fibrinogen fibrin common pathway thrombin xa prothrombin clot xa blocker apixaban rivaroxaban...
DESCRIPTION
Treatment VTE UFH, LMWH Bridge to WarfarinTRANSCRIPT
Fibrinogen Fibrin
Common Pathway
Thrombin
Xa
Prothrombin
Clot
Xa Blocker
ApixabanRivaroxaban
Dabigatran
New Oral Agents
Replacing Traditional Anticoagulants
Treatment VTEUFH, LMWH Bridge to Warfarin
Schulman S, et al NEJM 2009;361:2342-2352
RE-COVER Study
Dabigatran 150 mg, BID for 6 monthsDouble Blind, Double Dummy, Non-Inferiority
RE-COVER Study
VTE
Dabigatran 150 mg, BID
Warfarin INR 2-3
Parenteral AnticoagulantMedian 9 days
2.4% 1.6%
2.1% 1.9%
VTE Major Bld
Schulman S, et al NEJM 2009;361:2342-2352
6 months
Warfarin TTR= 60%
RE-COVER StudyIndex Events
Schulman S, et al NEJM 2009;361:2342-2352
Dabi1273
Warfarin1266
RE-COVER StudyMajor Bleeding
Schulman S, et al NEJM 2009;361:2342-2352
Dabi Warfarin
RE-COVERA limitation of the study is that the first
dose of dabigatran, was given only after initial parenteral anticoagulation therapy had been administered for median of 9 days
“There is no data to support the use of dabigatran monotherapy for acute venous thromboembolism”
Schulman S, et al NEJM 2009;361:2342-2352
Einstein Investigators NEJM 2010;363:2499-2510
Rivaroxaban 15 mg, PO, BID x 3 weeks then 20mg, QdayEnoxaparin 1mg/kg/Q12hrs bridge to Warfarin INR 2-3
Open Label, Non-Inferiority trial
Einstein DVT
DVT
Rivaroxaban15 mg, BID x 3 wks
20 mg, Qday
EnoxaparinWarfarin INR 2-3
Proximal DVT
2.1% 8.1%
3.0% 8.1%
VTE Major Bld
3, 6, 12 months
Einstein Investigators NEJM 2010;363:2499-2510
Warfarin TTR = 57.7%
Einstein Acute DVT StudyCauses of VTE
Riva Standard
Einstein Investigators NEJM 2010;363:2499-2510
Einstein Acute DVT StudySafety Outcomes
Einstein Investigators NEJM 2010;363:2499-2510
Riva Standard
Einstein Investigators NEJM 2012;366:1287-1297
Rivaroxaban 15 mg, PO, BID x 3 weeks then 20mg, QdayEnoxaparin 1mg/kg/Q12hrs bridge to Warfarin INR 2-3
Open Label, Non-Inferiority
Einstein PE
PE
Rivaroxaban15 mg, BID x 3 wks
20 mg, Qday
EnoxaparinWarfarin INR 2-3
2.1% 1.1%
1.8% 2.2%
VTE Major Bld
3, 6, 12 months
Einstein-PE Investigators NEJM 2012;366:1287-1297
Warfarin TTR = 62.7%
Non-Inferior
Einstein PECauses
Einstein Investigators NEJM 2012;366:1287-1297
Riva Standard
Einstein PEAnatomical Extent
Einstein Investigators NEJM 2012;366:1287-1297
Riva Standard
ED - OBS
History & PhysicalLaboratory Testing
Diagnosis DVTSelect Treatment
Hospital Admission OBS Discharge Plan
Secure Rx Communication Follow Up
Acquire Med
Pt Education
Contact PCP
D/C Summary
Phone call 24 hrs
Appointment 3-5 days
Discharge OBS
Your patient who has been on long term warfarin would like to convert to one of the new oral
anticoagulant.
Einstein Investigators NEJM 2010;363:2499-2510
Rivaroxaban 15 mg, PO, BID x 3 weeks then 20mg, QdayEnoxaparin 1mg/kg/Q12hrs bridge to Warfarin INR 2-3
Open Label, Non-Inferiority trial
Einstein DVT-Extend
DVT
Rivaroxaban20 mg, Qday
Placebo
1.3% 0.7%
7.1% 0%
VTE Major Bld
3, 6, 12 mo
Einstein Investigators NEJM 2010;363:2499-2510
6-12 mo
All Rxed
Schulman S, et al NEJM 2013;368:709-718
Double Blind, Randomized Trial
RE-MEDY
VTE
Dabigatran 150 mg, BID
Warfarin INR 2-3
Patient Rx3 to 12 months
1.8% 0.9%
1.3% 1.8%
VTE Major Bld
Schulman S, et al NEJM 2013;368:709-718
6 months
RE-SONATE
DVT
Dabigatran 150 mg, BID
Placebo
Patient Rx6 to 18 months
0.4% 0.3%
5.6% 0%
VTE Major Bld
Schulman S, et al NEJM 2013;368:709-718
6-18 months
Schulman S, et al NEJM 2013;368:709-718
RE-SONATE Study
Agnelli G, et al NEJM 2012;1-10
AMPLIFY-EXT
VTE
Rx 6-12 mo
Apixaban 2.5 mg, BID
Apixaban 5.0 mg, BID
Placebo
12 months
VTE Major Bld1.7% 0.2%
1.7% 0.1%
8.8% 0.5%
Agnelli G, et al NEJM 2013;368(8):699-708
AMPLIFY-EXT
Apixaban 2.5 Apixaban 5 Placebo
Agnelli G, et al NEJM 2013;368(8):699-708
Warfarin to NOAC
Agent Recommendation
Rivaroxaban Start when INR < 3.0 (we recommend < 2.0)
Apixaban Start when INR < 2.0
Dabigatran Start when INR < 2.0
NOAC= New Oral Anticoagulants
Non-Valvular Atrial Fibrillation
Atrial Fibrillation StudiesTrial RE-LY ARISTOTLE ROCKET-AF
Design Randomized Open LabelN=18,113
Randomized Double blindN=18,209
Randomized double blind & dummyN=14,000
Treatment Dabigatran150 mg, BID110 mg, BID
Apixaban5 mg, BID
Rivaroxaban20 mg, Qday
Comparator Warfarin 2-3(67% TTR)
Warfarin 2-3(66% TTR)
Warfarin 2-3(57.8% TTR)
Mean CHADS2 2.1 2.1 3.5
Modified Ahrens I, et al Thromb Haemost 2011;105
Time Therapeutic Range = TTR
Primary EndpointsAtrial Fibrillation Trials
Study NOAC VKA Outcome
RE-LY Dabigatran1.1%
Warfarin1.7%
RR 0.6695% CI 0.53-0.82
P < 0.001 superiority
ARISTOTLE Apixaban1.3%
Warfarin1.6%
HR 0.7995% CI 0.66-0.95P= < 0.001 Non- I
P= 0.01 Superiority
ROCKET-AF Rivaroxaban1.7%
Warfarin2.2%
HR 0.7995% CI 0.66-0.96
P = <0.001Non-Inferiority
Major BleedingAtrial Fibrillation Trials
Study NOAC VKA Outcome
RE-LY Dabigatran3.3%
Warfarin3.6%
RR 0.9395% CI 0.81-1.07
P = 0.31ARISTOTLE Apixaban
2.1%Warfarin3.1%
HR 0.6995% CI 0.60-0.8
P = < 0.001ROCKET-AF Rivaroxaban
5.6%Warfarin5.4%
HR 1.0495% CI 0.90-1.20
P = 0.58
Intracranial HemorrhageAtrial Fibrillation Trials
Study NOAC VKA Outcome
RE-LY Dabigatran0.3%
Warfarin0.7%
RR 0.4095% CI 0.27-0.60
P= <0.001ARISTOTLE Apixaban
0.3%Warfarin0.8%
HR 0.4295% CI 0.30-0.58
P = <0.001ROCKET-AF Rivaroxaban
0.5%Warfarin0.7%
HR 0.6795% CI 0.47-0.93
P = 0.02
Dosing SchedulesAtrial Fibrillation
Agent Dosing Recommendations
Dabigatran75mg, 150mg
CrCl > 30 cc/min: 150 mg, BIDCrCl 15 to 30 cc/min: 75 mg, BIDAvoid < 15 cc/min
Apixaban2.5mg, 5mg
CrCl > 15 cc/min: 5 mg, BIDAny 2 ( > 80 yrs, < 60 kg, SCr > 1.5mg/dL: 2.5 mg, BID)Avoid < 15 cc/min
Rivaroxaban10mg, 15mg, 20mg
CrCl > 50 cc/min: 20 mg, QdayCrCl 15-50 cc/min: 15 mg, QdayAvoid CrCl < 15 cc/min
Atrial Fibrillation StudiesWhen should new orals be started?
RE-LY (Dabigatran)Stroke within 14 daysSevere stroke within last 6 months
ARISTOTLE (Apixaban)Stroke within 7 days
ROCKET-AF (Rivaroxaban)Stroke within 14 daysSevere stroke within last 3 months
Modified-Ahrens I, et al Thromb Haemost 2011;105
Medically ill Patient
EXCLAIMExtended VTE Px Medically-ill
Endpoint Enoxaparin Placebo RRR
VTE 28 +/- 4 d 2.5% 4.0% -1.5395% CI -2.54 to -0.52
Major Bleed 0.8% 0.3% 0.5195% CI 0.12 to 0.89
Hull R, et al, Ann Intern Med 2010;153:8-18
ADOPT
Goldhaber S, et al NEJM 2011;365(23):2167-2177
Apixaban 2.5 mg BIDEnoxaparin 40mg, Qday
ADOPT StudyEndpoint Apixaban
2.5 mg BIDControl RRR
VTE during parenteral Rx
1.73% 1.61%Enox
1.0695% CI 0.69-1.63
Non-Inferior P=NSVTE at 30 days 2.71% 3.06%
Placebo0.87
95% CI 0.62-1.23Superior P=NS
Major Bleed 35 days
0.47% 0.19% 2.58P=0.04
CR Bleeding 35 days
2.67% 2.08% 1.28P=0.12
Goldhaber S, et al, NEJM, 2011; 365: 2167-2177
Cohen A, et al NEJM 2013;368:513-523
MAGELLAN StudyEndpoint Rivaroxaban
10 mg, QdayControl RRR
VTE at 10 days 2.7% 2.7%Enox
0.9795% CI 0.713-1.334
Non-Inferior P=0.0025VTE at 35 days 4.4% 5.7%
placebo0.77
95% CI 0.618-0.962Superior P=0.021
Major Bleed 35 days
1.1% 0.4% 2.9P=0.0004
CR Bleeding 35 days
4.1% 1.7% 2.5P < 0.0001
Cohen A, et al NEJM 2013;368:513-523
Extended VTE Prophylaxis In Medical PatientsNet Clinical Benefit of Factor Xa Inhibitors
0
3
6
3
6
EXCLAIM ADOPT MAGELLAN
Inci
denc
e (%
)
Hull R, et al, Ann Intern Med 2010;153:8-18 Cohen A, et al NEJM 2013;368:513-523
Goldhaber S, et al, NEJM, 2011; 365: 2167-2177
(n = 5,963) (n = 8,101)(n = 6,528)
*
*
* p < 0.05
0.3 0.8*
2.12.7
1.7
4.1*(Major Bleeding)
* p < 0.05
Key PointsBlack Box Warnings, Stroke, MI Risk,
Drug Interactions, Major Bleeding
Black Box WarningRivaroxaban & Apixaban
Patel M et al, NEJM 2011;365:883-891
ROCKET AF
Patel M, et al JACC 2013;61:651-658
Rocket AF StudyGroup Riva Warfarin HR P
value
TemporaryInterruption
6.2 (9) 5.05 (8) 1.280.49-3.31
0.62
PermanentDiscontinuation
25.6 (42) 23.28 (36) 1.100.71-1.72
0.66
After end of study 6.42 (22) 1.73 (6) 3.721.51-9.16
0.004
All Discontinuation + End of study
11.2 (73) 7.57 (50) 1.51.05-2.15
0.026
Patel M, et al JACC 2013;61:651-658
Interruption or DiscontinuationRivaroxaban
Rivaroxaban Events per 100-pt years
Warfarin Events per 100-pt years
Hazard Ratio (CI) P Value
All discontinuations and interruptions prior to the end of the study
16.49 14.05 1.21 (0.81-1.81) 0.35
Temporary Interruptions 6.20 5.05 1.28 (0.49-3.31) 0.62
Permanent Discontinuations 25.60 23.28 1.10 (0.71-1.72) 0.66
End of Study Transition to Open-Label 6.42 1.73 3.72 (1.51-9.16) 0.0044
All discontinuations and interruptions prior and after study
11.20 7.57 1.50 (1.05-2.15) 0.026
1.Temporary Interruption (Events starting 3 days after interruption until 3 days after resumption)
2.Early Permanent Study Drug Discontinuation (Events evaluated from 3-30 days after d/c)
3.End of Study Transition to Open-Label (Events evaluated from 3-30 days after d/c)
Warfarin
Rivaroxaban
81%
49%
Days after Last Dose at End of Study
Cum
ulat
ive
Prop
ortio
n w
ith IN
R >
2
Patel M, et al JACC 2013;61:651-658
Rocket AF Study
What happened in ROCKET AF ?
Warfarin patients continued warfarin Rivaroxaban patients discontinued study
drug and then began warfarinNot anticoagulated during warfarin
titrationNo “Bridging”
Strokes during the 30 days post studyWarfarin group – 6Rivaroxaban group - 22
Black Box WarningRivaroxaban
Epidural or Spinal HematomaUse of epidural catheterConcomitant use of NSAID, Anti-plateletTraumatic or repeated spinal punctureHistory of spinal deformity
Dosing RivaroxabanEpidural Catheters
Riva 10 mg6-8 hrs postop
4 PM – 6 PM
Epidural Placed
10 AMLeave PACU
Surgery8AM
RemoveEpidural
> 18 hrs from Last dose
Riva
Start Riva6 hrs afterEpidural Removed
Half-Life 7 – 11 hrs
NoonNextDay
Uchino K, et al Arch Intern Med 2012;172:397-402
7 Clinical Trials Evaluated2 Stroke Prophylaxis in Atrial Fibrillation1 Acute Venous Thromboembolism1 Acute Coronary Syndrome3 VTE Prophylaxis Joint Replacement Surgery
Dabigatran compared to control (warfarin, enoxaparin, placebo)
1. Increased absolute risk of MI or ACS 0.27%2. Increased relative risk of MI or ACS 33%
Uchino K, et al Arch Intern Med 2012;172:397-402
Eriksson B, et al Thromb Res 2012;130:396-402
Dabigatran & ACS EventsOrthopedic Surgery
ACS EventsAdjudicated
Dabi 150 mg(2665)
Dabi 220 mg(2611)
Enoxaparin(2639)
MI 1 1 5
Unstable Angina
1 0 0
Cardiac Death 0 0 3
Total Definite ACS
2 (0.8) 1 (0.04) 7 (0.27)
Eriksson B, et al Thromb Res 2012;130:396-402
Conclusion: No ACS signal identified
Major Bleeding
Pharmacologic CharacteristicsCharacteristics Dabigatran Rivaroxaban Apixaban
Target IIa Xa Xa
Bioavailability 7% 60%-80% 80%
Half-Life 12-17 hrs 7-11 hrs 12 hrs
Clearance 80% renal 60% renal33% biliary
25% renal75% biliary
Metabolism Conjugation to active glucuronides
CYP3A4CYP2J2
CYP3A4
P-GP interaction Yes Yes Yes minimal
Galanis T et al Thromb Thrombolysis 2011;31:310-320
Lab Tests
Useful Lab Test
Dabigatran Rivaroxaban Apixaban
Strong ECT Chromogenic Anti-Xa
Chromogenic Anti -Xa
TT aPTT, PT
aPTT
Weak PT / INR
Laboratory Testing New Oral Agents
Palladino M et al A J Hem 2012;87 Suppl:S127-S132
Novel Anticoagulant Comparison
Dabigatran Rivaroxaban Apixaban
Dialyzable Yes Probably Not Probably Not
Molecular Weight
628 Daltons 436 Daltons 460 Daltons
Protein Binding 35% >90% 87%
Catalytic Binding Site
Reversible Reversible Reversible
Reversing Agent
No Possibly Possibly
Erikkson BI, et al. Clin Pharmacokinet 2009;48:1-22.
Eerenberg E, et al Circulation 2011;124:1573-1579
COFACT (Prothrombin Complex Concentrate)1. Non-activated PCC2. Factor II, VII, IX, X3. Protein C, S, ATIII4. 50 IU PCC/kg dosing
Eerenberg E, et al Circulation 2011;124:1573-1579
Rivaroxaban 20 mg BID
Prothrombin Time
PCC
Placebo
PCC or Placebo
Eerenberg E, et al Circulation 2011;124:1573-1579
aPTT
PCC
Dabigatran 150mg BID
PCC or Placebo
Placebo
Eerenberg E, et al Circulation 2011;124:1573-1579
Dabigatran 150mg BID
PCC or Placebo
Placebo PCC
Thrombin Time
Eerenberg E, et al Circulation 2011;124:1573-1579
Dabigatran 150mg BID
PCC or Placebo
PCC
Placebo
ECT
Four Factor vs Three Factor PCCRivaroxaban Reversal
Agent Reduction PT (sec)
Beriplex (50 IU/kg) 2.5 sec – 3.5 sec
Profilnine (50 IU/kg) 0.6 – 1.0 sec
Levi M, et al Abstract ISTH July 2013
Rivaroxaban 20mg, BID x 4 days30 minute following infusion effect noted
PTTPT/INR
Abnormal
Impaired Hemodynamic Status
PCC
Recheck: CBC, PT/INR & PTT
GI BleedRivaroxaban
PRBC
Normal Hemodynamic Status
PCC
Recheck: CBC, PT/INR & PTT
Transfuse Transfuse
Re-Evaluate Re-Evaluate
PCC 50 IU/kg over 5-10 minutes
PTTCreatinine
Abnormal
Neuro Intact
Presence of any of following:Neuro Deterioration
Renal Dysfunction (CrCl < 50 ml/min)Recent Dabigatran Dose (< 6 hrs
prior)
Monitor Neuro Status
Dialysis
NeuroDeterioration
Recheck PTTQ6hrs x 24 hrs
Dialysis as indicatedby PTT/TT
NeuroIntact
Reassess Needfor Anticoagulation Neuro Stable
CNS BleedDabigatran
Dialysis removes 60%
Package Insert Recommendations
DabigatranFFP, Prothrombin Complex ConcentrateActivated Factor VIIDialysis
Rivaroxaban & ApixabanProthrombin Complex ConcentrateFour Factor Concentrate (KCentra)FFP