©2016 MFMER | slide-1 Review of Reversal Strategies for Warfarin and Target-Specific Oral Anticoagulants David Roy, PharmD PGY2 Emergency Medicine Pharmacy Resident Pharmacy Grand Rounds September 13, 2016
©2016 MFMER | slide-1
Review of Reversal Strategies for Warfarin and Target-Specific Oral Anticoagulants David Roy, PharmDPGY2 Emergency Medicine Pharmacy ResidentPharmacy Grand RoundsSeptember 13, 2016
©2016 MFMER | slide-2
Objectives• Review the evidence behind current guideline
recommendations for reversal of warfarin and target-specific oral anticoagulants
• Identify novel agents in clinical development for reversal of Factor Xa inhibitors
• Describe the risks and benefits of reversing anticoagulation
©2016 MFMER | slide-3
Anticoagulation on the Rise• 6 to 8 million Americans are prescribed OAC
• Increased global prescribing of anticoagulation; NOACs quickly replacing warfarin
McBane R, et al. Thromb Res 2016;139:160-5Barnes G, et al. Am J Med 2015. 128(12):1300-5
Kuramatsu J, et al. JAMA 2015;313(8):824-36Ruff CT, et al. Lancet 2014;383(9921):955-62Van Es N, et al. Blood 2014;124(12):1968-75
OAC: Oral anticoagulationNOAC: Novel oral anticoagulantsICH: Intracerebral hemorrhageNVAF: Nonvalvular atrial fibrillation
NOACs vs. WarfarinNVAF Treatment of DVT/PE
Efficacy Stroke risk ↓ 19% Similar VTE recurrence
Safety Major bleed ↓ 14%ICH ↓ 52% Major bleed ↓ 38%
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ICH Mortality
Selim M, et al. Stroke 2012;43:2539-2540Frontera J, et al. Neurocrit Care 2016; 24:6-46
WarfarinMeasure and reverse
Goal INR ≤ 1.4
NOACCan’t measure or reverse
• ICH mortality 40-50% with OAC• Increased age/comorbidities• Increased hematoma volume• Greater hematoma expansion
Modifiable Risk Factors
OAC: Oral anticoagulationNOAC: Novel oral anticoagulants
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Warfarin Reversal
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General Approach: Warfarin
INR Algorithm Antidote
AntidoteVitamin K
FFPPCC
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Vitamin K
• IV normalizes INR quicker than PO (6-8 hours); no difference at 24 hours
• 10mg IV recommend with all reversal agents in WAICH
Watson H, et al. Br J Haematol. 2001;115:145-9Frontera J, et al. Neurocrit Care 2016; 24:6-46
WAICH: Warfarin-associated Intracranial Hemorrhage
Factor Half-life (hr)VII (7) 8IX (9) 24X (10) 48II (2) 72
Vitamin K ???
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Fresh Frozen Plasma (FFP)
• 10-20 ml/kg increases factors by ~20%• 1 unit of FFP is 250ml• FFP = INR 1.6
• INR normalization depends on initial INR, volume of FFP
• Large volume required may lead to pulmonary edema, TRALI or TACO
• Requires ABO typing, thawingTRALI: Transfusion-related acute lung injuryTACO: Transfusion-associated circulatory overload
Chapman S, et al. Ann Pharmacother. 2011;45:869-75Makris M, et al. Thromb Haemost. 1997;77:477-80
Factor VII, IX, X, II
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Prothrombin Complex Concentrates (PCC)
Factor VII (+/-), IX, X, II(25x concentrated)
3-factor PCC
4-factor PCC
Sarode R, et al. Circulation. 2013;128:1234-43Goldstein, et al. Lancet. 2015;128:360-4
Voils SA, et al. Thromb Res. 2012;130(6):833-40
3F-PCC 4F-PCCFactor IIFactor IXFactor XFactor VIIProtein C/SAntithrombin IIIHeparinPrice ↑ 30%
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Vitamin K FFP
Vitamin K 3-factor PCC
Vitamin K 4-factor PCC
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FFP vs. 4-factor PCC• Randomized, open-label, non-inferiority: 4-factor PCC or
FFP for major bleed with INR>2• Hemostatic efficacy at 24 hours• INR reduction ≤ 1.3 at 30 minutes
Sarode R, et al. Circulation 2013. Aug 9 [Epub ahead of print]
Notable ExclusionPrior to ICH, GCS < 7 or mRS >3
History of thrombotic event (MI, DIC, stroke, TIA) within 3 months
History of antiphospholipid or lupus anticoagulant antibodiesSepsis
Expected survival < 3 daysExpected surgery < 1 day
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FFP vs. 4-factor PCC• 4-factor PCC (107 pts), FFP (109 pts)
• 12% of patients had ICH• 55% anticoagulated for atrial fibrillation
4-factor PCC FFP
Hemostasis @ 24hr 72.4% 65.4% 95% CI (-5.8-19.9)
INR ≤ 1.3 @ 30 min 62.2% 9.6%Noninferior
Visible Bleed 4-factor PCC FFP
Hemostasis @ 24hr 82.6% 50%
Nonvisible Bleed 4-factor PCC FFP
Hemostasis @ 24hr 69.3% 71.1%
ICH 4-factor PCC FFP
Hemostasis @ 24hr 41.7% 58.3%
Sarode R, et al. Circulation 2013. Sep 10; 128(11):1234-43
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Trial weaknesses• No clinical outcomes
• INR poor surrogate marker
• Hemostasis efficacy scale not validated
• Difficult for FFP to meet INR primary outcome; INR 1.6
• 4-factor PCC thromboembolic events: 8.7% vs. 5.5%
4-factor PCC FFP45-day mortality 9.7% 4.6%
Sarode R, et al. Circulation 2013. Sep 10; 128(11):1234-43
Assumption:↓INR = ↓ Hematoma Expansion = ↑ Outcomes ???
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3F-PCC vs. 4F-PCC• Only retrospective studies comparing 3-factor vs.
4-factor PCC• 4-factor PCC more rapidly corrects INR• Risk of thrombosis possibly decreased with 4-
factor PCC (proteins C/S, ATIII)• 4-factor PCC FDA-approved for warfarin reversal
Sarode R, et al. Circulation. 2013;128:1234-43Goldstein, et al. Lancet. 2015;128:360-4
Voils SA, et al. Thromb Res. 2012;130(6):833-40
©2016 MFMER | slide-15
Question #1From 2010-2012, how many Mayo Clinic (Rochester) patients had a thromboembolic event after receiving Bebulin for major bleed reversal?A. 2.5%B. 5%C. 10%D. 20%
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Risk of Reversal• Retrospective review of 3-PCC for reversal of
major bleeding or periprocedural at MCR
McBane R, et al. Thromb Res 2016;139:160-5MCR: Mayo Clinic Rochester
Major bleeding (n = 113)
Periprocedural(n = 52)
Thromboembolic events 24 (21%) 7 (13%)
Time to 1st complication 7.3 days (0-32) 13.4 days (1-30)
Arterial embolism 2 2
Stroke/TIA 5 0
Intracardiac thrombus 3 0
DVT 13 5
PE 1 0
Major Bleeding NA 7
Death 20 (18%) 8 (15%)
©2016 MFMER | slide-17
WAICH Reversal Summary• Risk/Benefit prior to reversal• Educate on limitations of PCC studies using INR
reduction as primary outcome• Administer 10mg IV Vitamin K with 4-factor PCC
INR 2-4
4-factor PCC 25 units/kg
(max 2500 units)
INR 4-6
4-factor PCC 35 units/kg
(max 3500 units)
INR > 6
4-factor PCC 50 units/kg
(max 5000 units)
Frontera J, et al. Neurocrit Care 2016; 24:6-46Kcentra [package insert]. CSL Behring
©2016 MFMER | slide-18
General Approach: NOAC
Identify medication
Assess magnitude of anticoagulation• Time of last dose• Renal function
Antidote
Renal function quantifies therapeutic anticoagulation levels
Activated charcoal if last dose within 2 hours
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Dabigatran Reversal
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Idarucizumab• FDA-approved humanized monoclonal antibody
for patients treated with dabigatran that require anticoagulation reversal
• Dabigatran 350x higher affinity for Idarucizumab than thrombin
Eikelboom JW, et al. Circulation. 2015;132:2412-2422
Dosing 5 gm IV (Two 2.5 g boluses within 15 minutes)T1/2 10.3 hours
Dabigatran-Idarucizumab Dissociation 40-50 hours
Onset of Action 1-2 minutesRoute of Elimination Renal
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Idarucizumab for Dabigatran Reversal (RE-VERSE AD)
Pollack C, et al. N Engl J Med 2015; 373: 511-520
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RE-VERSE AD
• Multicenter, prospective cohort study• 90 patient interim analysis• Two 2.5 gm infusions (5gm total)
A(Life-threatening bleed)
B(Urgent procedure)
Primary outcome: maximum % reversal
Secondary outcome: Normalization of dTT, ECT,
reduction in unbound dabigatran
Pollack C, et al. N Engl J Med 2015; 373: 511-520
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RE-VERSE AD Results• Primary: Maximum % reversal: 100%
• Secondary:
• No clinical outcomes
• Biochemical reversal ≠ clinical reversal?• 4 case reports suggest no
Normalization of clotting time
dTT ECT
Group A 98% 89%
Group B 93% 88%
Safety OutcomesDeath 18/90 (20%)
Serious Adverse Event 21/90 (23.3%)
MI 1/90 (1%)Stroke 1/90 (1%)
DVT/PE 3/90 (3.3%)
Pollack C, et al. N Engl J Med 2015; 373: 511-520Thorborg C, et al. Br J Anaesth 2016; 117(3):407-9
Henderson R, et al. J Cardiothorac Vasc Anesth 2016 [Epub ahead of print]Alhashem H, et al. Am J Emerg Med 2016 [Epub ahead of print]
Marino K, et al. Pharmacotherapy 2016 [Epub ahead of print]
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Question #2What is recommended as second-line therapy for Dabigatran reversal if bleeding persists after giving Idarucizumab?
A. Redose 2.5 gm IdarucizumabB. Activated charcoalC. Andexanet alfaD. 4-factor PCC
©2016 MFMER | slide-25
Refractory to Idarucizumab• Repeat 5gm Idarucizumab may be considered• Small clinical trials, animal studies support
activated 4-factor PCC (FEIBA) over other products
• Dialysis
Dickneite G, et al. N Engl J Med 2015; 373: 511-520
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Dabigatran Summary• Time of last dose; activated charcoal if < 2 hours• Renal function; anticipate level of anticoagulation• Idarucizumab 5 gm over 15 minutes• Consider FEIBA (activated 4-factor PCC) or
dialysis
Frontera J, et al. Neurocrit Care 2016; 24:6-46
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Apixaban/Rivaroxaban/Edoxaban Reversal
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Current Recommendations• Retrospective, observational data• Obtain time since last dose to estimate
anticoagulation exposure• Activated charcoal if < 2 hours
• Reversal guided by life-threatening severity of bleed, not laboratory testing
Frontera J, et al. Neurocrit Care 2016; 24:6-46
4-factor PCC 50 units/kg if within 3-5 half-lives
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Andexanet Alfa• Recombinant factor Xa decoy protein designed
to neutralize direct/indirect factor Xa inhibitors
Procoagulant Activity
Anticoagulant Activity
Lu G, et al. Nat Med. 2013; 19(4):446-51
Gla
S S
Factor Xa
S S
Andexanet alfa
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Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity
Siegal D, et al. N Engl J Med 2015; 373: 2413-2424
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• Phase 3 double-blind, placebo-controlled RCT in healthy volunteers (50-75 years old)
ANNEXA-A, ANNEXA-R
Siegal D, et al. N Engl J Med 2015; 373: 2413-2424
ANNEXA-A (Apixaban 5mg BID)
Bolus: 400mg IV Bolus: 400mg IVInfusion: 4 mg/min
x 120min
ANNEXA-R(Rivaroxaban 20mg daily)
Bolus: 800mg IV Bolus: 800mg IVInfusion: 8 mg/min
x 120min
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Endpoints (ANNEXA-A)94%
21%
0
20
40
60
80
100
Apixaban
Red
uctio
n in
Ant
i-Xa
Act
ivity
(%)
AnXa
Placebo
Siegal D, et al. N Engl J Med 2015; 373: 2413-2424
9.3
1.9
0
5
10
Apixaban
Red
uctio
n of
unb
ound
ap
ixab
an c
onc.
(n
g/m
L)
96%
7%0
20
40
60
80
100
Apixaban
Full
rest
orat
ion
of
thro
mbi
n (%
)
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ANNEXA-4: Andexanet Alfa for Acute Major Bleeding Associated with
Factor Xa Inhibitors
Connolly S, et al. N Engl J Med 2016
©2016 MFMER | slide-34
ANNEXA-4 Design
Connolly S, et al. N Engl J Med 2016
30 min Bolus
2-hr infusion After infusionAcute Major
Bleed
Last fXa inhibitor < 18hrs
Patient Screening Andexanet Tx
Bleeding/Laboratory Assessment
1 hr 4 hr 8 hr 12 hr
Day 1 Day 3 Day 30
Safety
Primary Efficacy Endpoints
• Change in anti-FXa activity• Clinical hemostasis (12hr)
Safety Endpoints
• Thrombotic events• Antibody development• 30-day all-cause mortality
©2016 MFMER | slide-35
Baseline characteristicsSafety population, n = 67 Efficacy population, n = 47
Age, mean ± SD 77.1 (10) 77.1 (10.1)
Male, n (%) 35 (52.2) 24 (51.1)
Caucasian, n (%) 54 (80.6) 36 (76.6)
Time @ presentation until andexanet bolus (hrs) ± SD 4.8 ± 1.93 4.8 ± 1.82
Est CrCl < 30 mL/min, n (%) 6 (9.0) 4 (8.5)
Indication for AnticoagulationAtrial fibrillation, n (%) 47 (70.1) 32 (68.1)
VTE, n (%) 15 (22.4) 12 (25.5)
Medical HistoryMI, n (%) 13 (19.4) 7 (14.9)
Stroke, n (%) 17 (25.4) 15 (31.9)
DVT, n (%) 20 (29.9) 16 (34.0)
PE, n (%) 6 (9.0) 4 (8.5)
Atrial fibrillation, n (%) 49 (73.1) 34 (72.3)
Connolly S, et al. N Engl J Med 2016
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Anti-factor Xa Activity
0
200
400
600
Baseline End ofBolus
End ofInfusion
4 hr 8 hr 12 hr
Ant
i-fac
tor X
a A
ctiv
ity
(ng/
ml)
Rivaroxaban(n = 26)
Connolly S, et al. N Engl J Med 2016
Median 277.0 16.8 30.6 177.7 127.1 97.9
% change (95% CI)
-89%(-58 to -94)
-86%(-55 to -93)
-39%(-27 to -45)
-49%(-43 to -57)
-64%(-51 to -70)
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Clinical Hemostatic Efficacy
Subgroup # of patients Excellent/Good Hemostasis, %(95% CI)
All patients with efficacy analysis 47 79 (64-89)
Drug
Rivaroxaban 26 81 (61-93)
Apixaban 20 75 (51-91)
Enoxaparin 1 100
Site of bleeding
Gastrointestinal 25 84 (64-96)
Intracranial 20 80 (56-94)
Other 2 0
Connolly S, et al. N Engl J Med 2016
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Safety• Thrombotic events
• 3 days: 4 patients (6%)• 30 days: 12 patients (18%)
• Only 18 patients (27%) restarted anticoagulation within 30 days
• 30-day all-cause mortality• 10 patients (15%)
Connolly S, et al. N Engl J Med 2016
FDA did not approve Andexanet alfa in August 2016
“…additional data needed for manufacturing and enoxaparin/edoxaban reversal”
©2016 MFMER | slide-39
Does reversal even help?
Although ICH-mortality is 40-50%, two-thirds of survivors can live an independent life
Togha M, et al. BMC Neurology 2004. 4(9)1-5
• Studies say no difference in ICH reversal• Others say reversal normalizes INR and
reduces hematoma expansion
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Question #3What additional information was requested when the FDA did not approve Andexanet alfa?
A. Clarification of thrombotic events in ANNEXA-4
B. Data related to enoxaparin reversalC. Data related to argatroban reversalD. Pharmacokinetic studies in liver failure
©2016 MFMER | slide-41
Summary• Assess risk/benefit of reversing anticoagulation
for intracranial hemorrhage• Warfarin reversal with 4F-PCC and Vitamin K
preferred• Dabigatran reversal with Idarucizumab• Xa Inhibitor reversal with 4-PCC until new
antidotes are approved
©2016 MFMER | slide-42
Questions & Discussion