswith apixaban was not
Superior to a shorter course with enoxaparin
Apixaban was associated with significantly more major bleeding
Events than was enoxaparin
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Q
mudimisgavshebagovil
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Thank you
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
DOAC for anti-phospholipid syndrome
ACL b2GP1 (IgG IgM) Lupus anti-coagulant (LAC)
ACL+ b2GP1 + LAC gtgt ldquoTriplerdquo APLA
Standard of treatment gtgt LMWH or Warfarin
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
The primary outcome The change in Endogenous Thrombin Potential (ETP) at day 42
Secondary outcomes The occurrence of thromboembolism up to day 210 after randomisation
Eligible patients Thrombotic APS and at least one VTE (No arterial events)
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Results 57 patients were assigned to rivaroxaban and 59 to warfarin
No thrombotic events were seen in either group during 6 months
Low risk patients
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
DOAC for anti-phospholipid syndrome RAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
Thrombin Generation
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
DOAC for anti-phospholipid syndrome TRAPS study
Rivaroxaban vs Warfarin to treat patients with thrombotic APS with or without
SLE a randomised controlled open-label phase 23 non-inferiority trial
Lancet 2016
High risk patients
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
Thrombophilia
ldquoAny disorder (inherited or acquired) associated with increased
tendency to venous thrombosisrdquo
Egeberg 1963
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
0
200
400
600
800
1000
1200DVT PE ALL
Silverstein MD Arch Int Med 1998
Olmsted county Minnesota
Age as risk factor for VTE
011000 11000
81000
תרשים1
PE
PE
DVT
DVT
VTE
VTE
Malignancy bull Cancer bull Cancer therapy
AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome
Acquired Risk Factors for VTE
Hematology bull MPD bull PNH
Trauma bull Trauma bull Surgery
bull Varicose veins
Hormones related
bull Estrogen OC bull HRT bull Estrogen RM
Immobilization bull Sitting bull Travel (Car Train) bull Long flights
Acute illness bull Heart Resp failure bull Stroke MI
bull Pregnancy bull Obesity bull Aging
bull Venous Catheter
Inherited Thrombophilia
11
156
217
7765
34725108
0
5
10
15
20
25
Controls
FVLPTM PS PC
FVLPTM ++
Combined AT
Relative Risk for 1st VTE in carriers
Rates per 1000Y
27 48
02 04
002
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
diams Late 2nd or 3rd trimester fetal loss
diams Neonatal purpura fulminant (PC PS) Skin necrosis
The ldquothresholdrdquo concept
- Slide Number 1
- Slide Number 2
- Slide Number 3
- תיאור מקרה
- Modified Wellrsquos criteria
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Slide Number 9
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- Slide Number 15
- Slide Number 16
- Slide Number 17
- Slide Number 18
- Slide Number 19
- תיאור מקרה
- Slide Number 21
- Slide Number 22
- Slide Number 23
- Slide Number 24
- Slide Number 25
- Slide Number 26
- Slide Number 27
- Slide Number 28
- Slide Number 29
- Slide Number 30
- ATTRACT study
- Slide Number 32
- Slide Number 33
- Slide Number 34
- Slide Number 35
- Slide Number 36
- תיאור מקרה
- Diagnosis of PE
- Slide Number 39
- Slide Number 40
- Slide Number 41
- Slide Number 42
- Slide Number 43
- Slide Number 44
- Slide Number 45
- תיאור מקרה
- Slide Number 47
- Slide Number 48
- Diagnosis of PE
- Diagnosis of PE
- Slide Number 51
- Slide Number 52
- Slide Number 53
- Slide Number 54
- Slide Number 55
- Slide Number 56
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- Slide Number 62
- Slide Number 63
- Slide Number 64
- Slide Number 65
- Slide Number 66
- Slide Number 67
- Slide Number 68
- Slide Number 69
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- Slide Number 74
- Slide Number 75
- Slide Number 76
- Slide Number 77
- Slide Number 78
- Slide Number 79
- Slide Number 80
- Slide Number 81
- Cancer associated thrombosis (CAT) is unique
- Slide Number 83
- Cancer patients
- Cancer patients
- Cancer patients
- Cancer patients Cancer-associated theombosis (CAT)
- Edoxaban - CAT
- Cancer patients
- Slide Number 90
- Slide Number 91
- Slide Number 92
- Venous Function
- Valve Thrombosis
- Circulatory Stasis
- Slide Number 96
- Padua Score
- Slide Number 98
- Slide Number 99
- Slide Number 100
- Slide Number 101
- Slide Number 102
- Slide Number 103
- Slide Number 104
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Thrombophilia
- Slide Number 111
- Slide Number 112
- Inherited Thrombophilia
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
-
| DVT | PE | ||||||
| 15-19 | 115 | 6 | 175 | ||||
| 20-24 | 294623115578 | 124324324324 | 418947439902 | ||||
| 25-29 | 351226415094 | 143181818182 | 494408233276 | ||||
| 30-34 | 33190529876 | 235606820461 | 567512119221 | ||||
| 35-39 | 325077399381 | 281967213115 | 607044612496 | ||||
| 40-44 | 411063153112 | 404565117349 | 815628270462 | ||||
| 45-49 | 440065298507 | 47976054732 | 919825845828 | ||||
| 50-54 | 592418032787 | 695776475513 | 12881945083 | ||||
| 55-59 | 610827754108 | 78242865463 | 1393256408739 | ||||
| 60-64 | 1129411764706 | 1365647592565 | 2495059357271 | ||||
| 65-69 | 1102678571429 | 1975555555556 | 3078234126984 | ||||
| 70-74 | 1736176239182 | 3152611319587 | 4888787558769 | ||||
| 75-79 | 1952003874561 | 3612906834971 | 5564910709532 | ||||
| 80-84 | 2429045193454 | 6037140768715 | 8466185962169 | ||||
| gt=85 | 2455329448256 | 7075487012987 | 9530816461243 |
| נשים | גברים | כולם | |||||||||||||||||
| גיל | ממ | IR | PY | ממ | IR | PY | ממ | PY | IR | ||||||||||
| 15-19 | 18 | 18 | 1000000 | 5 | 5 | 1000000 | 23 | 2000000 | 1150 | ||||||||||
| 20-24 | 45 | 41 | 1097561 | 10 | 13 | 769231 | 55 | 1866792 | 2946 | ||||||||||
| 25-29 | 55 | 51 | 1078431 | 18 | 18 | 1000000 | 73 | 2078431 | 3512 | ||||||||||
| 30-34 | 45 | 46 | 978261 | 19 | 20 | 950000 | 64 | 1928261 | 3319 | ||||||||||
| 35-39 | 27 | 35 | 771429 | 23 | 30 | 766667 | 50 | 1538095 | 3251 | ||||||||||
| 40-44 | 32 | 47 | 680851 | 23 | 35 | 657143 | 55 | 1337994 | 4111 | ||||||||||
| 45-49 | 29 | 51 | 568627 | 21 | 37 | 567568 | 50 | 1136195 | 4401 | ||||||||||
| 50-54 | 25 | 49 | 510204 | 34 | 70 | 485714 | 59 | 995918 | 5924 | ||||||||||
| 55-59 | 29 | 63 | 460317 | 25 | 59 | 423729 | 54 | 884046 | 6108 | ||||||||||
| 60-64 | 40 | 100 | 400000 | 44 | 128 | 343750 | 84 | 743750 | 11294 | ||||||||||
| 65-69 | 34 | 95 | 357895 | 36 | 130 | 276923 | 70 | 634818 | 11027 | ||||||||||
| 70-74 | 47 | 148 | 317568 | 44 | 213 | 206573 | 91 | 524140 | 17362 | ||||||||||
| 75-79 | 46 | 176 | 261364 | 34 | 229 | 148472 | 80 | 409835 | 19520 | ||||||||||
| 80-84 | 39 | 206 | 189320 | 29 | 320 | 90625 | 68 | 279945 | 24290 | ||||||||||
| gt=85 | 49 | 275 | 178182 | 10 | 161 | 62112 | 59 | 240294 | 24553 | ||||||||||
| 5600 | 8850010 | 3750 | 7748505 | 935 | 165985152169379 | 5633 | |||||||||||||
| 15-19 | 115 | ||||||||||||||||||
| 20-24 | 294623115578 | ||||||||||||||||||
| 25-29 | 351226415094 | ||||||||||||||||||
| 30-34 | 33190529876 | ||||||||||||||||||
| 35-39 | 325077399381 | ||||||||||||||||||
| 40-44 | 411063153112 | ||||||||||||||||||
| 45-49 | 440065298507 | ||||||||||||||||||
| 50-54 | 592418032787 | ||||||||||||||||||
| 55-59 | 610827754108 | ||||||||||||||||||
| 60-64 | 1129411764706 | ||||||||||||||||||
| 65-69 | 1102678571429 | ||||||||||||||||||
| 70-74 | 1736176239182 | ||||||||||||||||||
| 75-79 | 1952003874561 | ||||||||||||||||||
| 80-84 | 2429045193454 | ||||||||||||||||||
| gt=85 | 2455329448256 |
| תסחיף ריאתי | |||||||||||||||||||
| נשים | גברים | כולם | |||||||||||||||||
| גיל | ממ | IR | PY | ממ | IR | PY | ממ | PY | IR | ||||||||||
| 15-19 | 8 | 8 | 1000000 | 4 | 4 | 1000000 | 12 | 2000000 | 600 | ||||||||||
| 20-24 | 11 | 10 | 1100000 | 12 | 16 | 750000 | 23 | 1850000 | 1243 | ||||||||||
| 25-29 | 23 | 21 | 1095238 | 7 | 7 | 1000000 | 30 | 2095238 | 1432 | ||||||||||
| 30-34 | 28 | 29 | 965517 | 17 | 18 | 944444 | 45 | 1909962 | 2356 | ||||||||||
| 35-39 | 31 | 40 | 775000 | 12 | 16 | 750000 | 43 | 1525000 | 2820 | ||||||||||
| 40-44 | 25 | 37 | 675676 | 29 | 44 | 659091 | 54 | 1334767 | 4046 | ||||||||||
| 45-49 | 26 | 45 | 577778 | 29 | 51 | 568627 | 55 | 1146405 | 4798 | ||||||||||
| 50-54 | 37 | 73 | 506849 | 32 | 66 | 484848 | 69 | 991698 | 6958 | ||||||||||
| 55-59 | 27 | 59 | 457627 | 42 | 99 | 424242 | 69 | 881870 | 7824 | ||||||||||
| 60-64 | 43 | 107 | 401869 | 59 | 171 | 345029 | 102 | 746898 | 13656 | ||||||||||
| 65-69 | 55 | 154 | 357143 | 70 | 254 | 275591 | 125 | 632733 | 19756 | ||||||||||
| 70-74 | 64 | 202 | 316832 | 101 | 489 | 206544 | 165 | 523376 | 31526 | ||||||||||
| 75-79 | 88 | 337 | 261128 | 60 | 404 | 148515 | 148 | 409642 | 36129 | ||||||||||
| 80-84 | 94 | 497 | 189135 | 75 | 826 | 90799 | 169 | 279934 | 60371 | ||||||||||
| gt=85 | 123 | 690 | 178261 | 47 | 758 | 62005 | 170 | 240266 | 70755 | ||||||||||
| ALL | 683 | 8858052 | 596 | 7709737 | 12790 | 16567789 | |||||||||||||
| 7710 | 7730 | 7720 | |||||||||||||||||
| 15-19 | 600 | ||||||||||||||||||
| 20-24 | 1243 | ||||||||||||||||||
| 25-29 | 1432 | ||||||||||||||||||
| 30-34 | 2356 | ||||||||||||||||||
| 35-39 | 2820 | ||||||||||||||||||
| 40-44 | 4046 | ||||||||||||||||||
| 45-49 | 4798 | ||||||||||||||||||
| 50-54 | 6958 | ||||||||||||||||||
| 55-59 | 7824 | ||||||||||||||||||
| 60-64 | 13656 | ||||||||||||||||||
| 65-69 | 19756 | ||||||||||||||||||
| 70-74 | 31526 | ||||||||||||||||||
| 75-79 | 36129 | ||||||||||||||||||
| 80-84 | 60371 | ||||||||||||||||||
| gt=85 | 70755 |
| 15-19 | 15-19 | 15-19 | |||
| 20-24 | 20-24 | 20-24 | |||
| 25-29 | 25-29 | 25-29 | |||
| 30-34 | 30-34 | 30-34 | |||
| 35-39 | 35-39 | 35-39 | |||
| 40-44 | 40-44 | 40-44 | |||
| 45-49 | 45-49 | 45-49 | |||
| 50-54 | 50-54 | 50-54 | |||
| 55-59 | 55-59 | 55-59 | |||
| 60-64 | 60-64 | 60-64 | |||
| 65-69 | 65-69 | 65-69 | |||
| 70-74 | 70-74 | 70-74 | |||
| 75-79 | 75-79 | 75-79 | |||
| 80-84 | 80-84 | 80-84 | |||
| gt=85 | gt=85 | gt=85 |
PE
PE
DVT
DVT
VTE
VTE
Malignancy bull Cancer bull Cancer therapy
AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome
Acquired Risk Factors for VTE
Hematology bull MPD bull PNH
Trauma bull Trauma bull Surgery
bull Varicose veins
Hormones related
bull Estrogen OC bull HRT bull Estrogen RM
Immobilization bull Sitting bull Travel (Car Train) bull Long flights
Acute illness bull Heart Resp failure bull Stroke MI
bull Pregnancy bull Obesity bull Aging
bull Venous Catheter
Inherited Thrombophilia
11
156
217
7765
34725108
0
5
10
15
20
25
Controls
FVLPTM PS PC
FVLPTM ++
Combined AT
Relative Risk for 1st VTE in carriers
Rates per 1000Y
27 48
02 04
002
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
diams Late 2nd or 3rd trimester fetal loss
diams Neonatal purpura fulminant (PC PS) Skin necrosis
The ldquothresholdrdquo concept
- Slide Number 1
- Slide Number 2
- Slide Number 3
- תיאור מקרה
- Modified Wellrsquos criteria
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Slide Number 9
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- Slide Number 15
- Slide Number 16
- Slide Number 17
- Slide Number 18
- Slide Number 19
- תיאור מקרה
- Slide Number 21
- Slide Number 22
- Slide Number 23
- Slide Number 24
- Slide Number 25
- Slide Number 26
- Slide Number 27
- Slide Number 28
- Slide Number 29
- Slide Number 30
- ATTRACT study
- Slide Number 32
- Slide Number 33
- Slide Number 34
- Slide Number 35
- Slide Number 36
- תיאור מקרה
- Diagnosis of PE
- Slide Number 39
- Slide Number 40
- Slide Number 41
- Slide Number 42
- Slide Number 43
- Slide Number 44
- Slide Number 45
- תיאור מקרה
- Slide Number 47
- Slide Number 48
- Diagnosis of PE
- Diagnosis of PE
- Slide Number 51
- Slide Number 52
- Slide Number 53
- Slide Number 54
- Slide Number 55
- Slide Number 56
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- Slide Number 62
- Slide Number 63
- Slide Number 64
- Slide Number 65
- Slide Number 66
- Slide Number 67
- Slide Number 68
- Slide Number 69
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- Slide Number 74
- Slide Number 75
- Slide Number 76
- Slide Number 77
- Slide Number 78
- Slide Number 79
- Slide Number 80
- Slide Number 81
- Cancer associated thrombosis (CAT) is unique
- Slide Number 83
- Cancer patients
- Cancer patients
- Cancer patients
- Cancer patients Cancer-associated theombosis (CAT)
- Edoxaban - CAT
- Cancer patients
- Slide Number 90
- Slide Number 91
- Slide Number 92
- Venous Function
- Valve Thrombosis
- Circulatory Stasis
- Slide Number 96
- Padua Score
- Slide Number 98
- Slide Number 99
- Slide Number 100
- Slide Number 101
- Slide Number 102
- Slide Number 103
- Slide Number 104
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Thrombophilia
- Slide Number 111
- Slide Number 112
- Inherited Thrombophilia
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
-
| DVT | PE | ||||||
| 15-19 | 115 | 6 | 175 | ||||
| 20-24 | 294623115578 | 124324324324 | 418947439902 | ||||
| 25-29 | 351226415094 | 143181818182 | 494408233276 | ||||
| 30-34 | 33190529876 | 235606820461 | 567512119221 | ||||
| 35-39 | 325077399381 | 281967213115 | 607044612496 | ||||
| 40-44 | 411063153112 | 404565117349 | 815628270462 | ||||
| 45-49 | 440065298507 | 47976054732 | 919825845828 | ||||
| 50-54 | 592418032787 | 695776475513 | 12881945083 | ||||
| 55-59 | 610827754108 | 78242865463 | 1393256408739 | ||||
| 60-64 | 1129411764706 | 1365647592565 | 2495059357271 | ||||
| 65-69 | 1102678571429 | 1975555555556 | 3078234126984 | ||||
| 70-74 | 1736176239182 | 3152611319587 | 4888787558769 | ||||
| 75-79 | 1952003874561 | 3612906834971 | 5564910709532 | ||||
| 80-84 | 2429045193454 | 6037140768715 | 8466185962169 | ||||
| gt=85 | 2455329448256 | 7075487012987 | 9530816461243 |
| נשים | גברים | כולם | |||||||||||||||||
| גיל | ממ | IR | PY | ממ | IR | PY | ממ | PY | IR | ||||||||||
| 15-19 | 18 | 18 | 1000000 | 5 | 5 | 1000000 | 23 | 2000000 | 1150 | ||||||||||
| 20-24 | 45 | 41 | 1097561 | 10 | 13 | 769231 | 55 | 1866792 | 2946 | ||||||||||
| 25-29 | 55 | 51 | 1078431 | 18 | 18 | 1000000 | 73 | 2078431 | 3512 | ||||||||||
| 30-34 | 45 | 46 | 978261 | 19 | 20 | 950000 | 64 | 1928261 | 3319 | ||||||||||
| 35-39 | 27 | 35 | 771429 | 23 | 30 | 766667 | 50 | 1538095 | 3251 | ||||||||||
| 40-44 | 32 | 47 | 680851 | 23 | 35 | 657143 | 55 | 1337994 | 4111 | ||||||||||
| 45-49 | 29 | 51 | 568627 | 21 | 37 | 567568 | 50 | 1136195 | 4401 | ||||||||||
| 50-54 | 25 | 49 | 510204 | 34 | 70 | 485714 | 59 | 995918 | 5924 | ||||||||||
| 55-59 | 29 | 63 | 460317 | 25 | 59 | 423729 | 54 | 884046 | 6108 | ||||||||||
| 60-64 | 40 | 100 | 400000 | 44 | 128 | 343750 | 84 | 743750 | 11294 | ||||||||||
| 65-69 | 34 | 95 | 357895 | 36 | 130 | 276923 | 70 | 634818 | 11027 | ||||||||||
| 70-74 | 47 | 148 | 317568 | 44 | 213 | 206573 | 91 | 524140 | 17362 | ||||||||||
| 75-79 | 46 | 176 | 261364 | 34 | 229 | 148472 | 80 | 409835 | 19520 | ||||||||||
| 80-84 | 39 | 206 | 189320 | 29 | 320 | 90625 | 68 | 279945 | 24290 | ||||||||||
| gt=85 | 49 | 275 | 178182 | 10 | 161 | 62112 | 59 | 240294 | 24553 | ||||||||||
| 5600 | 8850010 | 3750 | 7748505 | 935 | 165985152169379 | 5633 | |||||||||||||
| 15-19 | 115 | ||||||||||||||||||
| 20-24 | 294623115578 | ||||||||||||||||||
| 25-29 | 351226415094 | ||||||||||||||||||
| 30-34 | 33190529876 | ||||||||||||||||||
| 35-39 | 325077399381 | ||||||||||||||||||
| 40-44 | 411063153112 | ||||||||||||||||||
| 45-49 | 440065298507 | ||||||||||||||||||
| 50-54 | 592418032787 | ||||||||||||||||||
| 55-59 | 610827754108 | ||||||||||||||||||
| 60-64 | 1129411764706 | ||||||||||||||||||
| 65-69 | 1102678571429 | ||||||||||||||||||
| 70-74 | 1736176239182 | ||||||||||||||||||
| 75-79 | 1952003874561 | ||||||||||||||||||
| 80-84 | 2429045193454 | ||||||||||||||||||
| gt=85 | 2455329448256 |
| תסחיף ריאתי | |||||||||||||||||||
| נשים | גברים | כולם | |||||||||||||||||
| גיל | ממ | IR | PY | ממ | IR | PY | ממ | PY | IR | ||||||||||
| 15-19 | 8 | 8 | 1000000 | 4 | 4 | 1000000 | 12 | 2000000 | 600 | ||||||||||
| 20-24 | 11 | 10 | 1100000 | 12 | 16 | 750000 | 23 | 1850000 | 1243 | ||||||||||
| 25-29 | 23 | 21 | 1095238 | 7 | 7 | 1000000 | 30 | 2095238 | 1432 | ||||||||||
| 30-34 | 28 | 29 | 965517 | 17 | 18 | 944444 | 45 | 1909962 | 2356 | ||||||||||
| 35-39 | 31 | 40 | 775000 | 12 | 16 | 750000 | 43 | 1525000 | 2820 | ||||||||||
| 40-44 | 25 | 37 | 675676 | 29 | 44 | 659091 | 54 | 1334767 | 4046 | ||||||||||
| 45-49 | 26 | 45 | 577778 | 29 | 51 | 568627 | 55 | 1146405 | 4798 | ||||||||||
| 50-54 | 37 | 73 | 506849 | 32 | 66 | 484848 | 69 | 991698 | 6958 | ||||||||||
| 55-59 | 27 | 59 | 457627 | 42 | 99 | 424242 | 69 | 881870 | 7824 | ||||||||||
| 60-64 | 43 | 107 | 401869 | 59 | 171 | 345029 | 102 | 746898 | 13656 | ||||||||||
| 65-69 | 55 | 154 | 357143 | 70 | 254 | 275591 | 125 | 632733 | 19756 | ||||||||||
| 70-74 | 64 | 202 | 316832 | 101 | 489 | 206544 | 165 | 523376 | 31526 | ||||||||||
| 75-79 | 88 | 337 | 261128 | 60 | 404 | 148515 | 148 | 409642 | 36129 | ||||||||||
| 80-84 | 94 | 497 | 189135 | 75 | 826 | 90799 | 169 | 279934 | 60371 | ||||||||||
| gt=85 | 123 | 690 | 178261 | 47 | 758 | 62005 | 170 | 240266 | 70755 | ||||||||||
| ALL | 683 | 8858052 | 596 | 7709737 | 12790 | 16567789 | |||||||||||||
| 7710 | 7730 | 7720 | |||||||||||||||||
| 15-19 | 600 | ||||||||||||||||||
| 20-24 | 1243 | ||||||||||||||||||
| 25-29 | 1432 | ||||||||||||||||||
| 30-34 | 2356 | ||||||||||||||||||
| 35-39 | 2820 | ||||||||||||||||||
| 40-44 | 4046 | ||||||||||||||||||
| 45-49 | 4798 | ||||||||||||||||||
| 50-54 | 6958 | ||||||||||||||||||
| 55-59 | 7824 | ||||||||||||||||||
| 60-64 | 13656 | ||||||||||||||||||
| 65-69 | 19756 | ||||||||||||||||||
| 70-74 | 31526 | ||||||||||||||||||
| 75-79 | 36129 | ||||||||||||||||||
| 80-84 | 60371 | ||||||||||||||||||
| gt=85 | 70755 |
PE
DVT
DVT
VTE
VTE
Malignancy bull Cancer bull Cancer therapy
AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome
Acquired Risk Factors for VTE
Hematology bull MPD bull PNH
Trauma bull Trauma bull Surgery
bull Varicose veins
Hormones related
bull Estrogen OC bull HRT bull Estrogen RM
Immobilization bull Sitting bull Travel (Car Train) bull Long flights
Acute illness bull Heart Resp failure bull Stroke MI
bull Pregnancy bull Obesity bull Aging
bull Venous Catheter
Inherited Thrombophilia
11
156
217
7765
34725108
0
5
10
15
20
25
Controls
FVLPTM PS PC
FVLPTM ++
Combined AT
Relative Risk for 1st VTE in carriers
Rates per 1000Y
27 48
02 04
002
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
diams Late 2nd or 3rd trimester fetal loss
diams Neonatal purpura fulminant (PC PS) Skin necrosis
The ldquothresholdrdquo concept
- Slide Number 1
- Slide Number 2
- Slide Number 3
- תיאור מקרה
- Modified Wellrsquos criteria
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Slide Number 9
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- Slide Number 15
- Slide Number 16
- Slide Number 17
- Slide Number 18
- Slide Number 19
- תיאור מקרה
- Slide Number 21
- Slide Number 22
- Slide Number 23
- Slide Number 24
- Slide Number 25
- Slide Number 26
- Slide Number 27
- Slide Number 28
- Slide Number 29
- Slide Number 30
- ATTRACT study
- Slide Number 32
- Slide Number 33
- Slide Number 34
- Slide Number 35
- Slide Number 36
- תיאור מקרה
- Diagnosis of PE
- Slide Number 39
- Slide Number 40
- Slide Number 41
- Slide Number 42
- Slide Number 43
- Slide Number 44
- Slide Number 45
- תיאור מקרה
- Slide Number 47
- Slide Number 48
- Diagnosis of PE
- Diagnosis of PE
- Slide Number 51
- Slide Number 52
- Slide Number 53
- Slide Number 54
- Slide Number 55
- Slide Number 56
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- Slide Number 62
- Slide Number 63
- Slide Number 64
- Slide Number 65
- Slide Number 66
- Slide Number 67
- Slide Number 68
- Slide Number 69
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- Slide Number 74
- Slide Number 75
- Slide Number 76
- Slide Number 77
- Slide Number 78
- Slide Number 79
- Slide Number 80
- Slide Number 81
- Cancer associated thrombosis (CAT) is unique
- Slide Number 83
- Cancer patients
- Cancer patients
- Cancer patients
- Cancer patients Cancer-associated theombosis (CAT)
- Edoxaban - CAT
- Cancer patients
- Slide Number 90
- Slide Number 91
- Slide Number 92
- Venous Function
- Valve Thrombosis
- Circulatory Stasis
- Slide Number 96
- Padua Score
- Slide Number 98
- Slide Number 99
- Slide Number 100
- Slide Number 101
- Slide Number 102
- Slide Number 103
- Slide Number 104
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Thrombophilia
- Slide Number 111
- Slide Number 112
- Inherited Thrombophilia
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
-
| DVT | PE | ||||||
| 15-19 | 115 | 6 | 175 | ||||
| 20-24 | 294623115578 | 124324324324 | 418947439902 | ||||
| 25-29 | 351226415094 | 143181818182 | 494408233276 | ||||
| 30-34 | 33190529876 | 235606820461 | 567512119221 | ||||
| 35-39 | 325077399381 | 281967213115 | 607044612496 | ||||
| 40-44 | 411063153112 | 404565117349 | 815628270462 | ||||
| 45-49 | 440065298507 | 47976054732 | 919825845828 | ||||
| 50-54 | 592418032787 | 695776475513 | 12881945083 | ||||
| 55-59 | 610827754108 | 78242865463 | 1393256408739 | ||||
| 60-64 | 1129411764706 | 1365647592565 | 2495059357271 | ||||
| 65-69 | 1102678571429 | 1975555555556 | 3078234126984 | ||||
| 70-74 | 1736176239182 | 3152611319587 | 4888787558769 | ||||
| 75-79 | 1952003874561 | 3612906834971 | 5564910709532 | ||||
| 80-84 | 2429045193454 | 6037140768715 | 8466185962169 | ||||
| gt=85 | 2455329448256 | 7075487012987 | 9530816461243 |
| נשים | גברים | כולם | |||||||||||||||||
| גיל | ממ | IR | PY | ממ | IR | PY | ממ | PY | IR | ||||||||||
| 15-19 | 18 | 18 | 1000000 | 5 | 5 | 1000000 | 23 | 2000000 | 1150 | ||||||||||
| 20-24 | 45 | 41 | 1097561 | 10 | 13 | 769231 | 55 | 1866792 | 2946 | ||||||||||
| 25-29 | 55 | 51 | 1078431 | 18 | 18 | 1000000 | 73 | 2078431 | 3512 | ||||||||||
| 30-34 | 45 | 46 | 978261 | 19 | 20 | 950000 | 64 | 1928261 | 3319 | ||||||||||
| 35-39 | 27 | 35 | 771429 | 23 | 30 | 766667 | 50 | 1538095 | 3251 | ||||||||||
| 40-44 | 32 | 47 | 680851 | 23 | 35 | 657143 | 55 | 1337994 | 4111 | ||||||||||
| 45-49 | 29 | 51 | 568627 | 21 | 37 | 567568 | 50 | 1136195 | 4401 | ||||||||||
| 50-54 | 25 | 49 | 510204 | 34 | 70 | 485714 | 59 | 995918 | 5924 | ||||||||||
| 55-59 | 29 | 63 | 460317 | 25 | 59 | 423729 | 54 | 884046 | 6108 | ||||||||||
| 60-64 | 40 | 100 | 400000 | 44 | 128 | 343750 | 84 | 743750 | 11294 | ||||||||||
| 65-69 | 34 | 95 | 357895 | 36 | 130 | 276923 | 70 | 634818 | 11027 | ||||||||||
| 70-74 | 47 | 148 | 317568 | 44 | 213 | 206573 | 91 | 524140 | 17362 | ||||||||||
| 75-79 | 46 | 176 | 261364 | 34 | 229 | 148472 | 80 | 409835 | 19520 | ||||||||||
| 80-84 | 39 | 206 | 189320 | 29 | 320 | 90625 | 68 | 279945 | 24290 | ||||||||||
| gt=85 | 49 | 275 | 178182 | 10 | 161 | 62112 | 59 | 240294 | 24553 | ||||||||||
| 5600 | 8850010 | 3750 | 7748505 | 935 | 165985152169379 | 5633 | |||||||||||||
| 15-19 | 115 | ||||||||||||||||||
| 20-24 | 294623115578 | ||||||||||||||||||
| 25-29 | 351226415094 | ||||||||||||||||||
| 30-34 | 33190529876 | ||||||||||||||||||
| 35-39 | 325077399381 | ||||||||||||||||||
| 40-44 | 411063153112 | ||||||||||||||||||
| 45-49 | 440065298507 | ||||||||||||||||||
| 50-54 | 592418032787 | ||||||||||||||||||
| 55-59 | 610827754108 | ||||||||||||||||||
| 60-64 | 1129411764706 | ||||||||||||||||||
| 65-69 | 1102678571429 | ||||||||||||||||||
| 70-74 | 1736176239182 | ||||||||||||||||||
| 75-79 | 1952003874561 | ||||||||||||||||||
| 80-84 | 2429045193454 | ||||||||||||||||||
| gt=85 | 2455329448256 |
DVT
DVT
VTE
VTE
Malignancy bull Cancer bull Cancer therapy
AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome
Acquired Risk Factors for VTE
Hematology bull MPD bull PNH
Trauma bull Trauma bull Surgery
bull Varicose veins
Hormones related
bull Estrogen OC bull HRT bull Estrogen RM
Immobilization bull Sitting bull Travel (Car Train) bull Long flights
Acute illness bull Heart Resp failure bull Stroke MI
bull Pregnancy bull Obesity bull Aging
bull Venous Catheter
Inherited Thrombophilia
11
156
217
7765
34725108
0
5
10
15
20
25
Controls
FVLPTM PS PC
FVLPTM ++
Combined AT
Relative Risk for 1st VTE in carriers
Rates per 1000Y
27 48
02 04
002
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
diams Late 2nd or 3rd trimester fetal loss
diams Neonatal purpura fulminant (PC PS) Skin necrosis
The ldquothresholdrdquo concept
- Slide Number 1
- Slide Number 2
- Slide Number 3
- תיאור מקרה
- Modified Wellrsquos criteria
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Slide Number 9
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- Slide Number 15
- Slide Number 16
- Slide Number 17
- Slide Number 18
- Slide Number 19
- תיאור מקרה
- Slide Number 21
- Slide Number 22
- Slide Number 23
- Slide Number 24
- Slide Number 25
- Slide Number 26
- Slide Number 27
- Slide Number 28
- Slide Number 29
- Slide Number 30
- ATTRACT study
- Slide Number 32
- Slide Number 33
- Slide Number 34
- Slide Number 35
- Slide Number 36
- תיאור מקרה
- Diagnosis of PE
- Slide Number 39
- Slide Number 40
- Slide Number 41
- Slide Number 42
- Slide Number 43
- Slide Number 44
- Slide Number 45
- תיאור מקרה
- Slide Number 47
- Slide Number 48
- Diagnosis of PE
- Diagnosis of PE
- Slide Number 51
- Slide Number 52
- Slide Number 53
- Slide Number 54
- Slide Number 55
- Slide Number 56
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- Slide Number 62
- Slide Number 63
- Slide Number 64
- Slide Number 65
- Slide Number 66
- Slide Number 67
- Slide Number 68
- Slide Number 69
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- Slide Number 74
- Slide Number 75
- Slide Number 76
- Slide Number 77
- Slide Number 78
- Slide Number 79
- Slide Number 80
- Slide Number 81
- Cancer associated thrombosis (CAT) is unique
- Slide Number 83
- Cancer patients
- Cancer patients
- Cancer patients
- Cancer patients Cancer-associated theombosis (CAT)
- Edoxaban - CAT
- Cancer patients
- Slide Number 90
- Slide Number 91
- Slide Number 92
- Venous Function
- Valve Thrombosis
- Circulatory Stasis
- Slide Number 96
- Padua Score
- Slide Number 98
- Slide Number 99
- Slide Number 100
- Slide Number 101
- Slide Number 102
- Slide Number 103
- Slide Number 104
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Thrombophilia
- Slide Number 111
- Slide Number 112
- Inherited Thrombophilia
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
-
| DVT | PE | ||||||
| 15-19 | 115 | 6 | 175 | ||||
| 20-24 | 294623115578 | 124324324324 | 418947439902 | ||||
| 25-29 | 351226415094 | 143181818182 | 494408233276 | ||||
| 30-34 | 33190529876 | 235606820461 | 567512119221 | ||||
| 35-39 | 325077399381 | 281967213115 | 607044612496 | ||||
| 40-44 | 411063153112 | 404565117349 | 815628270462 | ||||
| 45-49 | 440065298507 | 47976054732 | 919825845828 | ||||
| 50-54 | 592418032787 | 695776475513 | 12881945083 | ||||
| 55-59 | 610827754108 | 78242865463 | 1393256408739 | ||||
| 60-64 | 1129411764706 | 1365647592565 | 2495059357271 | ||||
| 65-69 | 1102678571429 | 1975555555556 | 3078234126984 | ||||
| 70-74 | 1736176239182 | 3152611319587 | 4888787558769 | ||||
| 75-79 | 1952003874561 | 3612906834971 | 5564910709532 | ||||
| 80-84 | 2429045193454 | 6037140768715 | 8466185962169 | ||||
| gt=85 | 2455329448256 | 7075487012987 | 9530816461243 |
| נשים | גברים | כולם | |||||||||||||||||
| גיל | ממ | IR | PY | ממ | IR | PY | ממ | PY | IR | ||||||||||
| 15-19 | 18 | 18 | 1000000 | 5 | 5 | 1000000 | 23 | 2000000 | 1150 | ||||||||||
| 20-24 | 45 | 41 | 1097561 | 10 | 13 | 769231 | 55 | 1866792 | 2946 | ||||||||||
| 25-29 | 55 | 51 | 1078431 | 18 | 18 | 1000000 | 73 | 2078431 | 3512 | ||||||||||
| 30-34 | 45 | 46 | 978261 | 19 | 20 | 950000 | 64 | 1928261 | 3319 | ||||||||||
| 35-39 | 27 | 35 | 771429 | 23 | 30 | 766667 | 50 | 1538095 | 3251 | ||||||||||
| 40-44 | 32 | 47 | 680851 | 23 | 35 | 657143 | 55 | 1337994 | 4111 | ||||||||||
| 45-49 | 29 | 51 | 568627 | 21 | 37 | 567568 | 50 | 1136195 | 4401 | ||||||||||
| 50-54 | 25 | 49 | 510204 | 34 | 70 | 485714 | 59 | 995918 | 5924 | ||||||||||
| 55-59 | 29 | 63 | 460317 | 25 | 59 | 423729 | 54 | 884046 | 6108 | ||||||||||
| 60-64 | 40 | 100 | 400000 | 44 | 128 | 343750 | 84 | 743750 | 11294 | ||||||||||
| 65-69 | 34 | 95 | 357895 | 36 | 130 | 276923 | 70 | 634818 | 11027 | ||||||||||
| 70-74 | 47 | 148 | 317568 | 44 | 213 | 206573 | 91 | 524140 | 17362 | ||||||||||
| 75-79 | 46 | 176 | 261364 | 34 | 229 | 148472 | 80 | 409835 | 19520 | ||||||||||
| 80-84 | 39 | 206 | 189320 | 29 | 320 | 90625 | 68 | 279945 | 24290 | ||||||||||
| gt=85 | 49 | 275 | 178182 | 10 | 161 | 62112 | 59 | 240294 | 24553 | ||||||||||
| 5600 | 8850010 | 3750 | 7748505 | 935 | 165985152169379 | 5633 | |||||||||||||
| 15-19 | 115 | ||||||||||||||||||
| 20-24 | 294623115578 | ||||||||||||||||||
| 25-29 | 351226415094 | ||||||||||||||||||
| 30-34 | 33190529876 | ||||||||||||||||||
| 35-39 | 325077399381 | ||||||||||||||||||
| 40-44 | 411063153112 | ||||||||||||||||||
| 45-49 | 440065298507 | ||||||||||||||||||
| 50-54 | 592418032787 | ||||||||||||||||||
| 55-59 | 610827754108 | ||||||||||||||||||
| 60-64 | 1129411764706 | ||||||||||||||||||
| 65-69 | 1102678571429 | ||||||||||||||||||
| 70-74 | 1736176239182 | ||||||||||||||||||
| 75-79 | 1952003874561 | ||||||||||||||||||
| 80-84 | 2429045193454 | ||||||||||||||||||
| gt=85 | 2455329448256 |
DVT
VTE
VTE
Malignancy bull Cancer bull Cancer therapy
AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome
Acquired Risk Factors for VTE
Hematology bull MPD bull PNH
Trauma bull Trauma bull Surgery
bull Varicose veins
Hormones related
bull Estrogen OC bull HRT bull Estrogen RM
Immobilization bull Sitting bull Travel (Car Train) bull Long flights
Acute illness bull Heart Resp failure bull Stroke MI
bull Pregnancy bull Obesity bull Aging
bull Venous Catheter
Inherited Thrombophilia
11
156
217
7765
34725108
0
5
10
15
20
25
Controls
FVLPTM PS PC
FVLPTM ++
Combined AT
Relative Risk for 1st VTE in carriers
Rates per 1000Y
27 48
02 04
002
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
diams Late 2nd or 3rd trimester fetal loss
diams Neonatal purpura fulminant (PC PS) Skin necrosis
The ldquothresholdrdquo concept
- Slide Number 1
- Slide Number 2
- Slide Number 3
- תיאור מקרה
- Modified Wellrsquos criteria
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Slide Number 9
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- Slide Number 15
- Slide Number 16
- Slide Number 17
- Slide Number 18
- Slide Number 19
- תיאור מקרה
- Slide Number 21
- Slide Number 22
- Slide Number 23
- Slide Number 24
- Slide Number 25
- Slide Number 26
- Slide Number 27
- Slide Number 28
- Slide Number 29
- Slide Number 30
- ATTRACT study
- Slide Number 32
- Slide Number 33
- Slide Number 34
- Slide Number 35
- Slide Number 36
- תיאור מקרה
- Diagnosis of PE
- Slide Number 39
- Slide Number 40
- Slide Number 41
- Slide Number 42
- Slide Number 43
- Slide Number 44
- Slide Number 45
- תיאור מקרה
- Slide Number 47
- Slide Number 48
- Diagnosis of PE
- Diagnosis of PE
- Slide Number 51
- Slide Number 52
- Slide Number 53
- Slide Number 54
- Slide Number 55
- Slide Number 56
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- Slide Number 62
- Slide Number 63
- Slide Number 64
- Slide Number 65
- Slide Number 66
- Slide Number 67
- Slide Number 68
- Slide Number 69
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- Slide Number 74
- Slide Number 75
- Slide Number 76
- Slide Number 77
- Slide Number 78
- Slide Number 79
- Slide Number 80
- Slide Number 81
- Cancer associated thrombosis (CAT) is unique
- Slide Number 83
- Cancer patients
- Cancer patients
- Cancer patients
- Cancer patients Cancer-associated theombosis (CAT)
- Edoxaban - CAT
- Cancer patients
- Slide Number 90
- Slide Number 91
- Slide Number 92
- Venous Function
- Valve Thrombosis
- Circulatory Stasis
- Slide Number 96
- Padua Score
- Slide Number 98
- Slide Number 99
- Slide Number 100
- Slide Number 101
- Slide Number 102
- Slide Number 103
- Slide Number 104
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Thrombophilia
- Slide Number 111
- Slide Number 112
- Inherited Thrombophilia
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
-
| DVT | PE | ||||||
| 15-19 | 115 | 6 | 175 | ||||
| 20-24 | 294623115578 | 124324324324 | 418947439902 | ||||
| 25-29 | 351226415094 | 143181818182 | 494408233276 | ||||
| 30-34 | 33190529876 | 235606820461 | 567512119221 | ||||
| 35-39 | 325077399381 | 281967213115 | 607044612496 | ||||
| 40-44 | 411063153112 | 404565117349 | 815628270462 | ||||
| 45-49 | 440065298507 | 47976054732 | 919825845828 | ||||
| 50-54 | 592418032787 | 695776475513 | 12881945083 | ||||
| 55-59 | 610827754108 | 78242865463 | 1393256408739 | ||||
| 60-64 | 1129411764706 | 1365647592565 | 2495059357271 | ||||
| 65-69 | 1102678571429 | 1975555555556 | 3078234126984 | ||||
| 70-74 | 1736176239182 | 3152611319587 | 4888787558769 | ||||
| 75-79 | 1952003874561 | 3612906834971 | 5564910709532 | ||||
| 80-84 | 2429045193454 | 6037140768715 | 8466185962169 | ||||
| gt=85 | 2455329448256 | 7075487012987 | 9530816461243 |
VTE
VTE
Malignancy bull Cancer bull Cancer therapy
AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome
Acquired Risk Factors for VTE
Hematology bull MPD bull PNH
Trauma bull Trauma bull Surgery
bull Varicose veins
Hormones related
bull Estrogen OC bull HRT bull Estrogen RM
Immobilization bull Sitting bull Travel (Car Train) bull Long flights
Acute illness bull Heart Resp failure bull Stroke MI
bull Pregnancy bull Obesity bull Aging
bull Venous Catheter
Inherited Thrombophilia
11
156
217
7765
34725108
0
5
10
15
20
25
Controls
FVLPTM PS PC
FVLPTM ++
Combined AT
Relative Risk for 1st VTE in carriers
Rates per 1000Y
27 48
02 04
002
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
diams Late 2nd or 3rd trimester fetal loss
diams Neonatal purpura fulminant (PC PS) Skin necrosis
The ldquothresholdrdquo concept
- Slide Number 1
- Slide Number 2
- Slide Number 3
- תיאור מקרה
- Modified Wellrsquos criteria
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Slide Number 9
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- Slide Number 15
- Slide Number 16
- Slide Number 17
- Slide Number 18
- Slide Number 19
- תיאור מקרה
- Slide Number 21
- Slide Number 22
- Slide Number 23
- Slide Number 24
- Slide Number 25
- Slide Number 26
- Slide Number 27
- Slide Number 28
- Slide Number 29
- Slide Number 30
- ATTRACT study
- Slide Number 32
- Slide Number 33
- Slide Number 34
- Slide Number 35
- Slide Number 36
- תיאור מקרה
- Diagnosis of PE
- Slide Number 39
- Slide Number 40
- Slide Number 41
- Slide Number 42
- Slide Number 43
- Slide Number 44
- Slide Number 45
- תיאור מקרה
- Slide Number 47
- Slide Number 48
- Diagnosis of PE
- Diagnosis of PE
- Slide Number 51
- Slide Number 52
- Slide Number 53
- Slide Number 54
- Slide Number 55
- Slide Number 56
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- Slide Number 62
- Slide Number 63
- Slide Number 64
- Slide Number 65
- Slide Number 66
- Slide Number 67
- Slide Number 68
- Slide Number 69
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- Slide Number 74
- Slide Number 75
- Slide Number 76
- Slide Number 77
- Slide Number 78
- Slide Number 79
- Slide Number 80
- Slide Number 81
- Cancer associated thrombosis (CAT) is unique
- Slide Number 83
- Cancer patients
- Cancer patients
- Cancer patients
- Cancer patients Cancer-associated theombosis (CAT)
- Edoxaban - CAT
- Cancer patients
- Slide Number 90
- Slide Number 91
- Slide Number 92
- Venous Function
- Valve Thrombosis
- Circulatory Stasis
- Slide Number 96
- Padua Score
- Slide Number 98
- Slide Number 99
- Slide Number 100
- Slide Number 101
- Slide Number 102
- Slide Number 103
- Slide Number 104
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Thrombophilia
- Slide Number 111
- Slide Number 112
- Inherited Thrombophilia
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
-
| DVT | PE | ||||||
| 15-19 | 115 | 6 | 175 | ||||
| 20-24 | 294623115578 | 124324324324 | 418947439902 | ||||
| 25-29 | 351226415094 | 143181818182 | 494408233276 | ||||
| 30-34 | 33190529876 | 235606820461 | 567512119221 | ||||
| 35-39 | 325077399381 | 281967213115 | 607044612496 | ||||
| 40-44 | 411063153112 | 404565117349 | 815628270462 | ||||
| 45-49 | 440065298507 | 47976054732 | 919825845828 | ||||
| 50-54 | 592418032787 | 695776475513 | 12881945083 | ||||
| 55-59 | 610827754108 | 78242865463 | 1393256408739 | ||||
| 60-64 | 1129411764706 | 1365647592565 | 2495059357271 | ||||
| 65-69 | 1102678571429 | 1975555555556 | 3078234126984 | ||||
| 70-74 | 1736176239182 | 3152611319587 | 4888787558769 | ||||
| 75-79 | 1952003874561 | 3612906834971 | 5564910709532 | ||||
| 80-84 | 2429045193454 | 6037140768715 | 8466185962169 | ||||
| gt=85 | 2455329448256 | 7075487012987 | 9530816461243 |
VTE
Malignancy bull Cancer bull Cancer therapy
AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome
Acquired Risk Factors for VTE
Hematology bull MPD bull PNH
Trauma bull Trauma bull Surgery
bull Varicose veins
Hormones related
bull Estrogen OC bull HRT bull Estrogen RM
Immobilization bull Sitting bull Travel (Car Train) bull Long flights
Acute illness bull Heart Resp failure bull Stroke MI
bull Pregnancy bull Obesity bull Aging
bull Venous Catheter
Inherited Thrombophilia
11
156
217
7765
34725108
0
5
10
15
20
25
Controls
FVLPTM PS PC
FVLPTM ++
Combined AT
Relative Risk for 1st VTE in carriers
Rates per 1000Y
27 48
02 04
002
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
diams Late 2nd or 3rd trimester fetal loss
diams Neonatal purpura fulminant (PC PS) Skin necrosis
The ldquothresholdrdquo concept
- Slide Number 1
- Slide Number 2
- Slide Number 3
- תיאור מקרה
- Modified Wellrsquos criteria
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Slide Number 9
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- Slide Number 15
- Slide Number 16
- Slide Number 17
- Slide Number 18
- Slide Number 19
- תיאור מקרה
- Slide Number 21
- Slide Number 22
- Slide Number 23
- Slide Number 24
- Slide Number 25
- Slide Number 26
- Slide Number 27
- Slide Number 28
- Slide Number 29
- Slide Number 30
- ATTRACT study
- Slide Number 32
- Slide Number 33
- Slide Number 34
- Slide Number 35
- Slide Number 36
- תיאור מקרה
- Diagnosis of PE
- Slide Number 39
- Slide Number 40
- Slide Number 41
- Slide Number 42
- Slide Number 43
- Slide Number 44
- Slide Number 45
- תיאור מקרה
- Slide Number 47
- Slide Number 48
- Diagnosis of PE
- Diagnosis of PE
- Slide Number 51
- Slide Number 52
- Slide Number 53
- Slide Number 54
- Slide Number 55
- Slide Number 56
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- Slide Number 62
- Slide Number 63
- Slide Number 64
- Slide Number 65
- Slide Number 66
- Slide Number 67
- Slide Number 68
- Slide Number 69
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- Slide Number 74
- Slide Number 75
- Slide Number 76
- Slide Number 77
- Slide Number 78
- Slide Number 79
- Slide Number 80
- Slide Number 81
- Cancer associated thrombosis (CAT) is unique
- Slide Number 83
- Cancer patients
- Cancer patients
- Cancer patients
- Cancer patients Cancer-associated theombosis (CAT)
- Edoxaban - CAT
- Cancer patients
- Slide Number 90
- Slide Number 91
- Slide Number 92
- Venous Function
- Valve Thrombosis
- Circulatory Stasis
- Slide Number 96
- Padua Score
- Slide Number 98
- Slide Number 99
- Slide Number 100
- Slide Number 101
- Slide Number 102
- Slide Number 103
- Slide Number 104
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Thrombophilia
- Slide Number 111
- Slide Number 112
- Inherited Thrombophilia
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
-
Malignancy bull Cancer bull Cancer therapy
AI diseases bull IBD RA SLE ITP bull Nephrotic syndrome
Acquired Risk Factors for VTE
Hematology bull MPD bull PNH
Trauma bull Trauma bull Surgery
bull Varicose veins
Hormones related
bull Estrogen OC bull HRT bull Estrogen RM
Immobilization bull Sitting bull Travel (Car Train) bull Long flights
Acute illness bull Heart Resp failure bull Stroke MI
bull Pregnancy bull Obesity bull Aging
bull Venous Catheter
Inherited Thrombophilia
11
156
217
7765
34725108
0
5
10
15
20
25
Controls
FVLPTM PS PC
FVLPTM ++
Combined AT
Relative Risk for 1st VTE in carriers
Rates per 1000Y
27 48
02 04
002
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
diams Late 2nd or 3rd trimester fetal loss
diams Neonatal purpura fulminant (PC PS) Skin necrosis
The ldquothresholdrdquo concept
- Slide Number 1
- Slide Number 2
- Slide Number 3
- תיאור מקרה
- Modified Wellrsquos criteria
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Slide Number 9
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- Slide Number 15
- Slide Number 16
- Slide Number 17
- Slide Number 18
- Slide Number 19
- תיאור מקרה
- Slide Number 21
- Slide Number 22
- Slide Number 23
- Slide Number 24
- Slide Number 25
- Slide Number 26
- Slide Number 27
- Slide Number 28
- Slide Number 29
- Slide Number 30
- ATTRACT study
- Slide Number 32
- Slide Number 33
- Slide Number 34
- Slide Number 35
- Slide Number 36
- תיאור מקרה
- Diagnosis of PE
- Slide Number 39
- Slide Number 40
- Slide Number 41
- Slide Number 42
- Slide Number 43
- Slide Number 44
- Slide Number 45
- תיאור מקרה
- Slide Number 47
- Slide Number 48
- Diagnosis of PE
- Diagnosis of PE
- Slide Number 51
- Slide Number 52
- Slide Number 53
- Slide Number 54
- Slide Number 55
- Slide Number 56
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- Slide Number 62
- Slide Number 63
- Slide Number 64
- Slide Number 65
- Slide Number 66
- Slide Number 67
- Slide Number 68
- Slide Number 69
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- Slide Number 74
- Slide Number 75
- Slide Number 76
- Slide Number 77
- Slide Number 78
- Slide Number 79
- Slide Number 80
- Slide Number 81
- Cancer associated thrombosis (CAT) is unique
- Slide Number 83
- Cancer patients
- Cancer patients
- Cancer patients
- Cancer patients Cancer-associated theombosis (CAT)
- Edoxaban - CAT
- Cancer patients
- Slide Number 90
- Slide Number 91
- Slide Number 92
- Venous Function
- Valve Thrombosis
- Circulatory Stasis
- Slide Number 96
- Padua Score
- Slide Number 98
- Slide Number 99
- Slide Number 100
- Slide Number 101
- Slide Number 102
- Slide Number 103
- Slide Number 104
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Thrombophilia
- Slide Number 111
- Slide Number 112
- Inherited Thrombophilia
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
-
Inherited Thrombophilia
11
156
217
7765
34725108
0
5
10
15
20
25
Controls
FVLPTM PS PC
FVLPTM ++
Combined AT
Relative Risk for 1st VTE in carriers
Rates per 1000Y
27 48
02 04
002
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
diams Late 2nd or 3rd trimester fetal loss
diams Neonatal purpura fulminant (PC PS) Skin necrosis
The ldquothresholdrdquo concept
- Slide Number 1
- Slide Number 2
- Slide Number 3
- תיאור מקרה
- Modified Wellrsquos criteria
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Slide Number 9
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- Slide Number 15
- Slide Number 16
- Slide Number 17
- Slide Number 18
- Slide Number 19
- תיאור מקרה
- Slide Number 21
- Slide Number 22
- Slide Number 23
- Slide Number 24
- Slide Number 25
- Slide Number 26
- Slide Number 27
- Slide Number 28
- Slide Number 29
- Slide Number 30
- ATTRACT study
- Slide Number 32
- Slide Number 33
- Slide Number 34
- Slide Number 35
- Slide Number 36
- תיאור מקרה
- Diagnosis of PE
- Slide Number 39
- Slide Number 40
- Slide Number 41
- Slide Number 42
- Slide Number 43
- Slide Number 44
- Slide Number 45
- תיאור מקרה
- Slide Number 47
- Slide Number 48
- Diagnosis of PE
- Diagnosis of PE
- Slide Number 51
- Slide Number 52
- Slide Number 53
- Slide Number 54
- Slide Number 55
- Slide Number 56
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- Slide Number 62
- Slide Number 63
- Slide Number 64
- Slide Number 65
- Slide Number 66
- Slide Number 67
- Slide Number 68
- Slide Number 69
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- Slide Number 74
- Slide Number 75
- Slide Number 76
- Slide Number 77
- Slide Number 78
- Slide Number 79
- Slide Number 80
- Slide Number 81
- Cancer associated thrombosis (CAT) is unique
- Slide Number 83
- Cancer patients
- Cancer patients
- Cancer patients
- Cancer patients Cancer-associated theombosis (CAT)
- Edoxaban - CAT
- Cancer patients
- Slide Number 90
- Slide Number 91
- Slide Number 92
- Venous Function
- Valve Thrombosis
- Circulatory Stasis
- Slide Number 96
- Padua Score
- Slide Number 98
- Slide Number 99
- Slide Number 100
- Slide Number 101
- Slide Number 102
- Slide Number 103
- Slide Number 104
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Thrombophilia
- Slide Number 111
- Slide Number 112
- Inherited Thrombophilia
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
-
11
156
217
7765
34725108
0
5
10
15
20
25
Controls
FVLPTM PS PC
FVLPTM ++
Combined AT
Relative Risk for 1st VTE in carriers
Rates per 1000Y
27 48
02 04
002
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
diams Late 2nd or 3rd trimester fetal loss
diams Neonatal purpura fulminant (PC PS) Skin necrosis
The ldquothresholdrdquo concept
- Slide Number 1
- Slide Number 2
- Slide Number 3
- תיאור מקרה
- Modified Wellrsquos criteria
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Slide Number 9
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- Slide Number 15
- Slide Number 16
- Slide Number 17
- Slide Number 18
- Slide Number 19
- תיאור מקרה
- Slide Number 21
- Slide Number 22
- Slide Number 23
- Slide Number 24
- Slide Number 25
- Slide Number 26
- Slide Number 27
- Slide Number 28
- Slide Number 29
- Slide Number 30
- ATTRACT study
- Slide Number 32
- Slide Number 33
- Slide Number 34
- Slide Number 35
- Slide Number 36
- תיאור מקרה
- Diagnosis of PE
- Slide Number 39
- Slide Number 40
- Slide Number 41
- Slide Number 42
- Slide Number 43
- Slide Number 44
- Slide Number 45
- תיאור מקרה
- Slide Number 47
- Slide Number 48
- Diagnosis of PE
- Diagnosis of PE
- Slide Number 51
- Slide Number 52
- Slide Number 53
- Slide Number 54
- Slide Number 55
- Slide Number 56
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- Slide Number 62
- Slide Number 63
- Slide Number 64
- Slide Number 65
- Slide Number 66
- Slide Number 67
- Slide Number 68
- Slide Number 69
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- Slide Number 74
- Slide Number 75
- Slide Number 76
- Slide Number 77
- Slide Number 78
- Slide Number 79
- Slide Number 80
- Slide Number 81
- Cancer associated thrombosis (CAT) is unique
- Slide Number 83
- Cancer patients
- Cancer patients
- Cancer patients
- Cancer patients Cancer-associated theombosis (CAT)
- Edoxaban - CAT
- Cancer patients
- Slide Number 90
- Slide Number 91
- Slide Number 92
- Venous Function
- Valve Thrombosis
- Circulatory Stasis
- Slide Number 96
- Padua Score
- Slide Number 98
- Slide Number 99
- Slide Number 100
- Slide Number 101
- Slide Number 102
- Slide Number 103
- Slide Number 104
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Thrombophilia
- Slide Number 111
- Slide Number 112
- Inherited Thrombophilia
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
-
Blood 20091135314
Unaffected (no defect)
AT
PC
PS
PT
FVL
FVL PT mutation Most carriers remain asymptomatic
PC PS AT deficiency Higher chance of thrombosis but many carriers asymptomatic
High vs low risk thrombophilia
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
diams Late 2nd or 3rd trimester fetal loss
diams Neonatal purpura fulminant (PC PS) Skin necrosis
The ldquothresholdrdquo concept
- Slide Number 1
- Slide Number 2
- Slide Number 3
- תיאור מקרה
- Modified Wellrsquos criteria
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Slide Number 9
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- Slide Number 15
- Slide Number 16
- Slide Number 17
- Slide Number 18
- Slide Number 19
- תיאור מקרה
- Slide Number 21
- Slide Number 22
- Slide Number 23
- Slide Number 24
- Slide Number 25
- Slide Number 26
- Slide Number 27
- Slide Number 28
- Slide Number 29
- Slide Number 30
- ATTRACT study
- Slide Number 32
- Slide Number 33
- Slide Number 34
- Slide Number 35
- Slide Number 36
- תיאור מקרה
- Diagnosis of PE
- Slide Number 39
- Slide Number 40
- Slide Number 41
- Slide Number 42
- Slide Number 43
- Slide Number 44
- Slide Number 45
- תיאור מקרה
- Slide Number 47
- Slide Number 48
- Diagnosis of PE
- Diagnosis of PE
- Slide Number 51
- Slide Number 52
- Slide Number 53
- Slide Number 54
- Slide Number 55
- Slide Number 56
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- Slide Number 62
- Slide Number 63
- Slide Number 64
- Slide Number 65
- Slide Number 66
- Slide Number 67
- Slide Number 68
- Slide Number 69
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- Slide Number 74
- Slide Number 75
- Slide Number 76
- Slide Number 77
- Slide Number 78
- Slide Number 79
- Slide Number 80
- Slide Number 81
- Cancer associated thrombosis (CAT) is unique
- Slide Number 83
- Cancer patients
- Cancer patients
- Cancer patients
- Cancer patients Cancer-associated theombosis (CAT)
- Edoxaban - CAT
- Cancer patients
- Slide Number 90
- Slide Number 91
- Slide Number 92
- Venous Function
- Valve Thrombosis
- Circulatory Stasis
- Slide Number 96
- Padua Score
- Slide Number 98
- Slide Number 99
- Slide Number 100
- Slide Number 101
- Slide Number 102
- Slide Number 103
- Slide Number 104
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Thrombophilia
- Slide Number 111
- Slide Number 112
- Inherited Thrombophilia
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
-
Screening for genetic thrombophilia
Thrombophilia should not be performed in most situations Be used only if the information will influence a decision important to the patient Should not be performed during acute thrombosis or the
initial 3m of anticoagulation
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
diams Late 2nd or 3rd trimester fetal loss
diams Neonatal purpura fulminant (PC PS) Skin necrosis
The ldquothresholdrdquo concept
- Slide Number 1
- Slide Number 2
- Slide Number 3
- תיאור מקרה
- Modified Wellrsquos criteria
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Slide Number 9
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- Slide Number 15
- Slide Number 16
- Slide Number 17
- Slide Number 18
- Slide Number 19
- תיאור מקרה
- Slide Number 21
- Slide Number 22
- Slide Number 23
- Slide Number 24
- Slide Number 25
- Slide Number 26
- Slide Number 27
- Slide Number 28
- Slide Number 29
- Slide Number 30
- ATTRACT study
- Slide Number 32
- Slide Number 33
- Slide Number 34
- Slide Number 35
- Slide Number 36
- תיאור מקרה
- Diagnosis of PE
- Slide Number 39
- Slide Number 40
- Slide Number 41
- Slide Number 42
- Slide Number 43
- Slide Number 44
- Slide Number 45
- תיאור מקרה
- Slide Number 47
- Slide Number 48
- Diagnosis of PE
- Diagnosis of PE
- Slide Number 51
- Slide Number 52
- Slide Number 53
- Slide Number 54
- Slide Number 55
- Slide Number 56
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- Slide Number 62
- Slide Number 63
- Slide Number 64
- Slide Number 65
- Slide Number 66
- Slide Number 67
- Slide Number 68
- Slide Number 69
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- Slide Number 74
- Slide Number 75
- Slide Number 76
- Slide Number 77
- Slide Number 78
- Slide Number 79
- Slide Number 80
- Slide Number 81
- Cancer associated thrombosis (CAT) is unique
- Slide Number 83
- Cancer patients
- Cancer patients
- Cancer patients
- Cancer patients Cancer-associated theombosis (CAT)
- Edoxaban - CAT
- Cancer patients
- Slide Number 90
- Slide Number 91
- Slide Number 92
- Venous Function
- Valve Thrombosis
- Circulatory Stasis
- Slide Number 96
- Padua Score
- Slide Number 98
- Slide Number 99
- Slide Number 100
- Slide Number 101
- Slide Number 102
- Slide Number 103
- Slide Number 104
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Thrombophilia
- Slide Number 111
- Slide Number 112
- Inherited Thrombophilia
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
-
Screening for genetic thrombophilia
Do not perform thrombophilia following provoked VTE
A positive thrombophilia is not a sufficient basis to offer extended AC following an episode of provoked VTE
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
diams Late 2nd or 3rd trimester fetal loss
diams Neonatal purpura fulminant (PC PS) Skin necrosis
The ldquothresholdrdquo concept
- Slide Number 1
- Slide Number 2
- Slide Number 3
- תיאור מקרה
- Modified Wellrsquos criteria
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Slide Number 9
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- Slide Number 15
- Slide Number 16
- Slide Number 17
- Slide Number 18
- Slide Number 19
- תיאור מקרה
- Slide Number 21
- Slide Number 22
- Slide Number 23
- Slide Number 24
- Slide Number 25
- Slide Number 26
- Slide Number 27
- Slide Number 28
- Slide Number 29
- Slide Number 30
- ATTRACT study
- Slide Number 32
- Slide Number 33
- Slide Number 34
- Slide Number 35
- Slide Number 36
- תיאור מקרה
- Diagnosis of PE
- Slide Number 39
- Slide Number 40
- Slide Number 41
- Slide Number 42
- Slide Number 43
- Slide Number 44
- Slide Number 45
- תיאור מקרה
- Slide Number 47
- Slide Number 48
- Diagnosis of PE
- Diagnosis of PE
- Slide Number 51
- Slide Number 52
- Slide Number 53
- Slide Number 54
- Slide Number 55
- Slide Number 56
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- Slide Number 62
- Slide Number 63
- Slide Number 64
- Slide Number 65
- Slide Number 66
- Slide Number 67
- Slide Number 68
- Slide Number 69
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- Slide Number 74
- Slide Number 75
- Slide Number 76
- Slide Number 77
- Slide Number 78
- Slide Number 79
- Slide Number 80
- Slide Number 81
- Cancer associated thrombosis (CAT) is unique
- Slide Number 83
- Cancer patients
- Cancer patients
- Cancer patients
- Cancer patients Cancer-associated theombosis (CAT)
- Edoxaban - CAT
- Cancer patients
- Slide Number 90
- Slide Number 91
- Slide Number 92
- Venous Function
- Valve Thrombosis
- Circulatory Stasis
- Slide Number 96
- Padua Score
- Slide Number 98
- Slide Number 99
- Slide Number 100
- Slide Number 101
- Slide Number 102
- Slide Number 103
- Slide Number 104
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Thrombophilia
- Slide Number 111
- Slide Number 112
- Inherited Thrombophilia
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
-
Screening for genetic thrombophilia
Do not perform thrombophilia following unprovoked VTE A negative thrombophilia is not a sufficient basis to stop AC following an episode
of unprovoked VTE in a patient with low bleeding risk and willingness to continue
therapy
If a patient with unprovoked VTE and low bleeding risk is planning to stop
anticoagulation test for thrombophilia if test results would change this decision
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
diams Late 2nd or 3rd trimester fetal loss
diams Neonatal purpura fulminant (PC PS) Skin necrosis
The ldquothresholdrdquo concept
- Slide Number 1
- Slide Number 2
- Slide Number 3
- תיאור מקרה
- Modified Wellrsquos criteria
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Slide Number 9
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- Slide Number 15
- Slide Number 16
- Slide Number 17
- Slide Number 18
- Slide Number 19
- תיאור מקרה
- Slide Number 21
- Slide Number 22
- Slide Number 23
- Slide Number 24
- Slide Number 25
- Slide Number 26
- Slide Number 27
- Slide Number 28
- Slide Number 29
- Slide Number 30
- ATTRACT study
- Slide Number 32
- Slide Number 33
- Slide Number 34
- Slide Number 35
- Slide Number 36
- תיאור מקרה
- Diagnosis of PE
- Slide Number 39
- Slide Number 40
- Slide Number 41
- Slide Number 42
- Slide Number 43
- Slide Number 44
- Slide Number 45
- תיאור מקרה
- Slide Number 47
- Slide Number 48
- Diagnosis of PE
- Diagnosis of PE
- Slide Number 51
- Slide Number 52
- Slide Number 53
- Slide Number 54
- Slide Number 55
- Slide Number 56
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- Slide Number 62
- Slide Number 63
- Slide Number 64
- Slide Number 65
- Slide Number 66
- Slide Number 67
- Slide Number 68
- Slide Number 69
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- Slide Number 74
- Slide Number 75
- Slide Number 76
- Slide Number 77
- Slide Number 78
- Slide Number 79
- Slide Number 80
- Slide Number 81
- Cancer associated thrombosis (CAT) is unique
- Slide Number 83
- Cancer patients
- Cancer patients
- Cancer patients
- Cancer patients Cancer-associated theombosis (CAT)
- Edoxaban - CAT
- Cancer patients
- Slide Number 90
- Slide Number 91
- Slide Number 92
- Venous Function
- Valve Thrombosis
- Circulatory Stasis
- Slide Number 96
- Padua Score
- Slide Number 98
- Slide Number 99
- Slide Number 100
- Slide Number 101
- Slide Number 102
- Slide Number 103
- Slide Number 104
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Thrombophilia
- Slide Number 111
- Slide Number 112
- Inherited Thrombophilia
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
-
Screening for genetic thrombophilia
Do not test for thrombophilia in asymptomatic family members of patients with VTE or hereditary thrombophilia
A family history of VTE confers an excess risk of thrombosis counseled
regarding use of prophylaxis in high risk situations
J Thromb Thrombolysis 2016
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
diams Late 2nd or 3rd trimester fetal loss
diams Neonatal purpura fulminant (PC PS) Skin necrosis
The ldquothresholdrdquo concept
- Slide Number 1
- Slide Number 2
- Slide Number 3
- תיאור מקרה
- Modified Wellrsquos criteria
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Slide Number 9
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- Slide Number 15
- Slide Number 16
- Slide Number 17
- Slide Number 18
- Slide Number 19
- תיאור מקרה
- Slide Number 21
- Slide Number 22
- Slide Number 23
- Slide Number 24
- Slide Number 25
- Slide Number 26
- Slide Number 27
- Slide Number 28
- Slide Number 29
- Slide Number 30
- ATTRACT study
- Slide Number 32
- Slide Number 33
- Slide Number 34
- Slide Number 35
- Slide Number 36
- תיאור מקרה
- Diagnosis of PE
- Slide Number 39
- Slide Number 40
- Slide Number 41
- Slide Number 42
- Slide Number 43
- Slide Number 44
- Slide Number 45
- תיאור מקרה
- Slide Number 47
- Slide Number 48
- Diagnosis of PE
- Diagnosis of PE
- Slide Number 51
- Slide Number 52
- Slide Number 53
- Slide Number 54
- Slide Number 55
- Slide Number 56
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- Slide Number 62
- Slide Number 63
- Slide Number 64
- Slide Number 65
- Slide Number 66
- Slide Number 67
- Slide Number 68
- Slide Number 69
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- Slide Number 74
- Slide Number 75
- Slide Number 76
- Slide Number 77
- Slide Number 78
- Slide Number 79
- Slide Number 80
- Slide Number 81
- Cancer associated thrombosis (CAT) is unique
- Slide Number 83
- Cancer patients
- Cancer patients
- Cancer patients
- Cancer patients Cancer-associated theombosis (CAT)
- Edoxaban - CAT
- Cancer patients
- Slide Number 90
- Slide Number 91
- Slide Number 92
- Venous Function
- Valve Thrombosis
- Circulatory Stasis
- Slide Number 96
- Padua Score
- Slide Number 98
- Slide Number 99
- Slide Number 100
- Slide Number 101
- Slide Number 102
- Slide Number 103
- Slide Number 104
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Thrombophilia
- Slide Number 111
- Slide Number 112
- Inherited Thrombophilia
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
-
Screening for genetic thrombophilia
diams Unprovoked VTE
diams Recurrent VTE
diams Positive family history
diams Unusual site of thrombosis (CSVT Mesenteric or Portal vv)
diams Reccurrent early pregnancy fetal loss (APLA)
diams Late 2nd or 3rd trimester fetal loss
diams Neonatal purpura fulminant (PC PS) Skin necrosis
The ldquothresholdrdquo concept
- Slide Number 1
- Slide Number 2
- Slide Number 3
- תיאור מקרה
- Modified Wellrsquos criteria
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Slide Number 9
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- Slide Number 15
- Slide Number 16
- Slide Number 17
- Slide Number 18
- Slide Number 19
- תיאור מקרה
- Slide Number 21
- Slide Number 22
- Slide Number 23
- Slide Number 24
- Slide Number 25
- Slide Number 26
- Slide Number 27
- Slide Number 28
- Slide Number 29
- Slide Number 30
- ATTRACT study
- Slide Number 32
- Slide Number 33
- Slide Number 34
- Slide Number 35
- Slide Number 36
- תיאור מקרה
- Diagnosis of PE
- Slide Number 39
- Slide Number 40
- Slide Number 41
- Slide Number 42
- Slide Number 43
- Slide Number 44
- Slide Number 45
- תיאור מקרה
- Slide Number 47
- Slide Number 48
- Diagnosis of PE
- Diagnosis of PE
- Slide Number 51
- Slide Number 52
- Slide Number 53
- Slide Number 54
- Slide Number 55
- Slide Number 56
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- Slide Number 62
- Slide Number 63
- Slide Number 64
- Slide Number 65
- Slide Number 66
- Slide Number 67
- Slide Number 68
- Slide Number 69
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- Slide Number 74
- Slide Number 75
- Slide Number 76
- Slide Number 77
- Slide Number 78
- Slide Number 79
- Slide Number 80
- Slide Number 81
- Cancer associated thrombosis (CAT) is unique
- Slide Number 83
- Cancer patients
- Cancer patients
- Cancer patients
- Cancer patients Cancer-associated theombosis (CAT)
- Edoxaban - CAT
- Cancer patients
- Slide Number 90
- Slide Number 91
- Slide Number 92
- Venous Function
- Valve Thrombosis
- Circulatory Stasis
- Slide Number 96
- Padua Score
- Slide Number 98
- Slide Number 99
- Slide Number 100
- Slide Number 101
- Slide Number 102
- Slide Number 103
- Slide Number 104
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Thrombophilia
- Slide Number 111
- Slide Number 112
- Inherited Thrombophilia
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
-
The ldquothresholdrdquo concept
- Slide Number 1
- Slide Number 2
- Slide Number 3
- תיאור מקרה
- Modified Wellrsquos criteria
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Slide Number 9
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- Slide Number 15
- Slide Number 16
- Slide Number 17
- Slide Number 18
- Slide Number 19
- תיאור מקרה
- Slide Number 21
- Slide Number 22
- Slide Number 23
- Slide Number 24
- Slide Number 25
- Slide Number 26
- Slide Number 27
- Slide Number 28
- Slide Number 29
- Slide Number 30
- ATTRACT study
- Slide Number 32
- Slide Number 33
- Slide Number 34
- Slide Number 35
- Slide Number 36
- תיאור מקרה
- Diagnosis of PE
- Slide Number 39
- Slide Number 40
- Slide Number 41
- Slide Number 42
- Slide Number 43
- Slide Number 44
- Slide Number 45
- תיאור מקרה
- Slide Number 47
- Slide Number 48
- Diagnosis of PE
- Diagnosis of PE
- Slide Number 51
- Slide Number 52
- Slide Number 53
- Slide Number 54
- Slide Number 55
- Slide Number 56
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- Slide Number 62
- Slide Number 63
- Slide Number 64
- Slide Number 65
- Slide Number 66
- Slide Number 67
- Slide Number 68
- Slide Number 69
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- Slide Number 74
- Slide Number 75
- Slide Number 76
- Slide Number 77
- Slide Number 78
- Slide Number 79
- Slide Number 80
- Slide Number 81
- Cancer associated thrombosis (CAT) is unique
- Slide Number 83
- Cancer patients
- Cancer patients
- Cancer patients
- Cancer patients Cancer-associated theombosis (CAT)
- Edoxaban - CAT
- Cancer patients
- Slide Number 90
- Slide Number 91
- Slide Number 92
- Venous Function
- Valve Thrombosis
- Circulatory Stasis
- Slide Number 96
- Padua Score
- Slide Number 98
- Slide Number 99
- Slide Number 100
- Slide Number 101
- Slide Number 102
- Slide Number 103
- Slide Number 104
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Thrombophilia
- Slide Number 111
- Slide Number 112
- Inherited Thrombophilia
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
-
- Slide Number 1
- Slide Number 2
- Slide Number 3
- תיאור מקרה
- Modified Wellrsquos criteria
- Slide Number 6
- Slide Number 7
- Slide Number 8
- Slide Number 9
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- Slide Number 15
- Slide Number 16
- Slide Number 17
- Slide Number 18
- Slide Number 19
- תיאור מקרה
- Slide Number 21
- Slide Number 22
- Slide Number 23
- Slide Number 24
- Slide Number 25
- Slide Number 26
- Slide Number 27
- Slide Number 28
- Slide Number 29
- Slide Number 30
- ATTRACT study
- Slide Number 32
- Slide Number 33
- Slide Number 34
- Slide Number 35
- Slide Number 36
- תיאור מקרה
- Diagnosis of PE
- Slide Number 39
- Slide Number 40
- Slide Number 41
- Slide Number 42
- Slide Number 43
- Slide Number 44
- Slide Number 45
- תיאור מקרה
- Slide Number 47
- Slide Number 48
- Diagnosis of PE
- Diagnosis of PE
- Slide Number 51
- Slide Number 52
- Slide Number 53
- Slide Number 54
- Slide Number 55
- Slide Number 56
- Slide Number 57
- Slide Number 58
- Slide Number 59
- Slide Number 60
- Slide Number 61
- Slide Number 62
- Slide Number 63
- Slide Number 64
- Slide Number 65
- Slide Number 66
- Slide Number 67
- Slide Number 68
- Slide Number 69
- Slide Number 70
- Slide Number 71
- Slide Number 72
- Slide Number 73
- Slide Number 74
- Slide Number 75
- Slide Number 76
- Slide Number 77
- Slide Number 78
- Slide Number 79
- Slide Number 80
- Slide Number 81
- Cancer associated thrombosis (CAT) is unique
- Slide Number 83
- Cancer patients
- Cancer patients
- Cancer patients
- Cancer patients Cancer-associated theombosis (CAT)
- Edoxaban - CAT
- Cancer patients
- Slide Number 90
- Slide Number 91
- Slide Number 92
- Venous Function
- Valve Thrombosis
- Circulatory Stasis
- Slide Number 96
- Padua Score
- Slide Number 98
- Slide Number 99
- Slide Number 100
- Slide Number 101
- Slide Number 102
- Slide Number 103
- Slide Number 104
- Slide Number 105
- Slide Number 106
- Slide Number 107
- Slide Number 108
- Slide Number 109
- Thrombophilia
- Slide Number 111
- Slide Number 112
- Inherited Thrombophilia
- Slide Number 114
- Slide Number 115
- Slide Number 116
- Slide Number 117
- Slide Number 118
- Slide Number 119
- Slide Number 120
- Slide Number 121
- Slide Number 122
- Slide Number 123
-