1. ACCP Cardiology PRN Journal Club

2. Announcements Thank you attending the ACCP Cardiology PRN Journal Club – Thank you if you attended before or have been attending I have created a PB Works Site that will house our recorded calls, handouts, and Summary/Q&A documents. The link is https://accpcardsprnjournalclub.pbworks.com/ If there are any suggestions, please let us know.

3. Idarucizumab for Dabigatran Reversal Ted Berei, PharmD, MBA PGY2 Cardiology Resident Abbott Northwestern Hospital, Minneapolis Heart Institute Minneapolis, MN

4. Disclosures Presenters have no conflicts to report related to financial or personal relationships with commercial entities (or their competitors) that may be referenced in this presentation

5. Background Dabigatran is FDA approved for the treatment of DVT/PE, non-valvular atrial fibrillation, and DVT prophylaxis Clinical situations occur (i.e. major bleeds, emergent surgery, etc.) where complete reversal of anticoagulation is desirable Idarucizumab (Praxbind®) is a first-in-class monoclonal antibody that binds both free and thrombin-bound Dabigatran (as well as glucuronide metabolites) Dabigatran [package insert]. Available at: http://www.uptodate.com/contents/dabigatran-druginformation?source =search_result&search=dabigatran&selectedTitle=1~112. Idarucizumab [package insert]. Available at: http://www.uptodate.com/contents/ idarucizumab-drug-information?source =search_result&search=idarucizumab&selectedTitle =1~16.http://www.uptodate.com/contents/ idarucizumab-drug-information?source

6. Current Reversal Practices No current practice standard when it comes to reversing dabigatran Dilute thrombin time (dTT) and chromogenic ecarin clotting time (ECT) can be calibrated to correlate with serum Dabigatran levels Thrombin time and aPTT can also be used to detect “presence” of dabigatran Mixed results with using a variety of methods: Hemodialysis Four-Factor Prothrombin Complex Concentrate (PCC) Recombinant Factor VIIa (rFVIIa) Fresh Frozen Plasma (FFP) Ann of Pharm. 2013;47: 841-854.

7. Idarucizumab (Praxbind®) Phase I and II trials in > 200 patients established Idarucizumab was well tolerated (doses up to 8g) Affinity for dabigatran ~ 350x higher than Dabigatran’s affinity for thrombin Once bound, idarucizumab neutralized dabigatran’s anticoagulant effect Property AdministrationIntravenous Dosing5g total (2 – 2.5 g boluses separated by NO more than 15 minutes) T 1/2 Biphasic; initial = 45 minutes, terminal = ~ 4.4-8.1 hours Onset of Action1-2 minutes Route of EliminationRenal StorageRequires refrigeration Stability2 years Thromb Haemost. 2015;113:943-951 Blood. 2014;124 Circulation. 2015;132:2412-2422

8. FDA Approval & Availability Approved by the FDA in October 2015 FDA labeling: Reversal of dabigatran for emergency surgery/urgent procedures or in life- threatening or uncontrolled bleeding Supplied as 2.5g vials (5g total dose) Cost = ~ $ 4,200 for 5g dose

9. Funded by Boehringer Ingelheim (manufacturers of dabigatran) Multi-center, prospective, cohort study Will enroll 300 total patients 400 centers, 38 countries NO randomization or placebo arm Analysis of the first 90 patients enrolled in REVERSE-AD was presented REVERSE-AD: Background N Engl J Med, 2015, 373: 511-520

10. REVERSE-AD: Study Objectives Demonstrate the efficacy and safety of idarucizumab for the reversal of the anticoagulant effects of dabigatran in patients who presented with serious bleeding or who require urgent surgery or intervention N Engl J Med, 2015, 373: 511-520

11. REVERSE-AD: Trial Design 300 patients total 90 patients analyzed for this cohort snapshot Groups A (n = 51) Overt, uncontrollable, or life- threatening bleeding B (n = 39) Emergent procedure or surgery required within 8 hours Idarucizumab Administered as 2- 2.5g boluses (5g total dose, 50 mL each) Boluses administered within 15 minutes of one another N Engl J Med, 2015, 373: 511-520

12. REVERSE-AD: Trial Design, Laboratory Monitoring Circulation. 2015;132:2412-2422.

13. Maximum % reversal of the anticoagulant effect of dabigatran within 4 hours, based on central laboratory determination of the dTT or ECT Calculated as: ([Pre-dose test result (seconds) – Minimum post-dose test result (seconds)]/ [Pre- dose test result (seconds) – Upper limit of normal range (seconds)] x 100) REVERSE-AD: Primary Endpoint N Engl J Med, 2015, 373: 511-520

14. REVERSE-AD: Patient Population (Group A) Overt major or life-threatening bleeding judged by the physician to require a reversal agent Inclusion CriteriaExclusion Criteria - Age ≥18 years - Currently taking dabigatran etexilate - Bleeding associated with hypotension requiring use of intravenous inotropic agents - Patients with minor bleeds (epistaxis, hematuria) who can be managed with standard supportive care - Fatal bleeding - Symptomatic intracranial bleeding - Bleeding necessitating surgical intervention - Patients with no clinical signs of bleeding - Reduction in hemoglobin of at least 5 g/dL - Transfusion of at least 4 units of blood or packed cells - Contraindications to study medication including known hypersensitivity to the drug or its excipients. N Engl J Med, 2015, 373: 511-520

15. REVERSE-AD: Patient Population (Group B) Requiring emergency surgery or procedure for a condition other than bleeding (within 8 hours) Inclusion CriteriaExclusion Criteria - Current treatment with dabigatran- A surgery or procedure which is elective or where the risk of uncontrolled or unmanageable bleeding is low - Age ≥18 years- Contraindications to study medication including known hypersensitivity to the drug or its excipients (such as subjects with hereditary fructose intolerance who may react to sorbitol) N Engl J Med, 2015, 373: 511-520

16. REVERSE-AD: Baseline Characteristics CharacteristicGroup A (N = 51) Group B (N = 39) Total (N = 90) Age (yr, median)777676.5 Male321850 Atrial Fibrillation as indication for dabigatran473986 Time since last intake of Dabigatran < 12 hr171532 12 to, 24 hr211031 24 to, 48 hr121022 > 48 hr145 Elevated ECT at baseline402868 Elevated dTT at baseline473481 Type of Bleeding Intracranial18- Trauma-related9-9 GI20- Other11- Dose of Dabigatran 150mg BID141529 110mg BID342458 75mg BID101 N Engl J Med, 2015, 373: 511-520

17. Median maximum percentage reversal in the patients in group A and in those in group B was 100% (95% confidence interval, 100 to 100) 22 patients with a normal dTT and 9 with a normal ECT based on central laboratory testing Excluded from final efficacy analysis dTT = 68 patients assessed  (40 patients Group A, 28 patients Group B) ECT = 81 patients assessed  (47 patients Group A, 34 patients Group B) REVERSE-AD: Results N Engl J Med, 2015, 373: 511-520

18. REVERSE-AD: Results (Primary Outcome) * Dilute Thrombin Time (dTT) * Group AGroup B Mean dTT at baseline54.1 (n=51, SD=23.6)53.2 (n=39, SD=38.5) Mean dTT between vials29.7 (n=51, SD=2.46)32.9 (n=39, SD=20.9) Mean dTT 10-30 min after second vial29.8 (n=51, SD=2.42)31.3 (n=39, SD=12.4) Mean dTT 4 h +/- 30 min after second vial29.6 (n=46, SD= 2.59)35.8 (n=37. SD=25.5) N Engl J Med, 2015, 373: 511-520

19. REVERSE-AD: Results (Primary Outcome) * Ecarin Clotting Time (ECT) * Group AGroup B Mean ECT at baseline113 (n=51, SD= 79.0)111 (n=39, SD=97.1) Mean ECT between vials38.2 (n=51, SD=6.00)45.3 (n=39, SD=44.0) Mean ECT 10-30 min after second vial39.3 (n=51, SD=6.72)44.6 (n=39, SD=43.5) Mean ECT 4 h +/- 30 min after second vial37.7 (n=47, SD=4.06)59.0 (n=37, SD=85.3) N Engl J Med, 2015, 373: 511-520

20. REVERSE-AD: Results (Secondary Outcome) * Unbound (free) dabigatran [ng/mL] * Group AGroup B Mean unbound dabigatran at baseline161 (n=48, SD=166)218 (n=39, SD=503) Mean unbound dabigatran between vials1.11 (n=48, SD= 0.288)34.6 (n=39, SD=206) Mean unbound dabigatran 10-30 min after second vial 1.08 (n=48, SD=0.431)18.5 (n=39, SD=107) Mean unbound dabigatran 4 h +/- 30 min after second vial 1.01 (n=46, SD=0.0516)63.9 (n=38, SD=277) N Engl J Med, 2015, 373: 511-520

21. REVERSE-AD: Results (Secondary Outcomes) ** Time to cessation of bleeding (for Group A only) Median investigator-reported time to the cessation of bleeding for patients was 11.4 hours Occurrence of major bleeding (for group B only) intraoperatively and up to 24 hours post-surgery Of the 36 patients who received a procedure: Normal intraoperative hemostasis was reported in 33 (92%) patients Mildly abnormal hemostasis during the procedure was reported in 2 patients Moderately abnormal hemostasis reported in 1 patient N Engl J Med, 2015, 373: 511-520

22. REVERSE-AD: Results (Adverse Events) Deaths 18 total (9 in each group) 10 due to vascular causes (5 fatal bleeds) 9 deaths occurred > 96 hours after treatment and appear related to index event Thrombotic Events Occurred in five patients overall (none were on any anti-thrombotic agents at the time of these events) N Engl J Med, 2015, 373: 511-520

23. Idarucizumab is safe and effective for reversing the anticoagulant effects of dabigatran for patients presenting with overt, uncontrollable, life-threatening bleeding or needing urgent surgery or procedure within 8 hours REVERSE-AD: Author’s Conclusions

24. Small population analyzed in a non-randomized way without placebo or alternative intervention dTT and ECT are not readily available at most institutions Idarucizumab was effective at mitigating dabigatran’s anticoagulant effect Deaths appear related to index admission as opposed to drug Rebound effect of dabigatran at 24 hours witnessed in both A and B group Median investigator-reported time to the cessation of bleeding for group A patients was 11.4 hours REVERSE-AD: Reviewer’s Conclusions

25. Demonstrated that idarucizumab safely and efficaciously reverses anticoagulation induced by dabigatran administration Standardization of laboratory testing and monitoring will be necessary on an institution-to-institution basis dTT vs. ECT vs. TT vs. aPTT Consideration must be given to time of last dabigatran dose and native renal function when deciding whether idarucizumab is appropriate T 1/2 : 12-17 hours; Elderly: 14-17 hours; Mild/moderate: 15-18 hours; Severe: 28 hours Must be vigilant about perioperative DOAC use CrCl ≥ 50 mL/min = 1-2 days | CrCl < 50 mL/min = 3-5 days i.e. discontinuation at the appropriate time depending on renal function Local hemostasis protocols need to clearly define how idarucizumab should be used based on the clinical situation in conjunction with other reversal options REVERSE-AD: Takeaways

26. Potential Pathway for Utilization Patient Presentation Attempt to determine dabigatran presence (i.e. local clotting assays) Consider: Last dose, renal function, age Local Hemostasis Protocol (utilization of PCC, rFVIIa, FFP, hemodialysis, etc.) Non Life-Threatening Bleeding Life-Threatening or Urgent Bleeding Urgent Surgery or Procedure Idarucizumab 5g +/- other interventions Resume anticoagulation as soon as possible depending on patient specific factors Activated Charcoal? Coags monitoring for normalization Circulation. 2015;132:2412-2422.

27. Clinical Questions Where does idarucizumab fit into local hemostasis protcols? Which coagulation assays should be used? How often should we monitor them? Do we have thresholds for determining the appropriateness of idarucizumab administration based on these? Is re-dosing necessary? If so, how often and how much? Can we use idarucizumab to allow for thrombolytic qualification in TIA patients?

28. Looking Ahead……. Complete trial enrollment for REVERSE-AD is expected by 2017 Aripazine (PER977) - universal reversal agent for oral direct thrombin and factor XA inhibitors, injectable UFH, LMWH, and fondaparinux Synthetic molecule IV administration Stored at room temp Currently only phase II trials underway

29. References 1.Dabigatran [package insert]. Available at: http://www.uptodate.com/contents/dabigatran-druginformation?source =search_result&search=dabigatran&selectedTitle=1~112. Accessed February 17, 2016. 2.Idarucizumab [package insert]. Available at: http://www.uptodate.com/contents/ idarucizumab-drug- information?source =search_result&search=idarucizumab&selectedTitle =1~16. Accessed February 17, 2016.http://www.uptodate.com/contents/ idarucizumab-drug- information?source 3.Nitzki-George, D, Wozniak I, Caprini, J. Current State of Knowledge on Oral Anticoagulant Reversal Using Procoagulant Factors. Ann of Pharm. 2013;47: 841-854. 4.Glund S, Moschetti V, Norris S, et al. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost. 2015;113:943- 951. 5. Glund S, Stangier J, Schmohl M,et al. Idarucizumab, a specific antidote for dabigatran: Immediate, complete and sustained reversal of dabigatran induced anticoagulation in elderly and renally impaired subjects. Blood. 2014;124. 6. Eikelboom JW, Quinlan DJ, van Ryn J, et al. Idarucizumab: The antidote for reversal of dabigatran. Circulation. 2015;132:2412-2422. 7. Pollack, CV, Reilly, PA, Eikelboom, J, et al. Idarucizumab for Dabigatran Reversal. N Engl J Med, 2015, 373: 511-520

30. Acknowledgements Journal Club Mentor Jeff Langford, PharmD, BCPS Program Director Matthew Lillyblad, PharmD, BCPS ACC Cardiology PRN Journal Club Coordinator Craig Beavers, PharmD, FAHA, AACC, BCPS AQ-Cardiology, CACP

31. Idarucizumab for Dabigatran Reversal Ted Berei, PharmD, MBA PGY2 Cardiology Resident Abbott Northwestern Hospital, Minneapolis Heart Institute Minneapolis, MN

32. Thank you for attending! If you would like to have your resident present, would like to be a mentor, or have questions or comments please e-mail the journal club at accpcardsprnjournalclub@gmail.com or craig.beaverspharmd@gmail.comcraig.beaverspharmd@gmail.com Join us next month when Zachary Noel, PGY-2 in Cardiology at University of Kentucky Healthcare, will present