Everything Your Pharmacist Wished You Knew About Anticoagulant Reversal Darrel W. Hughes, Pharm.D., BCPS University Health System & UT Health Science

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1 Everything Your Pharmacist Wished You Knew About Anticoagulant Reversal Darrel W. Hughes, Pharm.D., BCPS University Health System & UT Health Science Center at San Antonio Department of Pharmacotherapy & Pharmacy Services

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

3 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

4 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

5 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-???

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7 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

8 Warfarin Pharmacokinetics Hepatic metabolism CYP2C9 and 2C19 Onset of action ~24 to 72 hours Peak effects in 5 to 7 days 99% protein bound

9 Why is INR Supratherapeutic? Medication non-compliance Dietary non-compliance Drug interaction There is no way to know for certain

10 Warfarin & Drug Interactions Displacement from protein binding P-450 enzyme 2C9 inducers/inhibitors Reduction/destruction of gut flora Synergistic anticoagulant effect

11 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

12 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

13 Recommendations If INR No evidence of bleeding American College of Chest Physicians guidelines recommend against routine vitamin K administration

14 Major Gastrointestinal Bleeding 37 yo male Two day history of melena Warfarin for secondary prevention of VTE INR reported 7.3 New massive hematemesis

15 Bleeding: Major vs. Non-Major Bleeding at a critical site Intracranial/CNS, pericardial, airway, hemothorax, intra-abdominal or retroperitoneal, intramuscular or intraarticular Hemodynamic instability Clinically overt bleeding Hemoglobin decrease 2 g/dl Administration of 2 units of prbcs

16 Major Bleeding and Mortality Intracranial hemorrhage 50% mortality Gastrointestinal bleeding 10% mortality Airway/nasal bleeding ~1% mortality

17 INR vs. Clotting Factors

18 VKA Reversal Product Time to Effect Duration of Effect Evidence of Efficacy Thrombosis Risk Oral Vit K 24 h Days ++++ NS IV Vit K 8-12 h Days ++++ NS FFP Immediate h ++ NS PCC Immediate h +++ Higher w/ activated PCC Recombinant factor VIIa Immediate 2-6 h + ++ IV intravenous; FFP fresh frozen plasma; PCC prothrombin (II) complex concentrate

19 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

20 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???

21 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

22 4F PCC vs. FFP PCC FFP Onset Immediate Acquisition + infusion time Duration 3-6 hours 3-6 hours Volume Low ( ml) ml/kg (2-3 L) Risk Thrombosis TRALI, TACO, Allergic Rx, Infection Cost Mucho dinero?????

23 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

24 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

25 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

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27 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 28

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 29

29 Hematoma Expansion 30

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 31

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 32

32 Prothrombin Complex Conc. Safety Contraindications: Heparin induced thrombocytopenia Disseminated intravasuclar coagulation Black boxed warning: Thromboembolic events

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34 Hold The Phone! What if the patient s INR was 1.8? 35

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 had hematoma expansion > 33% 36

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38 Hold The Phone! Patient takes new direct oral anticoagulant (DOAC) and not warfarin 39

39 Direct Oral Anticoagulant (DOAC) Direct Thrombin Inhibitors Dabigatran (Pradaxa ) Direct Xa Inhibitors Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Edoxaban (Savaysa ) 40

40 Coagulation Cascade

41 Pharmacokinetics Profiles Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Dose Frequency QD-BID QD-BID BID Bioavailability (%) Peak Action (hours) Half-life (hours) Elimination (% renal) Dosing Monitoring FIXED NONE Dabigatran (Pradaxa ) Package Insert. Boehringer Ingelhein Pharmaceuticals, Inc.: Ridgefield, CT, Rivaroxaban (Xarelto ) Package Insert. Janssen Pharmaceuticals, Inc..: Titusville, NJ, Apixaban. In: DRUGDEX System [Intranet database]. Version 5.1. Greenwood Village, Colo: Thomson Healthcare.

42 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 43

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 44

44 Reversal Strategies: Dabigatran Idarucizumab Dosing Dabigatran taken within 24 hrs or hrs ago and INR/PTT 5 gram IV x 1 dose Consider additional 5 gm dose if Re-bleeding or INR/PTT 2 nd emergent surgery needed and INR/PTT Onset within minutes Hemostasis ~ 11 hours w/ 24 hr duration

45 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 46

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 47

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

48 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

49 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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51 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

52 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 53

53 Questions?