An Update on Reversal Agents for NOACs: Where Are We Now? NOAC = non-vitamin K antagonist oral anticoagulant Moderator Christian T. Ruff, MD, MPH Assistant Professor of Medicine TIMI Study Group Brigham and Women's Hospital Harvard Medical School Boston, Massachusetts

Joshua N. Goldstein, MD, PhD Arash Afshinnik, MD Panelists Joshua N. Goldstein, MD, PhD Associate Professor of Surgery Harvard Medical School Director Center for Neurologic Emergencies Massachusetts General Hospital Boston, Massachusetts Arash Afshinnik, MD Director of Neurocritical Care Assistant Clinical Professor Department of Neurologic Surgery Division of Neurology University of California, San Francisco Fresno, California Carmelo Graffagnino, MD Medical Director Duke Comprehensive Stroke Center Professor and Chief Division of Vascular Neurology, Stroke and Neurocritical Care Department of Neurology Duke University Medical Center Durham, North Carolina Panelists Layout (Title slide layout)

This program will include discussion of investigational drugs not approved by the FDA for use in the United States. FDA = US Food and Drug Administration

Overview NOACs are at least as effective as warfarin in the prevention of stroke in patients with atrial fibrillation and in VTE treatment and prevention Easier to administer Safer with respect to bleeding, particularly serious bleeding Overall, an approximate 50% reduction in fatal and life-threatening bleeding (particularly ICH) events across trials NOACs were developed without a reversal agent Many eligible patients are still not receiving NOACs partially because of perceived fear of bleeding, lack of antidote ICH = intracranial hemorrhage  VTE = venous thromboembolism Ruff CT, et al. Lancet. 2014;383:955-962.

X Better to Prevent Than Treat Most bleeding events can be effectively managed with supportive care and are not associated with any bad long-term outcomes Serious bleeding is a lot less common with NOACs Avoid concomitant use of antiplatelet agents, NSAIDs Monitor renal function and dose appropriately Due to short half-lives of NOACs, temporarily stopping them may be all that is required X https://www.shutterstock.com/pic-9264850/stock-photo-bottle-of-aspirin-with-a-clipping-path-on-white-background.html?src=7FsxZdq4TCldbgNAO_IF1Q-1-1 Also available at https://webmd.box.com/s/rklan4twhjybtld7p390kyqzg1ahvl7e NSAID = nonsteroidal anti-inflammatory drug Characteristic Rivaroxaban[a] Apixaban[b] Dabigatran[c] Edoxaban[d] Half-life, h 5-9 ~12 12-17 10-14 Renal clearance, % 33* 27 80 50 *33% renally cleared; 33% excreted unchanged in urine. a. Xarelto® PI 2016; b. Eliquis® PI 2015; c. Pradaxa® PI 2015; d. Savaysa™ PI 2015.

Coagulation Cascade Warfarin Apixaban Edoxaban Rivaroxaban Dabigatran Clot XII XIIa XI XIa IX IXa VIIa VII Xa X VIIIa TF Va Prothrombin II Thrombin IIa Fibrinogen I Fibrin Ia Warfarin Apixaban Edoxaban Rivaroxaban No permissions budget. Dabigatran Makaryus JN, et al. Nat Rev Cardiol. 2013;10:397-409.

Is Testing Helpful? Dabigatran Factor Xa inhibitors APTT, dilute TT, ECA, ECT can determine if drug levels are present Normal TT likely excludes relevant dabigatran level Factor Xa inhibitors Anti-Xa can detect drug levels PT may detect if drug is present https://www.shutterstock.com/pic-327930536/stock-photo-medical-equipment-blood-test.html?src=QI-j8N-l221WNA8cm3Gjdw-1-0 APTT = activated partial thromboplastin time ECA = ecarin chromogenic assay ECT = ecarin clotting time PT = prothrombin time TT = thrombin time Cuker A, et al. J Am Coll Cardiol. 2014;64:1128-1139.

Reversal Agents Idarucizumab Andexanet alfa Ciraparantag Structure   Idarucizumab Andexanet alfa Ciraparantag Structure Humanized Fab fragment Recombinant factor Xa variant Synthetic small molecule Target Dabigatran Factor Xa inhibitors UFH, LMWH, NOACs (not warfarin) Mechanism Binds dabigatran with high affinity Competes with factor Xa for inhibitor binding Noncovalent hydrogen bond (exact mechanism unclear) Reconstitution None Add 10 mL sterile water Administration 2 × 2.5 g/50 mL IV bolus, may require repeat dose 400 mg IV bolus plus 2-hour infusion* Single 100 mg IV dose (dose under investigation) Status FDA-Approved 10/16/2015 Not yet approved IV = intravenous LMWH = low-molecular-weight heparin UFH = unfractionated heparin *Dose being studied in ANNEXA-4; dosing will depend on which FXa inhibitor was taken, and when it was taken. Hu TY, et al. Vasc Health Risk Manag. 2016;12:35-44.

REVERSE-AD: Trial Design Group A (n = 298) Patients taking dabigatran with uncontrolled bleeding 0-15 min 90 days follow-up Hospital arrival 5 g idarucizumab (2 ×2.5 g IV) Pre-2nd vial 2 h 4 h 12 h 24 h 30 d 90 d Pre-1st vial 1 h Blood samples Group B (n = 196) Patients taking dabigatran requiring emergency surgery dTT = diluted thrombin time Primary endpoint: Maximum reversal within 4 h based on dTT, ECT Pollack CV, et al. Thromb Haemost. 2015;114:198-205.

REVERSE-AD: Mortality Patients had life-threatening conditions Deaths: Group A (bleeding, n = 298): 12.3% (30 days); 18.7% (90 days) Group B (surgery, n = 196): 12.4% (30 days); 18.5% (90 days) Idarucizumab Given two 2.5 g loading doses, 15 minutes apart = 5 g total Rapidly eliminates dabigatran from circulation Allows the body to establish hemostasis There were 18 deaths overall, with 9 in each study group; 10 deaths were due to vascular causes, including 5 fatal bleeding events. Pollack CV. ESC 2016.

ANNEXA-4: Andexanet Alfa Recombinant modified human factor Xa decoy protein  Multicenter, prospective, open-label, single-group study N = 67 (interim analysis) Patients with acute major bleeding ≤18 hours after the administration of a fXa inhibitor Bolus of andexanet followed by a 2-hour infusion Patients were evaluated for changes in measures of anti-fXa activity and clinical hemostatic efficacy during a 12-hour period All the patients were followed for 30 days fXa = factor Xa Connolly SJ, et al. N Engl J Med. 2016;375:1131-1141.

ANNEXA-4: Mortality Interim Analysis Safety group, n = 67 All patients who received andexanet Death = 15% Patients with ICH: 6/28 died = 21% Efficacy group, n = 47 Patients with baseline anti-fXa activity ≥ 75 ng/mL (or ≥ 0.5 IU/mL for enoxaparin) Table 2 page 1136 The prespecified safety population included all the patients who received andexanet, and the efficacy population included only patients in whom the baseline anti–factor Xa activity was later determined to be 75 ng per milliliter or more (or ≥0.5 IU per milliliter for those receiving enoxaparin) and the acute major bleeding episode was later adjudicated to meet the study criteria. Connolly SJ, et al. N Engl J Med. 2016;375:1131-1141.

The Bleeding Has Stopped -- What's Next? Reversal agents rapidly and safely remove the anticoagulant from the body When to restart anticoagulation is patient specific, but should be as early as possible due to high risk of thrombosis Reversal agents are not associated with immune reactions Reversal agents remove the anticoagulant rapidly without serious adverse events  

Ciraparantag (PER977) Universal reversal agent Synthetic molecule binds: Direct Xa inhibitors (apixaban, rivaroxaban, and edoxaban) Direct thrombin inhibitors (dabigatran) UFH, LMWH Hu TY, et al. Vasc Health Risk Manag. 2016;12:35-44.

Supply and Distribution How will reversal agents be incorporated into protocols? Where will the drugs be kept? Emergency department? Pharmacy? Blood bank? How are they stored? Need for refrigeration? Need for reconstitution? Who gives approval for use? Where are they needed? ICU, ED https://www.shutterstock.com/pic-193448417/stock-photo-portrait-of-a-doctor-talking-on-the-phone.html?src=spra8rkaebGBiNiBAlUDEw-1-7 ED = emergency department ICU = intensive care unit

Summary Reversal agents will provide reassurance and hopefully improve use of anticoagulation in at-risk patients NCDR PINNACLE Registry demonstrated that approximately half of eligible patients with AF do not receive anticoagulation[a] Patients on NOACs are less likely to have serious bleeding events than patients on warfarin Idarucizumab is available across the United States[b] Approval of andexanet alfa for fXa inhibitors expected soon Hospitals should be developing protocols to enable rapid and effective use of reversal agents   Find Praxbind. https://www.praxbind.com/find-praxbind. Accessed December 26, 2016. a. Hsu JC, et al. JAMA Cardiol. 2016;1:55-62. b. Praxbind (idarucizumab) website.

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