vte: a practical approachimcourseonline.com/files/updated2017files/m_02_0800_updated_g… · 2016...
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VTE: A PRACTICAL APPROACH
Samuel Z. Goldhaber, MDSection Head, Vascular Medicine
Director, Thrombosis Research GroupCardiovascular Division
Brigham and Women’s HospitalProfessor of Medicine
Harvard Medical SchoolJune 5, 2017
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DISCLOSURESResearch Support:
BiO2 Medical; Boehringer-Ingelheim; BMS; BTG EKOS; Daiichi; Janssen; NHLBI; Thrombosis Research Institute
Consultant:Agile; Bayer; Boehringer-Ingelheim; BMS; Daiichi; Janssen; Portola; Zafgen
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LEARNING OBJECTIVES1) Epidemiology
2) Risk Factors
3) NOAC Efficacy and Safety for VTE
4) Optimal Duration of Anticoagulation
5) Inflammation and aspirin
6) Psychological Impact of VTE
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FATAL SADDLE PE: 41 y.o. woman with sudden collapse
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Stroke
PE
AHA 2016 STATISTICS: PE IS THE #3 CAUSE OF CV DEATH
(Circulation 2016; 133: e38-e360)
MI
PE
STROKE
Up to180,000 PE deaths/year
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VTE INCIDENCE: INCREASING
140
120
100
80
60
40
20
085/86/88/89//199920012003200520072009
First-Time OccurrenceAn
nualEventRate,
per1
00,000
7381
95106 103 105
119
133
4958
6568 68
5460
68
24 2330
37 35
5059 65
VTE
DVTPE
(Huang W. Am J Med 2014; 127: 829-839)
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DECLINING PE MORTALITY, HIGH READMISSION RATES
(Minges KE. Am J Cardiol 2015; 116: 1436-1442)
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CARDIOVASCULAR RISK FACTORS AND VTE
(N=63,552 meta-analysis)RF RRObesity 2.3Hypertension 1.5Diabetes 1.4Cigarettes 1.2High Cholesterol 1.2
(Ageno W. Circulation 2008; 117: 93-102)
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HOSPITALIZATION FOR SYNCOPE (N=560): THINK OF PE (17% !!!)
HOSPITALIZATION with SYNCOPE PE %All patients 17%No alternative explanation 25%Alternative explanation for syncope 13%Wells Score “likely” (> 4 Wells Score Points) or elevated D-dimer 42%PE in main pulmonary artery 42%
(Prandoni P. NEJM 2016; 375: 1524-1531)
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VTE-INFLAMMATION LINK:RISK FACTORS
1) Pneumonia
2) Inflammatory bowel disease
3) Psoriasis
4) Systemic lupus erythematosus
5) ESRD/ Dialysis
6) Blood transfusion (preservatives)
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PSORIASIS: VTE RISK FACTOR
(Chung W-S. Thromb Haemost 2017; 117: in press)
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GENETIC RISK FACTORS
1) Factor V Leiden
2) Prothrombin Gene Mutation
3) Deficiency of protein C, S, or
antithrombin
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ACQUIRED RISK FACTORAntiphospholipid Antibody Syndrome
• Predisposes to MI, Stroke, PE• Predicts high risk of a recurrent
event if anticoagulation is discontinued
―Lupus Anticoagulant―Anticardiolipin Antibodies―Beta-2-Glycoprotein―Antiprothrombin
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ANTICOAGULATION:
THE FOUNDATION OF PE TREATMENT
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ACUTE VTE TREATMENT: NOAC EFFICACY
(van Es N, et al. Blood 2014; 124: 1968-1975)
(van Es N, et al. Blood 2014; 124: 1968-1975)
NOACs: noninferior to warfarin
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NOACs: 39% lower major bleeding 64% lower fatal bleeding, 63% less ICH than warfarin
ACUTE VTE TREATMENT: NOAC SAFETY (N=27,235)
(van Es N, et al. Blood 2014; 124: 1968-1975)
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2016 CHEST/ ACCP GUIDELINES FOR VTE
“Based on less bleeding with NOACs and greater convenience for patients and healthcare providers, we now suggest that a NOAC be used in preference to warfarin for the initial and long-term treatment of VTE.”. (CHEST 2016; 149: 315-352)
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NOAC DOSE Dabigatran 150 mg twice daily, starting after
5 days of LMWHRivaroxaban 15 mg twice daily for 3 weeks;
then 20 mg daily with dinnerApixaban 10 mg twice daily for 1 week;
then 5 mg twice daily; after 6 months, switch to ExtendedDuration Dose: 2.5 mg BID
Edoxaban 60 mg once daily, except for 30 mg daily with low GFR or weight
DOSING NOACS FOR PE
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OBJECTIVE NOACAntidote Dabigatran
Minimize Inflammation (heparin loading)
Dabigatran/ Edoxa
Minimize Bleeding Apixaban
Submassive PE Edoxaban
Severe CKD Apixaban
Once Daily Dosing Rivaroxaban/ Edoxaban
All Oral Therapy Rivaroxaban/ Apixaban
DIFFERENTIATING NOACS
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ANTIDOTES TO NOACSIdarucizumabTarget: DabigatranStructure: Humanized antibody fragment (FAb) to dabigatran; FDA approved in October 2015 (NEJM 2015; 373: 511-520)
Andexanet alpha Target: FXa inhibitorsStructure: FXa lacking catalytic & binding activity;This decoy looks like FXa. Antidote for rivaroxaban, apixaban, edoxaban
(NEJM 2016; 375:1131-1141)
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OPTIMAL DURATION:
ANTICOAGULATION
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1) VTE is mostly a chronic inflammatory disease, like MI or diabetes mellitus.2) VTE does not disappear after 3 months of anticoagulation. 3) VTE lurks subclinically, waiting
to recur.4) VTE requires lifelong attention to risk factor reduction with heart-healthy lifestyles (exercise, nutrition) and medication.
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(Prandoni.Haematolo-gica 2007; 92: 199-205)
(N=1,626 DVT patients)
High VTE RecurrenceRate
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LONG-TERM VTE MORTALITY
• Danish cohort: 128,223 VTE vs. 640,760 general population patients
• 30-year follow-up• VTE patients: inc’d death rate X 30 y• Most common cause of death: VTE
(Sogaard KK. Circulation 2014; epub June 26)
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PADIS-PE: 6 VERSUS 24 MONTHS OF WARFARIN
• 373 unprovoked PE patients• Goals: 1) prevent recurrent PE after
additional 18 months of warfarin compared with 6 month group, and to 2) compare recurrent PE rates in both groups, 2 years after completing warfarin therapy in all patients
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24 MONTHS VS. 6 MONTHS OF WARFARIN: PE
(PADIS-PE. JAMA 2015; 314: 31-40)
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PADIS-PE: 6 VERSUS 24 MONTHS OF WARFARIN
• Benefit of 18 additional months of warfarin is not maintained following cessation of warfarin.
• The group in which extended warfarin is completed develops new PE at a rate twice as high as the group that never had extended warfarin, suggesting a rebound effect.
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LONG VS SHORT-TERM VKA FOR VTE (N=3,716)—80% Reduction in
Recurrence
(Middeldorp S. JAMA 2015; 314: 72-73)
X 3.4 more major bleeds
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NOACS VS. PLACEBO: EXTENDED VTE TREATMENT
RE-SONATE
Dabigatran vs. placebo
↓92%
EINSTEIN-EXT
Rivaroxaban vs. placebo
↓82%
AMPLIFY-EXT
Apixaban vs. placebo
↓81%
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CHEST ACCP GUIDELINES 2016: DURATION OF RX
If unprovoked with low to moderate bleeding risk, we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B). If provoked by surgery or a nonsurgical transient risk factor, anticoagulate for 3 months (Grade 1B).
(CHEST 2016; 149: 315-352)
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EINSTEIN CHOICE: LONG-TERM PREVENTION OF
RECURRENT VTE
(Weitz JI. Thromb Haemost 2015; 114: 645-650)
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Both Rivaroxaban Doses Reduced Recurrent VTE Rates with Similar Risk of Bleeding versus ASA
Efficacy
(Weitz JI. NEJM 2017; 376: 1211-1222)
0
1
2
4
5
3
Days‡
ASA 100 mg od
Rivaroxaban 20 mg odRivaroxaban 10 mg od
1 30 60 90 120 150 180 210 240 270 300 330 360
Cum
ulat
ive
inci
denc
e (%
)
Rivaroxaban 20 mg vs ASA(0.5%) vs (0.3%)HR=2.01 (95% CI 0.50–8.04), p=0.32
Rivaroxaban 10 mg vs ASA(0.4%) vs (0.3%)HR=1.64 (95% CI 0.39–6.84), p=0.50
Major bleeding
ASA 100 mg od
Rivaroxaban 20 mg od
Rivaroxaban 10 mg od
Days
0
1
2
3
4
5
Cum
ulat
ive
inci
denc
e (%
)
1 30 60 90 120 150 180 210 240 270 300 330 367
Riva 20 mg vs ASA (1.5%) vs (4.4%)HR=0.34 (95% CI 0.20–0.59), p<0.001
Riva 10 mg vs ASA (1.2%) vs (4.4%)HR=0.26 , p<0.001
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RECURRENT VTE:PROVOKED vs UNPROVOKED
Riva 20 mg
Riva 10 mg ASA 100 mg
Provoked 1.4% 0.9% 3.6%
Unprovoked 1.8% 1.5% 5.6%
(Weitz JI. NEJM 2017; 376: 1211-1222)
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SPECIAL CONTRIBUTIONS OF EINSTEIN CHOICE
• Largest Extension Study ever of VTE (N=3,396 randomized patients)
• Largest Extension Study ever of Provoked VTE (N=1,976; 59%)
• Rivaroxaban: equally effective in recurrent VTE risk reduction (70%) in both provoked/ unprovoked VTE
(Weitz JI. NEJM 2017; 376: 1211-1222)
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CASE #1• 42 y.o. man suffers symptomatic
bilateral PE, despite enoxaparin prophylaxis, on Hospital Day #3, following gastric bypass surgery.
• No past history or family history of VTE
• Hypercoagulability workup is negative• How long do you anticoagulate?
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CASE #2• 23 y.o. woman suffers symptomatic
bilateral PE, 8 months after starting a third-generation estrogen-containing birth control pill.
• No past history or family history of VTE
• Hypercoagulability workup is negative• How long do you anticoagulate?
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PATHOPHYSIOLOGY/
INFLAMMATION
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PE: FILLED WITH WBCs and PLATELETS—INFLAMMATION
(Savchenko AS.J Thromb Haemostas2014; 12: 860-870)
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HEPARIN BLOCKS THE SYSTEMIC INFLAMMATORY
RESPONSE TO THROMBOSIS
(Poterucha T, Libby P, Goldhaber SZ. Thrombosisand Haemostasis 2017; 117: 437-444)
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THROMBIN-INDUCED
INFLAMMATION LEADS TO
THROMBOSIS(Croce K, Libby P. Intertwining of thrombosis and inflammation in atherosclerosis. Curr Opin Hematol 2007;14: 55)
Aspirin
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Effects of aspirin treatment on recurrent venous thromboembolism and other outcomes after adjustment for baseline characteristics: age (<50 years, 50–65, ≥65), sex (male vs female), qualifying event (deep-vein thrombosis only vs pulmonary embolism with or without deep-
vein thrombosis), body mass index (normal, overweight, obese) and duration of anticoagulation (<6, 6–9, ≥9 months).
Simes J et al. Circulation. 2014;130:1062-1071
Copyright © American Heart Association, Inc. All rights reserved.
LOW-DOSE ASPIRIN: 35% LESS VTE
(Circulation 2014; 130: 1062-1071)
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PE AND DVT:
PSYCHOLOGICAL IMPACT AND LACK
OF PUBLIC AWARENESS
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RX OF ANTIPSYCHOTIC, ANXIOLYTIC, SEDATIVE, AND ANTIDEPRESSANT DRUGS TO YOUNG VTE PATIENTS
(Hojen AA. Thrombosis Research 2015; 135: 643-647)
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THEMES FROM OUR PE SUPPORT GROUP (patients regionally referred) • Anger at delay in diagnosis• Feeling well, looking well, yet
harboring a major illness• Yearning for an answer to “why me?”• Protection of family members• Optimal duration of anticoagulation• NOAC versus VKA
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CODE PE: ROOM #1 (ALPHA) IN ED; “MASSIVE PE ON 10
OF LEVOPHED”• 62 y.o. woman awakened and
became dizzy, cold, sweaty, SOB, and faint while sitting on the toilet
• Called RN daughter who called 911• On low-dose aspirin VTE prophylaxis
for nondisplaced fibula fracture 10 days ago after a fall
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PRESENTATION TO ED• Markedly SOB; gasping, pale,
diaphoretic; RR=30/min; BP=70/ to 82/56 mm Hg; HR=134/min; O2 sat=89% RA; 98 kg (obese)
• PMH: Hypertension; Hyperlipidemia; no PE/ DVT; quit cigs 9 years ago
• Meds: Atenolol 25 mg/d; HCTZ 25 mg/d; simvastatin 40 mg/d
• FH: PGM had DVT; father d. MI-50s
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MANAGEMENT IN ED• TnT=0.06 U; WBC=15.4K;
Gluc=233; Creat=1.0; GFR=55; AST=137; Lactic Acid=4.5
• Levophed titrated up to 10 mcg/min; BP now 117/78 mm Hg
• IV heparin bolus 80 U/kg given• Bedside ECHO: Marked RV
dilatation/ HK; septum bows to LA; positive McConnell’s sign
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PE RESPONSE TEAM (PERT)PERTTeamActivationviaPagingSystem
PERTEvaluationbyOn-CallPhysician
Web-BasedVideoConference
DiscussionandConsensus
VascularMedicine
InterventionalCardiology
PulmonaryCriticalCare
Echocardiography
CardiothoracicSurgery
Radiology
OptionsandRecommendationsPresentedtothePatient,Family,andCareTeam
ACTION
(Dudzinski D, Piazza G. Circulation 2016; 133: 98-103)
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WHAT IS THE VERY
NEXT THING YOU
RECOMMEND DOING
AT THIS POINT?
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“VERY NEXT STEP” OPTIONS THAT WE DISCUSSED)
1) Begin heparin continuous IV infusion at 18 U/kg/h
2) Chest CT scan, with contrast3) EKOS with TPA 24 mg total dose4) TPA 100 mg/ 2h via peripheral IV5) Surgical pulmonary embolectomy6) Something else (none of the above)
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LYSIS CHOICES FOR PE1) Systemically administered (via
peripheral IV) thrombolysis:FDA Full Dose (TPA 100 mg)MOPETT Half Dose (TPA 50 mg)
2) Pharmacomechanical therapy with catheter-directed (ultrasound-facilitated) thrombolysis: TPA 24 mg
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WHAT WE DID (in collaboration with ED and pt)1) Begin heparin continuous IV
infusion at 10 U/kg/h, not 18 U/kg/h2) Ordered chest CT (in the queue)3) Decided on systemic lysis with
“half-dose TPA”, using MOPETT regimen
4) TPA 10 mg/ 1 min via peripheral IV5) TPA 40 mg/2h
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CLINICAL COURSE IN ED1) CCU bed reserved; transferred 2h
later, after CT was done.2) All symptoms of respiratory distress
resolved prior to her CT scan.3) Levophed was weaned.4) She felt “90% back to normal” prior
to discharge from ED.5) No bleeding, not even slight oozing,
at IV or phlebotomy puncture sites
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TPA 10mg/1 min followed by 40 mg/2 hNo bleeding complications/ no ICHPA Pressure (ECHO) lower with TPA
(Am J Cardiology 2013; 111: 273-277)
SUBMASSIVE PE: 50 mg TPA versus heparin (MOPETT) (N=121)
TPA PA systolic Controls P valueAdmission 50 51 0.4Within 48h 34 41 < 0.0016 months 31 49 < 0.00128 months 28 43 < 0.001
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HEPARIN DOSING: MOPETT• Patients are almost always on
heparin when decision is made to proceed with MOPETT-TPA
• Reduce heparin infusion to 10U/Kg/h• PTT at 6h; target: 60-100 seconds;
increase heparin by increasing infusion rate; do not bolus heparin
• Stop heparin at 24h and start NOAC
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Case PresentationThis 29 year old man with compound heterozygous Factor V Leiden and prothrombin gene mutation suffered a large R proximal vein DVT. He was treated with enoxaparin 120 mg twice daily for 5 days, followed by dabigatran 150 mg twice daily thereafter.
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NO COMPRESSION COMPRESSION
FA FV FAFV
ACUTE DVT in a 29 y.o. man
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DEFENDING A YOUNG LADYHe likes playing “pool” at the local bar and belongs to a competitive “pool league” that meets at the bar.He noted from the corner of his eye that a man in the bar was becoming increasingly rough and was starting to push and shake a female customer.He stepped in between the two of them to protect her.
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NO GOOD DEED SHALL GO UNPUNISHED
She escapes harm.However, a few minutes later, he is surrounded by a group of thugs. They stab him repeatedly in the L chest. He bled profusely. They leave him for dead and flee the bar. (They are subsequently arrested and imprisoned.)
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LEFT HEMOTHORAX
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Labs at the time of Admission
• HCT=27%•aPTT=62 seconds
The Thoracic Surgical Team recommends Emergency Surgery, with evacuation of the hematoma.
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QUESTION #1• To control bleeding within thoracic cavity, you recommend:A) “Tincture of Time” to allow
dabigatran to be metabolizedB) Fresh Frozen PlasmaC) Vitamin KD) Dabigatran Antibody: IdarucizumabE) Prothrombin Complex Concentrate
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TAKE HOME MESSAGES1. PE: #3 CV killer, with a 15%
Medicare readmission rate w/in 30d2. PE incidence is increasing.3. VTE is a chronic inflammatory
disease with a high recurrence rate after cessation of anticoagulation.
4. NOACs are much safer than warfarin, and NOACs are preferred by ACCP/ CHEST Guidelines.