Reversal of DOACs Breakthroughs and Their Aftermath

Geno J Merli, MD, MACP, FSVM, FHM Professor Medicine & Surgery Co-Director Jefferson Vascular Center Sidney Kimmel Medical College Thomas Jefferson University Hospitals Disclosure Financial Relationships Geno J. Merli, MD, MACP, FHM, FSVM

• Jannsen: Research (Medically ill) • Bristol-Meyer Squibb: Research ADIOS Study • Portola: Research • LoweRisk LLC, Co-Chief Development Officer Reversal of DOACs Breakthroughs and Aftermath

1. Has the emergence of reversal agents for DOACs impacted on prescribing behavior or improved clinical outcomes? 2. What education needs to be disseminated about reversal agents and how should that be done effectively? 3. How should reversal strategies be used appropriately and what can the ACC do to encourage appropriate use? 4. What is the expectation of availability for emerging reversal agents for DOACs? At minimum, should all stroke and trauma centers be required to carry all reversal agents? Assess Patient

History & Physical

Anticoagulant LABs Imaging Consultation

. Drug Class . CBC As Indicated As Indicated . Indication . PTT/PT By H&P By H&P . Last Dose . SCr . ½ Life . LFTs . Clearance . Thrombin Time Target Specific

Key Points Rivaroxaban Apixaban Edoxaban Target Factor Xa Factor Xa Factor Xa Factor IIa T ½ 7-11 hrs 12 hrs 6-11 hrs 12-17 hrs single doses 9-10 hrs multiple doses Clearance 30% Renal 25% Renal 33% Renal 80% Renal 60% Liver 75% Liver 60% Liver Metabolism CYP3A4 CYP3A4 No No CYP 450 CYP2J2

P-GP Yes Yes Yes Yes Dialysis removes 60% Dabigatran Intervention

Warfarin IIa Inhibitor Xa Inhibitor DOAC DOAC . Vit K + 4 PCC . Vit K + 4 PCC . Vit K + 3 PCC Idarucizumab . Vit K + 3 PCC . FFP . rF VIIa Andexanet

Goals of Intervention 1. Fluid Resuscitation 2. Provide Rescue Clotting Factors 3. Increase Production of Normal Clotting Factors 4. Provide Reversing Factor Reversal Agents Target Mechanism

Idarucizmab

Andexanet

Ruff C et al Circ 2016;134:248 (PER977)

Ruff C et al Circ 2016;134:248 DOAC Reversing Agents

Key Points Idarucizumab Andexanet Chemical structure Human Monoclonal Recombinant truncated Antibody fragment human Factor Xa variant (decoy) Onset < 5 min 2 min Half-Life Initial 47 minutes Terminal 6hrs Terminal 10.3 hrs Elimination Kidney Not reported Binding Non-competitive Competitive binding to binding to dabigatran direct Factor Xa inhibitors or to indirect Factor Xa inhibitors- activated AT III Target Affinity 350 greater affinity for Affinity for Direct FXa dabigatran than IIa inhibitors similar to that of native FXa Storage Refrigerate Refrigerate 51 Patients Serious Bleeding 39 Patients Urgent Surgery

Conclusion: Idarucizumab completely reversed the anticoagulant effect of Dabigatran within minutes.

Pollack C, et al N Engl J Med 2015;373:511 Idarucizumab Major Bleeding Criteria . Group A . Overt, uncontrollable, or life-threatening bleeding that was judged by the treating clinician to require a reversal agent. . Group B . who required surgery or other invasive procedures that could not be delayed for at least 8 hours and for which normal hemostasis was required.

Pollack C, et al N Engl J Med 2015;373:511 Idarucizumab Dosing Schedule

1. Prior to administration, flush preexisting IV line with sodium chloride 0.9%. 2. Administer dose undiluted as an IV bolus either via syringe or as an infusion by hanging the vials. Infusion of each vial should take no longer than 5 to 10 minutes with the second vial of 2.5 g administered no later than 15 minutes after the end of the first 2.5 g vial. 3. Do not administer any other infusion in the same IV line. 4. Baseline aPTT (at presentation), repeat at 2 hours postexposure (if exposure time is known) or post-presentation (if exposure time is unknown) and every 12 hours thereafter until aPTT returns to normal. 2.5 gm/50 mL (50 mL): $2100.00

Pollack C, et al N Engl J Med 2015;373:511 Thrombotic Events or Death 30 Days Idarucizumab

. 5 Patients DVT/PE . 2 days post Rxment: DVT/PE . 9 days post Rxment: DVT/PE/Left Atrial thrombus . 7 days post Rxment: DVT . 13 days post Rxment: NSTEMI . 26 days post Rxment: Stroke

Pollack C, et al N Engl J Med 2015;373:511 67 patients acute major bleeding within 18 hours after the administration of a factor Xa inhibitor.

Conclusion: andexanet substantially reduced anti–factor Xa activity in patients with acute major bleeding associated with factor Xa inhibitors, with effective hemostasis occurring in 79%. Connolly S, et al N Engl J Med 2016;375:1131 Andexanet Major Bleeding Criteria

1. Potentially life-threatening 2. Acute overt bleeding with signs or symptoms of hemodynamic compromise (e.g., severe hypotension hypotension, poor skin perfusion, mental confusion, or low cardiac output that could not otherwise be explained) 3. Acute overt bleeding associated with a decrease in hemoglobin of at least 2 g or a hemoglobin level of 8 g or less if no baseline hemoglobin level was available 4. Acute symptomatic bleeding in a critical area or organ (e.g., retroperitoneal, intraarticular, pericardial, intracranial, or intramuscular with the compartment syndrome).

Connolly S, et al N Engl J Med 2016;375:1131 Andexanet Dosing Schedule

. Apixaban or Rivaroxaban > 7 hours before Rxment . Bolus dose: 400 mg [15-30 min] . Infusion dose: 480 mg [over 2 hrs] . Enoxaparin, Edoxaban, or Rivaroxaban < 7 hours or less before Rxment or an Unknown time. . Bolus dose: 800 mg [15-30 min] . Infusion dose: 960 mg [over 2 hrs]

Connolly S, et al N Engl J Med 2016;375:1131 Thrombotic Events or Death 30 Days

Thrombotic Event 18% (12/67) 1 Myocardial Infarction 5 Strokes 7 DVTs 1 PE Some patient more than 1 event

4 Thrombotic Event within 3 days 8 Thrombotic Events within 4-30 days

Connolly S, et al N Engl J Med 2016;375:1131 Define Major Bleeding

Team Alert Patient Eval Labs Imaging

Reversal Agent

Post Reversal Management Approach to Bleeding

Ruff C et al Circ 2016;134:248

Serious Bleeding Urgent Surgery or Procedure

Bleeding Anticoagulation

ICH GI/GU Emergent Emergent Trauma Surgery Procedure

Assess Patient

Anticoagulant LABs Imaging Consultation

Intervention

Xa Inhibitor IIa Inhibitor DOAC DOAC Rivaroxaban

Connolly S, et al N Engl J Med 2016;375:1131 Apixaban

Connolly S, et al N Engl J Med 2016;375:1131 Connolly S, et al N Engl J Med 2016;375:1131 Connolly S, et al N Engl J Med 2016;375:1131 [email protected] Idarucizumab

DEVELOPMENT Fully humanized • then humanized and antibody fragment (Fab) directly expressed as a Fab fragment in hamster cells PROPERTIES • Potent binding affinity ~350 times higher than binding of dabigatran to thrombin • No procoagulant or anticoagulant effects expected • Short half life • Intravenous administration, immediate onset of action EXPECTED LOW RISK OF ADVERSE REACTIONS • No Fc receptor binding • No endogenous targets

Glund S et al. AHA 2013. Abstr 17765; Schiele F et al. Blood 2013;121:3554–62 Idarucizumab Healthy Volunteers

End of idarucizumab injection (5-min infusion) 70 Dabigatran plus: 65 Placebo (n=9) 2 g idarucizumab (day 4) (n=9) 60 4 g idarucizumab (day 4) (n=8) Normal upper reference limit (n=86)

55 Mean baseline (n=86) Dabigatran + placebo 50

dTT (s) dTT 45

40

35

30 –2 0 2 4 6 8 10 12 24 36 48 60 72

Dabigatran Time after end of infusion (hours) Glund S et al. AHA 2013. Abstr 17765 Dilute Thrombin Time Ecrin Clotting Time

51 Serious Bleeding 51 Serious Bleeding

Two 2.5 Gram IV, 15 mins apart Pollack C, et al NEJM 2015 Recombinant Modified Version Human FXa

Acts as a FXa decoy and retains high affinity for all FXa inhibitors

GLA domain FXa Inhibitor removed to prevent High affinity retained anticoagulant effect S419 A419

GLA

Catalytic Domain Activity eliminated to prevent S S thrombin generation

N-terminal residues retained to reduce immunogenicity

Ansell J. Nat Med. 2013;19(4)402. Andexanet Alfa: Apixaban Phase II

• Apixaban 5mg bid x 6 d prior to andexanet/placebo bolus Anti-FXa Activity • 420mg bolus + 4mg/min End of Bolus End of Infusion infusion over 2 hours: – > 90 % reversal at 2 minutes 250 Placebo (Cohorts 1-3, n=9) – > 90 % reversal at 2 hours – Highly statistically significant 200 420mg bolus only (n=6) 420mg bolus + 480mg

• Reversal sustained throughout infusion (n=6) antidote infusion 150 – Anti-FXa activity returns to normal decay curve after

termination of infusion 100 Xa Xa (ng/mL)

• Well tolerated; no thrombotic F - events or serious adverse 50 events reported Anti 0 • No antibodies to FXa or FX 0.0 0.2 0.4 0.6 1 2 3 4 5 6 7 8 9 10 detected Time after bolus in hours • Similar activity against rivaroxaban and enoxaparin Crowther MA, et al. J Thromb Haemost. 2013;11:AS20. Andexanet Alfa: Rivaroxaban Phase II

. Rivaroxaban 20mg qd x 6 d prior Anti-FXa Activity to andexanet/placebo . 800mg bolus + 8mg/min infusion End of Bolus End of Infusion over 2 hours: - > 90% reversal at 2 minutes 400 Placebo (Cohorts 1-3, n=9)

- > 90 % reversal at 2 hours 800mg bolus + 960mg - Highly statistically significant infusion (n=6) . Reversal sustained throughout 300 antidote infusion - Anti-FXa activity returns to Xa Xa (ng/mL) 200

normal decay curve after F - termination of infusion . Well tolerated; no thrombotic Anti 100 events or serious adverse events reported . No antibodies to FXa or FX 0 detected 0.0 0.2 0.4 0.6 1 2 3 4 5 6 7 8 9 10 Time after bolus in hours

Crowther MA, et al. Blood. 2013;122:A3636. Andexanet Alfa: Enoxaparin Phase II

Anti-FXa Activity

Placebo (Cohorts 1-3, n=9) . Hit clinical threshold for 0.5 210mg bolus only (Cohort 1, n=6) enoxaparin reversal 420mg bolus only (Cohort 2, n=6) (≤ 0.2 IU/ml) End of Bolus 210mg (Lyo) bolus only (Cohort 3, n=6) 0.4 . Restoration of thrombin

generation within normal 0.3 range . Well tolerated; no 0.2 thrombotic events or Xa Xa (IU/mL) Lower limit of

F 0.1 serious adverse events - detection reported Anti 0.0 . No antibodies to FXa or FX 0.0 0.2 0.4 0.6 1 2 3 4 5 6 7 8 9 10 detected Time after bolus in hours AnXa vs. Placebo *p<0.0001; **p<0.005

Crowther MA, et al. J Thromb Haemost. 2014;12(suppl 1):7.41 Thrombotic Events or Death 30 Days

Connolly S, et al N Engl J Med 2016;375:1131