New Approaches for Reversing Oral Factor Xa Inhibitors EXAMINING THE EVIDENCE A Midday Symposium and AGENDA Live Webinar conducted at the 2018 ASHP 11:30 a.m. – 11:35 a.m. Welcome and Introductions Midyear Clinical Meeting William E. Dager, Pharm.D., BCPS (AQ-Cardiology), FASHP, and Exhibition FCCM, FCCP, FCSHP, MCCM 11:35 a.m. – 11:50 a.m. Monday, December 3, 2018 Direct-acting Oral Factor Xa Inhibitors: 11:30 a.m. – 1:00 p.m. PT Current Reversal and Treatment Strategies Room 252, 200 Level, ACC North for DOAC-related Bleeding William E. Dager, Pharm.D., BCPS (AQ-Cardiology), FASHP, Anaheim Convention Center FCCM, FCCP, FCSHP, MCCM Anaheim, California 11:50 a.m. – 12:15 p.m. Overview of Key Clinical Trials: Reviewing the Evidence on Reversal of DOACs Mark Cipolle, M.D., Ph.D., FACS, FCCM 12:15 p.m. – 12:40 p.m. Clinical Considerations in Reversal of DOACs: Focus on Wise and Correct Use Jessica Rimsans, Pharm.D., BCPS Provided by ASHP Supported by an educational grant 12:40 p.m. – 1:00 p.m. from Portola Pharmaceuticals Faculty Discussion, Frequently Asked Questions New Approaches for Reversing Oral Factor Xa Inhibitors: Examining the Evidence New Approaches for Reversing Oral Factor Xa Inhibitors: Examining the Evidence William E. Dager, Pharm.D., BCPS (AQ‐Cardiology), FASHP, FCCM, FCCP, FCSHP, MCCM, Activity Chair Mark Cipolle, M.D., Ph.D., FACS, FCCM Jessica Rimsans, Pharm.D., BCPS Provided by ASHP Supported by an educational grant from Portola Pharmaceuticals Disclosures In accordance with ACCME and ACPE Standards for Commercial Support, ASHP policy requires that all faculty, planners, reviewers, staff, and others in a position to control the content of this presentation disclose their relevant financial relationships. •In this activity, no persons associated with this activity have disclosed any relevant financial relationships. Please be advised that this activity is being audio and/or video recorded for archival purposes and, in some cases, for repurposing of the content for enduring materials. 1 New Approaches for Reversing Oral Factor Xa Inhibitors: Examining the Evidence Learning Objectives •Review currently available agents for reversing direct‐ acting oral anticoagulants (DOACs). • Explain the risk factors for bleeding complications with DOACs as well as strategies for minimizing them. •Review current and emerging data for the treatment of bleeding in patients on DOAC therapy. • Illustrate using patient cases clinical situations for which reversal of DOAC therapy is warranted, including how it may be implemented. Current Reversal and Treatment Strategies for Anti‐Xa DOAC‐Related Bleeding William E Dager, Pharm.D., BCPS (AQ Cardiology), FASHP, FCCM, FCCP, FCSHP, MCCM Pharmacist Specialist –UC Davis Medical Center Sacramento, California Copyright © 2018 American Society of Health-System Pharmacists, Inc. All rights reserved. 2 New Approaches for Reversing Oral Factor Xa Inhibitors: Examining the Evidence Oral Anti‐Xa Anticoagulants Rivaroxaban Apixaban Edoxaban Betrixaban Prodrug No No No No Bioavailability > 80% > 50% 62% 34% Time to peak Cp 3 hr (Delayed by food) 3 hr 1.5 hr 3‐4 hr Half‐life 5‐9 hr (Elderly 11‐13hr) 9‐14 hr 8‐10 hr 19‐27 hr Dosing frequency Once daily Twice daily Once daily Once daily Renal excretion 36% 25% 35% 5‐7% Drug interactions CYP 3A4 or CYP 3A4 or P‐gp modifiers P‐gp modifiers P‐gp modifiers P‐gp modifiers CYP ‐ cytochrome P450; P‐gp ‐ P glycoprotein; hr –hours; Cp = peak plasma concentration Gross PL et al. Arterioscler Thromb Vasc Biol. 2008; 28:380‐6. Plitt A et al. J Cardiovasc Pharmacol Ther. 2014; 19:409‐16. Bevyxxa (betrixaban) prescribing information. Portola Pharmaceuticals. 2017 Jun. What is the situation? Goals of therapy? •Urgent •Semi‐Urgent •Not so Urgent Nutescu E, Dager WE, Kalus JS et al. Am J Health‐Syst Pharm. 2013; 70:1914‐29. Copyright © 2018 American Society of Health-System Pharmacists, Inc. All rights reserved. 3 New Approaches for Reversing Oral Factor Xa Inhibitors: Examining the Evidence Reversing an Oral Anti‐Xa Anticoagulant • Assessment o Urgency → paent seng, surgery? o Anticoagulant –last dose, how much is involved o Assay: Anti‐Xa, INR o Your role and what agents are available o Continuous Process • Withhold anticoagulation • Pharmacological intervention – Topical agents – Andexanet alfa – Prothrombin concentrate concentrate (PCC) (? Titrate to effect) – Plasmapheresis ? –Case report (Anti‐Xa ↓ 0.8 to 0.3 IU/mL in 2 hours) • Replace blood losses • Optimize management of comorbid situations Dager W. Anticoagulation Therapy 2nd Ed. 2018. Lam WW et al. Tex Heart Inst J 2015; 42:377‐80. DOAC –Agent Unclear Bleeding or need for urgent reversal Thrombin Time High Assessment ‐Amount of drug (↑ INR/PT etc) Thrombin Time Low Anti‐Xa Low • Thrombin time/Anti‐Xa Anti‐Xa High (assay dependent) ? ↑ aPTT > PT ‐ Bleeding risk ? ↑ PT > aPTT (assay dependent) ‐ Charcoal if ingestion recent ‐ Med Rec: Dosing QD/BID Rivaroxaban Dabigatran Bleeding Apixaban Edoxaban Betrixaban Urgent Supportive management ‐ Underlying condition Administer antidote ‐ Transfuse Non‐urgent ‐ Need for invasive procedure Consider adding hemostatic agent if Semi‐urgent Watch urgent – life threatening bleed Consider antidote Hemostatic agent if clinically necessary (low dose titrate to effect) Copyright © 2018 American Society of Health-System Pharmacists, Inc. All rights reserved. 4 New Approaches for Reversing Oral Factor Xa Inhibitors: Examining the Evidence Efficacy Outcomes (n=47) Outcome Result Change in anti‐Xa activity ~89% Change in hemostatic 79% of patients achieved good or efficacy through 12 hours excellent hemostasis post‐andexanet alfa (Visual 1 and 4 hr; CNS bleed – • Excellent 66% <20% mass effect by 12 hours) • Good – 13% Time from admission to dose administration: Does this create a negative 4.8 +/‐ 1.8 hr outcome bias? Connolly SJ et al. N Engl J Med. 2016; 375:1131–41. Potential INR Response with Higher DOAC Serum Concentrations INR Serum Concentration (ng/mL) Ofek F et al. Clin Ther. 2017; 39:1003‐10. Copyright © 2018 American Society of Health-System Pharmacists, Inc. All rights reserved. 5 New Approaches for Reversing Oral Factor Xa Inhibitors: Examining the Evidence Andexanet alfa Recombinant truncated human factor Xa variant (decoy) that Mechanism temporarily shuts down the activity of factor Xa (Does not remove it). Competitive binding to direct factor Xa inhibitors or to indirect factor Binding Xa inhibitor‐activated antithrombin Target affinity Affinity for direct factor Xa inhibitors. No effect on dabigatran Onset 2 min Half‐life Terminal = 6 hr Elimination Not reported $25,000 – $50,000 or more (CMS: New technology add‐on payment Cost (NTAP) ‐ FY2019 $14,062) Ruff CT et al. Circulation. 2016; 134:248‐61. Safety Outcomes (n=67) Event Incidence 30 day thromboembolic events 18% Antibodies to factor X, factor Xa, andexanet No issues alfa 30 day mortality 15% Connolly SJ et al. N Engl J Med. 2016; 375:1131–41. Copyright © 2018 American Society of Health-System Pharmacists, Inc. All rights reserved. 6 New Approaches for Reversing Oral Factor Xa Inhibitors: Examining the Evidence Andexanet Alfa: Reversing Oral Anti‐Xa Agents ng/mL Placebo Andexanet Infusion activity Xa Andexanet Bolus factor ‐ Anti Time (Hr) Siegal DM et al. N Engl J Med. 2015; 373:2413‐24. Use of PCC or aPCC* with Anti‐Xa DOAC Bleeding • No randomized comparisons to antidotes • Doses variable (8 – 100 units/kg) • Single doses and low doses in GI bleeds have worked – Onset seems to be rapid • No clear advantage –aPCC* over PCC with anti‐factor Xa agents (except heparin allergy) • Thrombosis has been reported ‐ ? If incidence higher • Mortality rates vary * = activated prothrombin complex concentrates (aPCC) Frontera JA et al. Neurocrit Care. 2016; 24:6‐46. Majeed A et al. Blood. 2017; 130:1706‐12. Shulman S et al. Thromb Haemost. 2018; 118:842‐51. Copyright © 2018 American Society of Health-System Pharmacists, Inc. All rights reserved. 7 New Approaches for Reversing Oral Factor Xa Inhibitors: Examining the Evidence PCC or aPCC with Anti‐Xa DOAC Bleeding Study Mortality VTE ANEXXA‐4 (Safety Population) (n=67) 15% 18% Majeed et al (n=84) –4factor PCC 32% 6% (1500‐2000 IU) Schulman et al (n=66) –4 factor PCC 14% 8% (2000 IU) Connolly SJ et al. N Engl J Med. 2016; 375:1131–41. Majeed A et al. Blood. 2017; 130:1706‐12. Shulman S et al. Thromb Haemost. 2018; 118:842‐51. Overall Goals •Stop or control the bleeding • Stabilize any comorbid conditions and observe • Identify contributing factors •Evaluate anticoagulation plan (? Restarting/prophylaxis) •Make any needed adjustments Copyright © 2018 American Society of Health-System Pharmacists, Inc. All rights reserved. 8 New Approaches for Reversing Oral Factor Xa Inhibitors: Examining the Evidence Overview of Key Clinical Trials: Reviewing the Evidence for Reversal of DOACs Mark Cipolle, M.D., Ph.D., FACS, FCCM Professor of Surgery, Sidney Kimmel School of Medicine Medical Director Trauma Program Christiana Care Health System Wilmington, Delaware As frontline providers caring for patients on DOACs who are bleeding, our biggest challenges are: 1. deciding who needs urgent reversal 2. knowing when, or if, to resume anticoagulation Copyright © 2018 American Society of Health-System Pharmacists, Inc. All rights reserved. 9 New Approaches for Reversing Oral Factor Xa Inhibitors: Examining the Evidence It’s all about balance! • 75‐year‐old man on dabigatran for atrial fibrillation slipped on the ice going to the gym • PT/INR and aPTT NORMAL • Thrombin Time (TT) >180 • Urgent craniectomy Copyright © 2018 American Society of Health-System Pharmacists, Inc. All rights reserved. 10 New Approaches for Reversing Oral Factor Xa Inhibitors: Examining the Evidence Comparison of bleeding rates between DOACs and warfarin: atrial fibrillation • Randomized trials –DOAC bleeding –Major bleeding = 2‐3% per year with DOAC –Intracranial hemorrhage (ICH) = 0.1 to 0.5% per year with DOAC •“Real world” N >50,000 – Dabigatran vs. warfarin •Major bleeding: 1.6 vs.