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Management of Bleeding on Factor Xa Inhibitor Therapy Does One Size Fit All? Nubriel Hernandez, PharmD PGY-1 Pharmacy Resident SUNY Downstate Medical Center Brooklyn, NY Disclosure I have no conflict of interest to report and I intend to reference unlabeled/unapproved uses of drugs or products in my presentation 2 Objectives Recognize current management strategies for patients who present with major bleeding episodes while on oral anticoagulation Understand the limitations of current strategies of factor Xa inhibition reversal

3 Oral Anticoagulants Warfarin was the first anticoagulant approved in 1954 Due to limitations of warfarin, new oral anticoagulants have been approved Novel anticoagulants: direct thrombin inhibitors and factor Xa inhibitors Yang J, et. al. Eur J Med Chem. 2015;101:41-51..4 Major Bleeding Rates for Factor Xa Inhibitors Bleeding Event Rates Per Year vs. Warfarin Rivaroxaba n Warfarin Apixaban

Warfarin Edoxaban Warfarin 3.6% 3.4% 2.13% 3.09% 2.75% 3.43% p=0.58 p<0.001

p<0.001 Major Bleeding vs. Warfarin Betrixaban Warfarin 2.4% (3/127) 3.9% (5/127) HR (95% CI): 0.609 (0.145-2.557) Connolly SJ, et. Al. Eur Heart J. 2013;34(20):1498-505. Eikelboom J et al. Am J Emerg Med. 2016;34(11S):3-8. 5 Pharmacokinetic Parameters Medication

Rivaroxaba Apixaban n (Eliquis) (Xarelto) Edoxaban Betrixaba (Savaysa n ) (Bevyxxa ) Onset of Action (hr) 2 to 4 3 to 4 1 to 2

3 to 4 Metabolism Hepatic CYP 3A4/5, 2J2, PGP substrate Hepatic CYP 3A4/5, 1A2, 2C8, 2C9, 2C19, 2J2, PGP substrate Minimal via CYP 3A4 PGP and ABCB1 substrate

Protein Binding (%) ~92 to 95 ~87 ~55 60 PGP: P-glycoprotein; CYP: Cytochrome P450; ABCB1: ATP Binding Cassette Subfamily B Member 1 T1/2 (hr) 5 to 9 8 to 15 10 to 14 19 to 27

Excretion (%) Urine: 11 Urine: 66 Lexicomp Online, Lexi-Drugs, Hudson, Ohio: Lexi-Comp, 6 Inc. Urine: 27 Urine: 50 Management of Factor Xa Toxicity Activated Charcoal Within 2-4 hours of exposure Dose: 50 g x1 dose 4 Factor Prothrombin Complex

Concentrates (4F-PCC) or activated Prothrombin Complex Concentrates (aPCC) Assessment of laboratory markers and symptoms of bleeding Hemodialysis ineffective Fresh Frozen Plasma (FFP) last line option? Tomaselli GF, et. al. J Am Coll Cardiol. 2017;70(24):3042- 7 Role of Factor Replacement Gulseth MP. Am J Health Syst Pharm. 2016;73(10 Suppl 2):S5S13. 8

Prothrombin Complex Concentrates (PCCs)* 3 factor PCCs (Bebulin or Profilnine) 4 factor PCCs (Kcentra); 50 Units/kg IV (Max: 5,000 Units) Activated PCCs (FEIBA); 50 100 Units/kg IV Differ in presence of factor VII Contraindicated: Active disseminated intravascular coagulopathy Recent history of heparin-induced thrombocytopenia (HIT) * These products are not FDA-indicated for reversal of bleeding with exposure to Factor Xa Inhibitors Tomaselli GF, et. al. J Am Coll Cardiol. 2017;70(24):3042- 9 Fresh Frozen Plasma Obtained from whole blood donation 1 Unit = 200-250 mL Requires ABO blood type matching and thawing May take up to 90 minutes from time of order to time of administration

Tomaselli GF, et. al. J Am Coll Cardiol. 2017;70(24):3042- 10 FFP vs 4F-PCC Category Infection Rates Increased Intravascula r Volume Anaphylaxis Speed of INR Correction Coagulation Factors Costs FFP 4F-PCC

~6 hrs ~10 mins All II, VII, IX and X $$

Lexicomp Online, Lexi-Drugs, Hudson, Ohio: Lexi-Comp, Inc. 11 Tomaselli GF, et. al. J Am Coll Cardiol. 2017;70(24):3042- $$$ Guideline Recommendations: Warfarin 4F-PCC based on patients weight and INR INR 2-4: 25 Units/kg INR 4-6: 50 Units/kg

Fixed low dose regimen of 4FPCC INR 2-4: 25 Units/kg 1,000 Units (non-major bleed) 1,500 Units (Intracrania l Hemorrhag e) * If 4F-PCC is not available: FFP 10-15 mL/kg Tomaselli GF, et. al. J Am Coll Cardiol. 2017;70(24):3042- 12

Guideline Recommendations Factor Xa Inhibitors 4F-PCC: 50 Units/kg aPCC: 50 Units/kg Tomaselli GF, et. al. J Am Coll Cardiol. 2017;70(24):3042- 13 Literature Review Klein L, Peters J, Miner J, Gorlin J. Evaluation of fixed dose 4-factor prothrombin complex concentrate for emergent warfarin reversal. Am J Emerg Med. 2015;33(9):1213-8. Study Design

Retrospective cohort study 38 subjects on chronic oral anticoagulation with warfarin; 1 subject on chronic oral anticoagulation with rivaroxaban Patients admitted to urban level I trauma center in MN Population from March 2014 to January 2015 4F-PCC 1,500 Units x1 dose; additional dose if deemed Intervention necessary (median dose 1659 Units) 36 patients (92.3%) had a successful INR reversal with target less than 2.0 and 28 patients (71.8%) had a Outcome successful INR reversal with target of 1.5 or less No thrombotic events reported within 7 days Number 14 Literature Review

Klein L, et.al. Am J Emerg Med. 2015;33(9):1213-8. 15 Literature Review Zahir H, Brown KS, Vandell AG, et al. Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation. 2015;131(1):82-90. Study Design Number Population Phase I, double-blind, randomized, placebo-controlled, 2-way crossover study 110 subjects; Part 1: 17 subjects and Part 2: 93 subjects Healthy men and women, aged 18 to 45 years, weighing 110 kg were eligible for study enrollment. All patients received edoxaban 60 mg by mouth

Interventio 4F-PCC in decreasing dosing increments (50, 25 and 10 Units/kg) or placebo n Outcome Average of 21% decrease in baseline normalized post-dose bleeding duration following administration of 50 Units/kg of 4F-PCC (mean ratio 4F-PCC versus placebo, 79.2; 95% CI, 61.5 101.9; p= 0.068) Complete reversal was observed following 4F-PCC dose of 50 Units/kg, partial reversal following 25 Units/kg and no reversal following 10 Units/kg No deaths, serious adverse events, or thromboembolic events 16 occurred Literature Review Majeed A, gren A, Holmstrm M, et al. Management of rivaroxaban- or apixabanassociated major bleeding with prothrombin complex concentrates: a cohort study. Blood. 2017;130(15):1706-1712. Study

Design Number Population Prospective cohort study 84 subjects; 39 were on apixaban and 45 were on rivaroxaban Patients requiring treatment with 4F-PCC who presented with a major bleeding event defined by the International Society of Thrombosis and Hemostasis (ISTH) Interventio 4F-PCC given as fixed dose dependent on weight: < 65 kg = 1,500 IU, > 65 kg = 2,000 IU n Outcome Hemostatic effectiveness in 58 patients (69.1%) and ineffective in 26 patients (30.9%) 27 patients (32%) died within 30 days of major bleeding event, of

which 20 had an intracranial hemorrhage PCCs were given at a median dose of 2000 Units, suggesting this dose may be adequate in patients who present with a major bleeding event 17 Summary One size does not fit all limited data to suggest that similar benefits exist for factor Xa inhibitors using fixed dose 4F-PCC FFP has greater disadvantages associated with its use as a reversal agent compared to 4F-PCC Acute ingestion Consider activated charcoal if time of ingestion is known, symptom management and watch for signs of bleeding 18 Test Your Knowledge

Test Your Knowledge Which strategies could be considered in a patient for Factor Xa reversal? a) b) c) d) e) Hemodialysis 4F-PCC given at a dose of 50 IU/kg 4F-PCC given at a dose of 10 IU/kg aPCC given at a dose of 50 IU/kg B and D 20 Test Your Knowledge What are current limiting factors in managing patients who present with bleeding while on Factor Xa Inhibitor Therapy? a)

b) c) d) Lack of specific reversal agent availability Limited data of 4F-PCC use in bleeding patients Limited availability and/or utility of laboratory markers All of the above 21 References Yang J, Su G, Ren Y, Chen Y. Synthesis of 3,4-diaminobenzoyl derivatives as factor Xa inhibitors. Eur J Med Chem. 2015;101:41-51. Lexicomp Online , Lexi-Drugs , Hudson, Ohio: Lexi-Comp, Inc.; accessed January 21, 2018. Tomaselli GF, Mahaffey KW, Cuker A, et al. 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2017;70(24):3042-3067. Levi M, Moore KT, Castillejos CF, et al. Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers. J Thromb Haemost. 2014;12(9):1428-36.

Zahir H, Brown KS, Vandell AG, et al. Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation. 2015;131(1):82-90. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124(14):1573-9. Gulseth MP. Overview of direct oral anticoagulant therapy reversal. Am J Health Syst Pharm. 2016;73(10 Suppl 2):S5-S13. Eikelboom J, Merli G. Bleeding with direct oral anticoagulants vs warfarin: clinical experience. Am J Emerg Med. 2016;34(11S):3-8. 22 References, Continued Majeed A, gren A, Holmstrm M, et al. Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study. Blood. 2017;130(15):1706-1712. Tellor KB, Barasch NS, Lee BM. Clinical experience reversing factor Xa inhibitors with four-factor prothrombin complex concentrate in a community hospital. Blood Transfus. 2017; 1-5. Connolly SJ, Eikelboom J, Dorian P, et al. Betrixaban compared with warfarin in patients with atrial fibrillation: results of a phase 2, randomized, dose-ranging study (Explore-Xa). Eur Heart J. 2013;34(20):1498-505. Klein L, Peters J, Miner J, Gorlin J. Evaluation of fixed dose 4-factor prothrombin complex concentrate for emergent warfarin reversal. Am J Emerg Med. 2015;33(9):1213-8.

Khorsand N, Veeger NJ, Muller M, et al. Fixed versus variable dose of prothrombin complex concentrate for counteracting vitamin K antagonist therapy. Transfus Med. 2011;21(2):116-23. Wang X, Mondal S, Wang J, et al. Effect of activated charcoal on apixaban pharmacokinetics in healthy subjects. Am J Cardiovasc Drugs. 2014;14(2):147-54. Yeh CH, Fredenburgh JC, Weitz JI. Oral direct factor Xa inhibitors. Circ Res. 2012;111(8):1069-78. Joseph R, Burner J, Yates S, Strickland A, Tharpe W, Sarode R. Thromboembolic outcomes after use of a fourfactor prothrombin complex concentrate for vitamin K antagonist reversal in a real-world setting. Transfusion. 2016;56(4):799-807. 23 Questions Available at: https://infocus.dellemc.com/william_schmarzo/most-excellent-big-data-questions-top-down-or-bottom-up-use-24 cases/.

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