Darrel W. Hughes, Pharm.D., BCPSUniversity Health System & UT Health Science Center at San Antonio

Department of Pharmacotherapy & Pharmacy Services

Everything Your Pharmacist Wished You Knew About Anticoagulant Reversal

Disclosure

• I have no relevant financial relationships to disclose relative to the content of this presentation

July 16, 2018

Objectives

• Describe strategies for managing complications of vitamin K antagonist (VKA) and direct oral anticoagulants (DOAC)

• Differentiate major and non-major bleeds

• Understand mechanisms for reversing the effects of VKA and DOAC

July 16, 2018

Bruised Septuagenarian

• 74 yo female presents to ED w/ bruising

• Warfarin for atrial fibrilation

– Reports no changes to her dose in years

• Recently prescribed sulfamethoxazole/trimethoprim for urinary tract infection

• Internationalized normalized ration (INR) is reported to be 8.6

July 16, 2018

Warfarin Trivia

• 1920 ~70% mortality of cattle in rural Wisconsin

• Coumarin in moldy, sweet clover

• WARFARIN

– Wisconsin Alumni Research Foundation

• Mainstay of antithrombotic therapy for decades

– 1950-???

July 16, 2018

Warfarin

• Inhibits vitamin K epoxide reductase

– Reduced synthesis• Clotting factors II, VII, IX, and X

• Anticoagulants proteins C and S

• Approved uses

– Prophy/treatment of thromboembolic disorders

– Embolic complications from atrial fibrillation

– Valve replacement

• Dosing

– Highly variable/patient dependent

July 16, 2018

Warfarin

• Pharmacokinetics

– Hepatic metabolism

• CYP2C9 and 2C19

– Onset of action ~24 to 72 hours

– Peak effects in 5 to 7 days

– 99% protein bound

July 16, 2018

Why is INR Supratherapeutic?

• Medication non-compliance

• Dietary non-compliance

• Drug interaction

• There is no way to know for certain

July 16, 2018

Warfarin & Drug Interactions

• Displacement from protein binding

• P-450 enzyme

– 2C9 inducers/inhibitors

• Reduction/destruction of gut flora

• Synergistic anticoagulant effect

July 16, 2018

She’s Asymptomatic

• What is your plan?

– Hold next dose, follow up with PCP

– Hold next dose, 1 mg oral vit K , follow up with PCP

– Hold next dose, 10 mg iv vit K, admit to hospital

– Hold next dose, dose of prothrombin complex concentrate (PCC), fresh frozen plasma, 10 mg intravenous phytonadione, admit to ICU

July 16, 2018

What To Do?

• 355 non-bleeding patients with INR between 5.0 an 9.0– Randomized to 1.25 mg of oral vit K or placebo

• No major bleeding at seven days– 2.5% vs. 1.1% for vit K vs. placebo, p=0.22 at 90 days

– More rapid and robust INR decay for vit K• 50% vs. 11% had INR < 3, p < 0.001, 24 hours after vit K

• Risk factors for slow INR decay – theoretically higher bleeding risk– Advanced age

– Decompensated heart failure

– Low weekly warfarin dose

– Active malignancy

July 16, 2018

Recommendations

• If INR 4.5-10

• No evidence of bleeding

• American College of Chest Physicians guidelines recommend against routine vitamin K administration

July 16, 2018

Major Gastrointestinal Bleeding

• 37 yo male

• Two day history of melena

• Warfarin for secondary prevention of VTE

• INR reported 7.3

• New massive hematemesis

July 16, 2018

Bleeding: Major vs. Non-Major

• Bleeding at a critical site

– Intracranial/CNS, pericardial, airway, hemothorax, intra-abdominal or retroperitoneal, intramuscular or intra-articular

• Hemodynamic instability

• Clinically overt bleeding

– Hemoglobin decrease ≥ 2 g/dL

– Administration of ≥ 2 units of pRBCs

July 16, 2018

Major Bleeding and Mortality

• Intracranial hemorrhage

– 50% mortality

• Gastrointestinal bleeding

– 10% mortality

• Airway/nasal bleeding

– ~1% mortality

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INR vs. Clotting Factors

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VKA Reversal

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Product Time to Effect

Duration of Effect

Evidence ofEfficacy

ThrombosisRisk

Oral Vit K 24 h Days ++++ NS

IV Vit K 8-12 h Days ++++ NS

FFP Immediate 12-24 h ++ NS

PCC Immediate 12-24 h +++ Higher w/ activated PCC

Recombinantfactor VIIa

Immediate 2-6 h + ++

IV – intravenous; FFP – fresh frozen plasma; PCC – prothrombin (II) complex concentrate

Know Your History (old school)

• 2008 ACCP Guidelines

• Serious or Life-threatening bleeding associated with vitamin K anatagonist

– Vitamin K 10 mg IV

– FFP or

– PCC or

– FVIIa

July 16, 2018

Most Recent Recommendations

• Serious or Life-threatening bleeding associated with vitamin K antagonist

– PCC4 “rather than plasma”

– Vitamin K 5-10 mg IV

• Changes

– Bye, bye plasma?

– FVIIa removed

– PCC3???

July 16, 2018

Fresh Frozen Plasma (FFP)

• Contains coagulation factors

– I, II, V, VII, IX, X, XI, XIII and antithrombin

• INR reversal

• Mean INR of FFP 1.7 (1.4 to 1.9)

• Less effective with ongoing bleeding

• Disadvantages

– Large volumes required (20-30 mL/kg)

– Prolong time to patient

– TRALI, TACO and anaphylaxis

– Risk of viral transmission

July 16, 2018

4F PCC vs. FFP

July 16, 2018

PCC FFP

Onset Immediate Acquisition + infusion time

Duration 3-6 hours 3-6 hours

Volume Low (40-120 mL) 15-30 mL/kg (2-3 L)

Risk Thrombosis TRALI, TACO, Allergic Rx,Infection

Cost Mucho dinero ?????

4F PCC vs. FFP

• Randomized 202 patients w/ major bleeding

• 24 hour hemostatic efficacy– 72.4% vs. 65.4% (7.1%; [95% CI, -5.8 to 19.9])

• Rapid INR normalization (30 minutes)– 62.2% vs 9.6% (52.6% [95%CI, 39.4 to 65.9])

• Safety– 66 of 103 vs. 71 of 109 patients experienced ≥1 adverse event

• Conclusion– Non-inferior efficacy for surrogate primary endpoint

July 16, 2018

Recommendation

• On VKA with major bleeding at any INR

– Supportive care

• Airway, Breathing and Circulation

– 4-factor PCC (KCentra)

– Plus IV vitamin K 5-10 mg

– Surgical/procedural management of bleeding site

July 16, 2018

Headache and Aphasia

• 66 yo male– Headache, aphasia and right sided weakness

• Vitals– 220/118 mmHg, P101, RR 16, T 98.8, pulse ox 98% RA

• Neuro– GCS 14– Somnolent, but responses to simple commands– Pupils midpoint, equal and reactive– L sided gaze preference– R facial weakness & R upper > lower extremity weakness– Expressive aphasia

• INR 5.6

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July 16, 2018

Oral Anticoagulants and ICH

• Increases intracranial hemorrhage (ICH) risk

– 7-10 times

– >10 fold risk if over 50 years of age

– Increased risk dramatic if INR >4.0

• ~60% ICHs occur while INR in the target range

• ICH risk greatest at the start of treatment

July 16, 2018 28

Do Early Interventions Matter?

• Hematoma Volume

– Correlates

• Mortality

• Depressed level of consciousness

– Hemorrhage growth ~40% of all ICH patients

• Growth of > 33% of baseline volume within 24 hours

July 16, 2018 29

Hematoma Expansion

July 16, 2018 30

Game Plan

• Hold antithrombotic therapy

• Vitamin K 10 mg iv piggy back

• Prothrombin complex concentrate (4F PCC) (Kcentra®)

– 4-factor PCC indicated for vitamin k antagonist reversal in patients with acute major bleeding

– Factor II, VII, IX, X, protein S and C

July 16, 2018 31

Dosing Prothrombin Complex Conc.

• Kcentra

– INR 2-3.9; 25 units/kg x 1 dose up to 2500 units

– INR 4-6; 35 units/kg x 1 dose up to 3500 units

– INR > 6; 50 units/kg x 1 dose up to 5000 units

• Recheck INR in 30 minutes

• Max dose based on 100 kg patient

• Don’t forget iv vitamin K to avoid rebound

July 16, 2018 32

Prothrombin Complex Conc. Safety

• Contraindications:

– Heparin induced thrombocytopenia

– Disseminated intravasuclar coagulation

• Black boxed warning:

– Thromboembolic events

July 16, 2018

July 16, 2018 34

Hold The Phone!

What if the patient’s INR was 1.8?

July 16, 2018 35

Re-Examining the Evidence• Phase III trial included INRs as low as 1.8

• Woo et al.– Retrospective review of ICH included INRs as low as 1.5

• Yanamadala et al.– 50% of neuro-injured patients INR 1.2-2.0 had hematoma

expansion > 33%

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July 16, 2018 38

Hold The Phone!Patient takes new direct oral anticoagulant (DOAC)

and not warfarin

July 16, 2018 39

Direct Oral Anticoagulant (DOAC)

• Direct Thrombin Inhibitors

– Dabigatran (Pradaxa®)

• Direct Xa Inhibitors

– Rivaroxaban (Xarelto®)

– Apixaban (Eliquis®)

– Edoxaban (Savaysa®)

July 16, 2018 40

Coagulation Cascade

Pharmacokinetics ProfilesDabigatran(Pradaxa®)

Rivaroxaban(Xarelto®)

Apixaban(Eliquis®)

Dose Frequency QD-BID QD-BID BID

Bioavailability (%) 3-7 66-100 50

Peak Action (hours) 1-2 2-4 3-4

Half-life (hours) 12-17 5-13 9-14

Elimination (% renal) 80 66 25

Dosing FIXED

Monitoring NONEDabigatran (Pradaxa®) Package Insert. Boehringer Ingelhein Pharmaceuticals, Inc.: Ridgefield, CT, 2012.Rivaroxaban (Xarelto®) Package Insert. Janssen Pharmaceuticals, Inc..: Titusville, NJ, 2011.

Apixaban. In: DRUGDEX® System [Intranet database]. Version 5.1. Greenwood Village, Colo: Thomson Healthcare.

Managing DOAC Bleeding

• Supportive care

– Airway, breathing, and circulation

• Is the bleeding major or non-major?

• Stop anti-coagulant

• Document time and amount of last dose

– Consider activated charcoal for dabigatran

• Up to 2 hours after a dose

• Note renal and/or hepatic impairment

July 16, 2018 43

Reversal Strategies: Dabigatran

• Dabigatran

– Idarucizumab (Praxbind®) approved 2015

• Humanized monoclonal antibiody

• Binds dabigatran and metabolite with a higher affinity than thrombin ~(350 X)

• Neutralizes the anticoagulant effect

– Consider activated charcoal if ingested < 2 hours ago

– Consider emergent dialysis

July 16, 2018 44

Reversal Strategies: Dabigatran

• Idarucizumab Dosing

– Dabigatran taken within 24 hrs or 24-48 hrsago and ↑INR/PTT

• 5 gram IV x 1 dose

• Consider additional 5 gm dose if– Re-bleeding or ↑INR/PTT

– 2nd emergent surgery needed and ↑INR/PTT

– Onset within minutes

• Hemostasis ~ 11 hours w/ 24 hr duration

July 16, 2018

Reversal Strategies: Dabigatran• Idarucizumab

• Prospective,observational cohort

– Serious bleeding n=51

– Urgent procedure n=39

– Single 5 gm iv dose normalized ECT and dTT~89%

– Sustained effect for 24 hours

July 16, 2018 46

Reversal Strategies: FXa Inhibitors

• Rivaroxaban/apixaban/edoxaban

– Supportive care

– Consider activated charcoal if ingested < 2 hours

– NOT dialyzable – due to high protein binding

– 4F-PCC (for now)

• 50 units/kg x 1 dose up to 5000 units

– Andexanet alpha coming soon…

July 16, 2018 47

Reversal Strategies: FXa Inhibitors

• Andexanet Alpha (Andexxa®)

– Recombinant human factor Xa protein

– Binds factor Xa inhibitors with high affinity

– Reverses anticoagulant activity

• Direct & indirect factor Xa inhinitors

– Food and Drug Administration approval May 2018

– Product launch in June 2018/early 2019

July 16, 2018

ANNEXA-4 Study Overview

• Multicenter, prospective, open-label study in patients with acute major bleeding

• Andexanet alpha

– Bolus → 2 hour infusion

– Two dosing strategy• 400/480 mg – Apixaban/rivaroxaban > 7 hrs prior

• 800/960 mg – Enoxaparin, edoxoban or rivaroxaban ≤ 7 hrs prior

– Co-primary outcomes• % change in anti-factor Xa activity

• Rate of excellent or good hemostatic efficacy 12 hrs

July 16, 2018

ANNEXA-4 Study Results

• Factor Xa inhibitor (n=67)– Rivaroxaban (n=32), apixaban (n=31), enoxaparin (n=4)

• Primary bleeding site– GI (n=33) or ICH (n=28)

• Co-primary outcomes– 39% and 30% relative decrease from baseline for

rivaroxaban and apixaban groups respectively

– 79% patients achieved excellent/good hemostasis 12 hours after andexanet

– 18% of patient experienced thrombotic event by 30-day follow up

July 16, 2018

July 16, 2018

Summary

• VKA & DOAC deplete or inhibit factors necessary for clot formation

• Major bleeding

– Critical site, hemodynamic instability, pRBCs

• Reversal of anticoagulant effect

– Supplementing depleted factors

– Binding factor inhibitors

• General supportive care

July 16, 2018

Summary for Major Bleeding• VKA

– 4F PCC (Kcentra®) • Standard of care for life threatening bleeding in patients on warfarin

• Staggered dose base of patient weight and INR

– Vitamin K to prevent rebound coagulopathy

• DOAC– Direct thrombin inhibitor (dabigatran)

• Idarucizumab

• Consider emergent dialysis for dabigatran

– Anti-Xa (apixaban, edoxaban or rivaroxaban)• Andexanet alpha if available or 4F PCC

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Questions?

July 16, 2018