DOACs Can Be Reversed!

Transcription

1 1 DOACs Can Be Reversed! AC Forum 14 th National Conference April 21, 2017 Adam Cuker, MD, MS Perelman School of Medicine University of Pennsylvania

2 2 Full disclosures (last 12 months) Research support NIH Biogen-Idec Spark Therapeutics T2 Biosystems Consultant/Advisory Board Sanofi/Genzyme Diagnostica Stago Biogen-Idec Off-label use Some treatments are not FDA-approved for DOAC reversal

3 3 Outline I. Basic principles of reversal II. Idarucizumab III. Andexanet alfa IV. Ciraparantag V. Prothrombin Complex Concentrate (PCC) VI. Activated PCC

4 4 Case (1) A 71-year old man presents to the emergency department at 8 PM on Saturday night with abdominal pain and hypotension. He has peritoneal signs on exam. Imaging reveals a ruptured appendix. PMH: Non-valvular atrial fibrillation, Hypertension, Dyslipidemia, Stroke 1 year ago Meds: HCTZ 25 mg QD, Atorvastatin 20 mg QD, Apixaban 5 mg BID Last dose of apixaban was 12 hours ago

5 5 Case (2) PT 12.8 s ( ) INR 1.1 APTT 31.6 s ( ) Anti-Xa Pending (will be available in 2 hours)

6 6 Case (3) Surgery wants to take him to the OR emergently. Two hours is too long to wait. What do you recommend? a) PT and APTT are normal. Patient is cleared to go to the OR without anticoagulant reversal. b) Treat patient with prothrombin complex concentrate before releasing him to the OR. c) Treat patient with idarucizumab before releasing him to the OR.

7 7 Indications for anticoagulant reversal Emergent surgery/procedure Serious bleeding

8 8 DOAC vs. warfarin: major bleeding DOACs are associated with a 28% lower risk of major bleeding than warfarin. Chai-Adisaksopha et al., Blood 2014;124:2450

9 9 DOAC vs. warfarin: ICH DOACs are associated with a 57% lower risk of ICH than warfarin. Chai-Adisaksopha et al., Blood 2014;124:2450

10 10 DOACs: potential reversal strategies For serious bleeding: Maximal supportive care (e.g. stopping DOAC, local hemostatic measures, volume resuscitation, transfusion support) Strategy Removal Bypassing Sequestration Example Activated charcoal Hemodialysis (dabigatran only) Prothrombin complex concentrate (PCC) Activated PCC rfviia Idarucizumab (dabigatran) Andexanet alfa (FXa inhibitors) Ciraparantag

11 11 Idarucizumab Monoclonal antibody fragment Dabigatran has 350-fold greater affinity for idarucizumab than thrombin FDA approval: October 2015 based on the REVERSE-AD study Blood 2013;121:3554; Thromb Haemost 2015;113:943; Lancet 2015;386:680

12 12 REVERSE-AD Group A (serious bleeding) Group B (urgent procedure) Idarucizumab 5 g IV Primary endpoint: Correction of coagulation assays Pollack et al., N Engl J Med 2015;373:511

13 13 Patient characteristics Bleeding Group (n=298) Procedure Group (n=196) Overall (n=494) Median age NVAF (%) Normal dtt (%)* *Results from an interim analysis of the first 90 subjects Pollack et al., N Engl J Med 2015;373:511; AHA 2016 available at

14 14 Correction in dilute TT Normalized in 98% Increase Pollack et al., N Engl J Med 2015;373:511

15 15 Clinical Outcomes: Bleeding Group AHA 2016 available at

16 16 Clinical Outcomes: Surgery Group AHA 2016 available at

17 17 Safety No infusion reactions 35 thromboembolic events in 31 of 494 patients (6.3%) at 90 days 7 MI, 8 CVA, 15 VTE, 1 systemic embolism ~2/3 occurred off antithrombotic therapy? occurred within 72 hrs AHA 2016 available at

18 18 Idarucizumab: conclusions & questions Rapidly corrects coagulation tests in patients taking dabigatran Appears to be safe and well-tolerated Does idarucizumab improve clinical outcomes in bleeding patients? How should patients be selected to receive idarucizumab (up to 25% had insignificant dabigatran levels at study entry)? What is the significance of increased dabigatran levels at 12 and 24 hrs? Should these patients be re-dosed?

19 19 Andexanet alfa Modified recombinant FXa Lacks catalytic and membranebinding activity Retains the ability to bind FXa inhibitors Not FDA-approved Lu et al., Nat Med 2013;19:446; Crowther et al., Circulation 2014;130:2116; Siegal et al., N Engl J Med 2015;373:2413

20 20 ANNEXA-4 Acute major bleeding on apixaban (n=31), edoxaban (n=0), rivaroxaban (n=32), enoxaparin (n=4) Andexanet bolus f/b 2 hour infusion 1 Endpoints: Reduction in anti-xa activity Hemostatic efficacy at 12 hours Connolly SJ et al., N Engl J Med 2016; 375:1131

21 21 Efficacy Median decrease in anti-xa at end of infusion: Rivaroxaban 89% Apixaban 93% 79% of subjects adjudicated as excellent or good hemostasis at 12 hrs. Connolly SJ et al., N Engl J Med 2016; 375:1131

22 22 Safety No infusion reactions or neutralizing antibodies 16 thrombotic events in 12 of 67 (17.9%) patients 1 MI, 6 CVA, 9 VTE 14 occurred off AC 4 occurred within 3 days of andexanet Connolly SJ et al., N Engl J Med 2016; 375:1131

23 23 Andexanet: conclusions & questions Rapidly corrects coagulation tests in patients taking FXa inhibitors How long does the continuous infusion need to be given? Is 2 hours enough? Does andexanet improve clinical outcomes in bleeding patients? Ongoing ANNEXA-4 phase 3b-4 study (target enrollment 450) Is andexanet prothrombotic?

24 24 PER977 (ciraparantag) Small molecule (~500 daltons) Positively charged Binds non-covalently to FXa inhibitors, UFH, LMWH, Fondaparinux Corrected coagulation test in healthy volunteers taking edoxaban Ansell et al., N Engl J Med 2014;371:2141

25 25 Prothrombin complex concentrate (PCC) Healthy males (n=12) Riva 20 mg Q12h 5 doses B/L Riva Saline PCC PT (s) factor PCC 50 IU/kg Saline Placebo ETP (%) Coagulation assays Eerenberg et al., Circulation 2011;124:1573

26 26 Activated PCC Age DOAC B/L 6 hrs 49 Rivaroxaban 81 Rivaroxaban 81 Rivaroxaban No patients had ICH expansion No thrombotic complications 83 Apixaban 69 Dabigatran Dibu et al., Neurocrit Care 2016;24:413

27 27 Take-home points Most DOAC-associated bleeds can be managed with supportive care alone The dawn of specific reversal agents for DOACs is upon us These agents correct coagulation test abnormalities within minutes of infusion More data are needed to define their safety and efficacy If reversal is required: Dabigatran Idarucizumab 5 g FXa inhibitor 4F-PCC 50 units/kg or APCC 50 units/kg

28 28 Back to the case What do you recommend? a) PT and APTT are normal. Patient is cleared to go to the OR without anticoagulant reversal. b) Treat patient with prothrombin complex concentrate before releasing him to the OR. c) Treat patient with idarucizumab before releasing him to the OR.

29 29 Thank you