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
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Warfarin
• Pharmacokinetics
– Hepatic metabolism
• CYP2C9 and 2C19
– Onset of action ~24 to 72 hours
– Peak effects in 5 to 7 days
– 99% protein bound
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Why is INR Supratherapeutic?
• Medication non-compliance
• Dietary non-compliance
• Drug interaction
• There is no way to know for certain
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Warfarin & Drug Interactions
• Displacement from protein binding
• P-450 enzyme
– 2C9 inducers/inhibitors
• Reduction/destruction of gut flora
• Synergistic anticoagulant effect
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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
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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
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Recommendations
• If INR 4.5-10
• No evidence of bleeding
• American College of Chest Physicians guidelines recommend against routine vitamin K administration
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Major Gastrointestinal Bleeding
• 37 yo male
• Two day history of melena
• Warfarin for secondary prevention of VTE
• INR reported 7.3
• New massive hematemesis
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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
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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
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4F PCC vs. FFP
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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
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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
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Hematoma Expansion
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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
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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
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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?
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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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Hold The Phone!Patient takes new direct oral anticoagulant (DOAC)
and not warfarin
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Direct Oral Anticoagulant (DOAC)
• Direct Thrombin Inhibitors
– Dabigatran (Pradaxa®)
• Direct Xa Inhibitors
– Rivaroxaban (Xarelto®)
– Apixaban (Eliquis®)
– Edoxaban (Savaysa®)
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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
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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
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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
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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
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