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ACCP Cardiology PRN Journal Club ACCP Cardiology PRN Journal Club

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Idarucizumab for Dabigatran Reversal Ted Berei, Pharm. D, MBA PGY 2 Cardiology Resident Abbott Idarucizumab for Dabigatran Reversal Ted Berei, Pharm. D, MBA PGY 2 Cardiology Resident Abbott Northwestern Hospital, Minneapolis Heart Institute Minneapolis, MN

Disclosures Presenters have no conflicts to report related to financial or personal relationships with 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

Background • Dabigatran is FDA approved for the treatment of DVT/PE, non-valvular atrial fibrillation, 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&selected. Title=1~112. Idarucizumab [package insert]. Available at: http: //www. uptodate. com/contents/ idarucizumab-drug-information? source =search_result&search=idarucizumab&selected. Title =1~16.

Current Reversal Practices • No current practice standard when it comes to reversing dabigatran Current Reversal Practices • No current practice standard when it comes to reversing dabigatran • Dilute thrombin time (d. TT) and chromogenic ecarin clotting time (ECT) can be calibrated to correlate with serum Dabigatran levels • Thrombin time and a. PTT 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 (r. FVIIa) • Fresh Frozen Plasma (FFP) Ann of Pharm. 2013; 47: 841 -854.

Idarucizumab (Praxbind®) Property • Phase I and II trials in > 200 patients established Idarucizumab (Praxbind®) Property • Phase I and II trials in > 200 patients established Idarucizumab was well tolerated (doses up to 8 g) Administration Dosing • Affinity for dabigatran ~ 350 x higher than Dabigatran’s affinity for thrombin 5 g 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 • Once bound, idarucizumab neutralized dabigatran’s anticoagulant effect Onset of Action Route of Elimination Intravenous 1 -2 minutes Renal Storage Stability Thromb Haemost. 2015; 113: 943 -951 Blood. 2014; 124 Circulation. 2015; 132: 2412 -2422 Requires refrigeration 2 years

FDA Approval & Availability • Approved by the FDA in October 2015 • FDA FDA Approval & Availability • Approved by the FDA in October 2015 • FDA labeling: • Reversal of dabigatran for emergency surgery/urgent procedures or in lifethreatening or uncontrolled bleeding • Supplied as 2. 5 g vials (5 g total dose) • Cost = ~ $ 4, 200 for 5 g dose

REVERSE-AD: Background • Funded by Boehringer Ingelheim (manufacturers of dabigatran) • Multi-center, prospective, cohort REVERSE-AD: Background • 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 N Engl J Med, 2015, 373: 511 -520

REVERSE-AD: Study Objectives Demonstrate the efficacy and safety of idarucizumab for the reversal of 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

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

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

REVERSE-AD: Primary Endpoint Maximum % reversal of the anticoagulant effect of dabigatran within 4 REVERSE-AD: Primary Endpoint Maximum % reversal of the anticoagulant effect of dabigatran within 4 hours, based on central laboratory determination of the d. TT 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) N Engl J Med, 2015, 373: 511 -520

REVERSE-AD: Patient Population (Group A) Overt major or life-threatening bleeding judged by the physician REVERSE-AD: Patient Population (Group A) Overt major or life-threatening bleeding judged by the physician to require a reversal agent Inclusion Criteria Exclusion 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/d. L - 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

REVERSE-AD: Patient Population (Group B) Requiring emergency surgery or procedure for a condition other REVERSE-AD: Patient Population (Group B) Requiring emergency surgery or procedure for a condition other than bleeding (within 8 hours) Inclusion Criteria Exclusion 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

REVERSE-AD: Baseline Characteristics Characteristic Group A (N = 51) Group B (N = 39) REVERSE-AD: Baseline Characteristics Characteristic Group A (N = 51) Group B (N = 39) Total (N = 90) Age (yr, median) 77 76 76. 5 Male 32 18 50 Atrial Fibrillation as indication for dabigatran 47 39 86 < 12 hr 17 15 32 12 to , 24 hr 21 10 31 24 to , 48 hr 12 10 22 > 48 hr 1 4 5 Elevated ECT at baseline 40 28 68 Elevated d. TT at baseline 47 34 81 Intracranial 18 - 18 Trauma-related 9 - 9 GI 20 - 20 Other 11 - 11 150 mg BID 14 15 29 110 mg BID 34 24 58 75 mg BID 1 0 1 Time since last intake of Dabigatran Type of Bleeding Dose of Dabigatran N Engl J Med, 2015, 373: 511 -520

REVERSE-AD: Results • Median maximum percentage reversal in the patients in group A and REVERSE-AD: Results • 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 d. TT and 9 with a normal ECT based on central laboratory testing • Excluded from final efficacy analysis • d. TT = 68 patients assessed (40 patients Group A, 28 patients Group B) • ECT = 81 patients assessed (47 patients Group A, 34 patients Group B) N Engl J Med, 2015, 373: 511 -520

REVERSE-AD: Results (Primary Outcome) * Dilute Thrombin Time (d. TT) * Group A Group REVERSE-AD: Results (Primary Outcome) * Dilute Thrombin Time (d. TT) * Group A Group B Mean d. TT at baseline 54. 1 (n=51, SD=23. 6) 53. 2 (n=39, SD=38. 5) Mean d. TT between vials 29. 7 (n=51, SD=2. 46) 32. 9 (n=39, SD=20. 9) Mean d. TT 10 -30 min after second vial 29. 8 (n=51, SD=2. 42) 31. 3 (n=39, SD=12. 4) Mean d. TT 4 h +/- 30 min after second vial 29. 6 (n=46, SD= 2. 59) 35. 8 (n=37. SD=25. 5) N Engl J Med, 2015, 373: 511 -520

REVERSE-AD: Results (Primary Outcome) * Ecarin Clotting Time (ECT) * Group A Group B REVERSE-AD: Results (Primary Outcome) * Ecarin Clotting Time (ECT) * Group A Group B Mean ECT at baseline 113 (n=51, SD= 79. 0) 111 (n=39, SD=97. 1) Mean ECT between vials 38. 2 (n=51, SD=6. 00) 45. 3 (n=39, SD=44. 0) Mean ECT 10 -30 min after second vial 39. 3 (n=51, SD=6. 72) Mean ECT 4 h +/- 30 min after second vial 37. 7 (n=47, SD=4. 06) N Engl J Med, 2015, 373: 511 -520 44. 6 (n=39, SD=43. 5) 59. 0 (n=37, SD=85. 3)

REVERSE-AD: Results (Secondary Outcome) * Unbound (free) dabigatran [ng/m. L] * Group A Mean REVERSE-AD: Results (Secondary Outcome) * Unbound (free) dabigatran [ng/m. L] * Group A Mean unbound dabigatran at baseline Mean unbound dabigatran between vials Group B 161 (n=48, SD=166) 218 (n=39, SD=503) 1. 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

REVERSE-AD: Results (Secondary Outcomes) ** Time to cessation of bleeding (for Group A only) 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

REVERSE-AD: Results (Adverse Events) Deaths • 18 total (9 in each group) • 10 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

REVERSE-AD: Author’s Conclusions Idarucizumab is safe and effective for reversing the anticoagulant effects of REVERSE-AD: Author’s Conclusions 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: Reviewer’s Conclusions • Small population analyzed in a non-randomized way without placebo or REVERSE-AD: Reviewer’s Conclusions • Small population analyzed in a non-randomized way without placebo or alternative intervention • d. TT 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: Takeaways • Demonstrated that idarucizumab safely and efficaciously reverses anticoagulation induced by dabigatran REVERSE-AD: Takeaways • 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 • d. TT vs. ECT vs. TT vs. a. PTT • 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 • Cr. Cl ≥ 50 m. L/min = 1 -2 days | Cr. Cl < 50 m. L/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

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

Clinical Questions • Where does idarucizumab fit into local hemostasis protcols? • Which coagulation 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?

Looking Ahead……. • Complete trial enrollment for REVERSE-AD is expected by 2017 • Aripazine Looking Ahead……. • Complete trial enrollment for REVERSE-AD is expected by 2017 • Aripazine (PER 977) - 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

References 1. 2. 3. 4. 5. 6. 7. Dabigatran [package insert]. Available at: http: References 1. 2. 3. 4. 5. 6. 7. Dabigatran [package insert]. Available at: http: //www. uptodate. com/contents/dabigatran-druginformation? source =search_result&search=dabigatran&selected. Title=1~112. Accessed February 17, 2016. Idarucizumab [package insert]. Available at: http: //www. uptodate. com/contents/ idarucizumab-druginformation? source =search_result&search=idarucizumab&selected. Title =1~16. Accessed February 17, 2016. 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. 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: 943951. 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. Eikelboom JW, Quinlan DJ, van Ryn J, et al. Idarucizumab: The antidote for reversal of dabigatran. Circulation. 2015; 132: 2412 -2422. Pollack, CV, Reilly, PA, Eikelboom, J, et al. Idarucizumab for Dabigatran Reversal. N Engl J Med, 2015, 373: 511 -520

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

Idarucizumab for Dabigatran Reversal Ted Berei, Pharm. D, MBA PGY 2 Cardiology Resident Abbott Idarucizumab for Dabigatran Reversal Ted Berei, Pharm. D, MBA PGY 2 Cardiology Resident Abbott Northwestern Hospital, Minneapolis Heart Institute Minneapolis, MN

Thank you for attending! • If you would like to have your resident present, 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 [email protected] com or craig. [email protected] com • Join us next month when Zachary Noel, PGY-2 in Cardiology at University of Kentucky Healthcare, will present