Review of Reversal Strategies for Warfarin and Target ... for reversal of warfarin and...

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Review of Reversal Strategies for Warfarin and Target-Specific Oral Anticoagulants David Roy, PharmDPGY2 Emergency Medicine Pharmacy ResidentPharmacy Grand RoundsSeptember 13, 2016


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


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%


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


Warfarin Reversal


General Approach: Warfarin

INR Algorithm Antidote

AntidoteVitamin K

FFPPCC


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 ???


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


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%


Vitamin K FFP

Vitamin K 3-factor PCC

Vitamin K 4-factor PCC


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


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


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 ???


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


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%


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%)


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


(max 3500 units)

INR > 6


(max 5000 units)

Frontera J, et al. Neurocrit Care 2016; 24:6-46Kcentra [package insert]. CSL Behring


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


Dabigatran Reversal


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


Idarucizumab for Dabigatran Reversal (RE-VERSE AD)

Pollack C, et al. N Engl J Med 2015; 373: 511-520


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


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]


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


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


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


Apixaban/Rivaroxaban/Edoxaban Reversal


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


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


Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity

Siegal D, et al. N Engl J Med 2015; 373: 2413-2424


• Phase 3 double-blind, placebo-controlled RCT in healthy volunteers (50-75 years old)

ANNEXA-A, ANNEXA-R


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


Endpoints (ANNEXA-A)94%

21%

0

20

40

60

80

100

Apixaban

Red

uctio

n in

Ant

i-Xa

Act

ivity

(%)

AnXa

Placebo


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 (%

)


ANNEXA-4: Andexanet Alfa for Acute Major Bleeding Associated with

Factor Xa Inhibitors

Connolly S, et al. N Engl J Med 2016


ANNEXA-4 Design


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


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)



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)


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)


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



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%)


FDA did not approve Andexanet alfa in August 2016

“…additional data needed for manufacturing and enoxaparin/edoxaban reversal”


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


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


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


Questions & Discussion

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