Reversal of DOACs Breakthroughs and Their Aftermath

Transcription

1 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

2 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

3 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?

4 Assess Patient History & Physical Anticoagulant LABs Imaging Consultation Drug Class Indication Last Dose ½ Life Clearance CBC As Indicated PTT/PT By H&P SCr LFTs Thrombin Time As Indicated By H&P

5 Target Specific Anticoagulants Key Points Rivaroxaban Apixaban Edoxaban Dabigatran Target Factor Xa Factor Xa Factor Xa Factor IIa T ½ 7-11 hrs 12 hrs 6-11 hrs single doses 9-10 hrs multiple doses hrs Clearance 30% Renal 60% Liver 25% Renal 75% Liver 33% Renal 60% Liver 80% Renal Metabolism CYP 450 CYP3A4 CYP2J2 CYP3A4 No No P-GP Yes Yes Yes Yes Dialysis removes 60% Dabigatran

6 Intervention Warfarin Vit K + 4 PCC Vit K + 3 PCC FFP rf VIIa IIa Inhibitor DOAC Idarucizumab Xa Inhibitor DOAC Vit K + 4 PCC Vit K + 3 PCC Andexanet Goals of Intervention 1. Fluid Resuscitation 2. Provide Rescue Clotting Factors 3. Increase Production of Normal Clotting Factors 4. Provide Anticoagulant Reversing Factor

7 Reversal Agents Target Mechanism Idarucizmab Andexanet Ruff C et al Circ 2016;134:248

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

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

10 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

11 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

12 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): $ Pollack C, et al N Engl J Med 2015;373:511

13 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

14 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

15 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

16 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

17 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

18 Define Major Bleeding Team Alert Patient Eval Labs Imaging Reversal Agent Post Reversal Management

19 Approach to Bleeding Ruff C et al Circ 2016;134:248

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21 Serious Bleeding

22 Urgent Surgery or Procedure

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26 Bleeding Anticoagulation ICH GI/GU Emergent Surgery Emergent Procedure Trauma Assess Patient Anticoagulant LABs Imaging Consultation Intervention Warfarin IIa Inhibitor DOAC Xa Inhibitor DOAC

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

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

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

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

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32 Idarucizumab DEVELOPMENT Monoclonal antibody then humanized and 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 Fully humanized antibody fragment (Fab) Glund S et al. AHA Abstr 17765; Schiele F et al. Blood 2013;121:

33 dtt (s) Idarucizumab Healthy Volunteers End of idarucizumab injection (5-min infusion) Dabigatran + placebo Dabigatran plus: Placebo (n=9) 2 g idarucizumab (day 4) (n=9) 4 g idarucizumab (day 4) (n=8) Normal upper reference limit (n=86) Mean baseline (n=86) Dabigatran Antidote Time after end of infusion (hours) Glund S et al. AHA Abstr 17765

34 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

35 Andexanet Alfa Recombinant Modified Version Human FXa Acts as a FXa decoy and retains high affinity for all FXa inhibitors GLA domain removed to prevent anticoagulant effect S419 A419 FXa Inhibitor High affinity retained GLA S S Catalytic Domain Activity eliminated to prevent thrombin generation N-terminal residues retained to reduce immunogenicity Ansell J. Nat Med. 2013;19(4)402.

36 Anti-FXa (ng/ml) Andexanet Alfa: Apixaban Phase II Apixaban 5mg bid x 6 d prior to andexanet/placebo bolus 420mg bolus + 4mg/min infusion over 2 hours: > 90 % reversal at 2 minutes > 90 % reversal at 2 hours Highly statistically significant Reversal sustained throughout antidote infusion Anti-FXa activity returns to normal decay curve after termination of infusion Well tolerated; no thrombotic events or serious adverse events reported No antibodies to FXa or FX detected Similar activity against rivaroxaban and enoxaparin End of Bolus Anti-FXa Activity End of Infusion Placebo (Cohorts 1-3, n=9) 420mg bolus only (n=6) 420mg bolus + 480mg infusion (n=6) Time after bolus in hours Crowther MA, et al. J Thromb Haemost. 2013;11:AS20.

37 Anti-FXa (ng/ml) Andexanet Alfa: Rivaroxaban Phase II Rivaroxaban 20mg qd x 6 d prior to andexanet/placebo 800mg bolus + 8mg/min infusion over 2 hours: - > 90% reversal at 2 minutes - > 90 % reversal at 2 hours - Highly statistically significant Reversal sustained throughout antidote infusion - Anti-FXa activity returns to normal decay curve after termination of infusion Well tolerated; no thrombotic events or serious adverse events reported No antibodies to FXa or FX detected End of Bolus Anti-FXa Activity End of Infusion Placebo (Cohorts 1-3, n=9) 800mg bolus + 960mg infusion (n=6) Time after bolus in hours Crowther MA, et al. Blood. 2013;122:A3636.

38 Anti-FXa (IU/mL) Andexanet Alfa: Enoxaparin Phase II Anti-FXa Activity Hit clinical threshold for enoxaparin reversal ( 0.2 IU/ml) Restoration of thrombin generation within normal range Well tolerated; no thrombotic events or serious adverse events reported No antibodies to FXa or FX detected 0.5 End of Bolus AnXa vs. Placebo *p<0.0001; **p<0.005 Lower limit of detection Placebo (Cohorts 1-3, n=9) 210mg bolus only (Cohort 1, n=6) 420mg bolus only (Cohort 2, n=6) 210mg (Lyo) bolus only (Cohort 3, n=6) Time after bolus in hours 41 Crowther MA, et al. J Thromb Haemost. 2014;12(suppl 1):7.

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