True/False: Idarucizumab can be utilized for the management of bleeding associated with dabigatran.

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1 Discuss the role of idarucizumab for the management of bleeding associated with dabigatran Understand dosing, preparation and administration of idarucizumab I have no financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation. True/False: Idarucizumab can be utilized for the management of bleeding associated with dabigatran. What dose of idarucizmab is recommended for reversal of dabigatran? Atrial fibrillation (A. fib) Most common arrhythmia Attributes to ~20% of ischemic strokes Associated with $2.6 billion in Medicare costs the first year Venous thromboembolism (VTE) Affects more than 1 million patients each year U.S. - ~$1.5 billion per year. Vascular Disease Vitamin K antagonist works on vitamin k dependent clotting factors Used to treat VTE, strokes, A. fib Clinical Characteristics: Narrow therapeutic index Food-drug interactions Drug-drug interactions Individual variation hepatic enzymes Routine monitoring

2 Dabigatran Rivaroxaban Apixaban Edoxaban 1954 Warfarin 2011 Rivaroxaban 2015 Edoxaban Indication 2010 Dabigatran 2012 Apixaban Mechanism of Action Time to Maximum Effect Anti-IIa (Thrombin) Inhibitor < 2 hours 1 4 hours 3 hours 1 3 hours Half-life hours 6 9 hours 8 15 hours 6 11 hours Elimination Renal Excretion Renal Renal Renal Intrinsic Pathway Extrinsic Pathway XII XIIa VII VIIa + TF XI XIA IX IXa + VIIIa Common Pathway X Xa + Va Prothrombin (II) Thrombin (IIa) Medications: Vitamin K antagonists Xa Inhibitors Thrombin Inhibitors Fibrinogen Fibrin XIII XIIIa Stable fibrin Clot Advantages Predictable pharmacokinetics Specific enzyme targeted Fixed dosing Rapid onset of action Comparable efficacy to warfarin Fewer interactions Clinical Implications No need for bridging therapy No need for routine monitoring Minimal adverse effects Few drug/food restrictions No readily available test to assess anticoagulant activity Renal failure Cost Dabigatran ~20 times more expensive than warfarin No specific antidote - for significant bleeding or an emergent need for reversal

3 FDA.gov Intrinsic Pathway Extrinsic Pathway XII XIIa VII VIIa + TF XI IX XIA IXa + VIIIa Common Pathway X Xa + Va Medications: Vitamin K antagonists Xa Inhibitors Thrombin Inhibitors Humanized monoclonal antibody fragment that binds dabigatran Neutralizes dabigatran activity 350 times higher binding affinity then dabigatran s affinity to thrombin Prothrombin (II) Thrombin (IIa) Fibrinogen Fibrin Idarucizumab-dabigatran complex renally eliminated XIII XIIIa Stable fibrin Clot Dosing: Recommended dose is 5 grams (two separate 50 ml vials each contains 2.5 grams) Infusion Bolus Injection Preparation: Use aseptic technique Inspect visually for particulate matter and discoloration prior to administration Administration should begin promptly or within 1 hour

4 Store vials in the refrigerator at 2 C to 8 C (36 F to 46 F). Do not freeze. Do not shake Unopened vial may be kept at room temperature up to 48 hours (in original packaging) Protect from light When exposed to light, it may be kept for 6 hours Primary Maximum percentage reversal of the anticoagulant effect within 4 hours of administration Secondary Restoration of hemostasis (normalization of dilute thrombin time or ECT AND reduction in unbound dabigatran concentration) 4 hours: 98% 12 hours: 90% 24 hours: 90% 4 hours: 89% 12 hours: 81% 24 hours: 81% 4 hours: 83% 12 hours:81% 24 hours: 81% 4 hours: 88% 12 hours: 54% 24 hours: 54% 18 deaths (9 in each group) 5 fatal bleeding 5 thrombotic events None receiving antithrombotic therapy 6 other events GI hemorrhage Post-op wound infection Delirium Heart failure Right ventricular failure Pulmonary edema Limitations No control group Small sample size Bias Shown to reverse the anticoagulation effects Has a role in therapy

5 Several New Oral Anticoagulants currently available and widely utilized in the US Concerns of no antidote for severe bleeding or emergent reversal has led to new products including idarucizumab True/False: Idarucizumab can be utilized for the management of bleeding associated with dabigatran. True What dose of idarucizmab is recommended for reversal of dabigatran? 5 grams (two separate 50 ml vials each contains 2.5 grams) Tummala R, Kavtaradze A, Gupta A, et al. Specific antidotes against direct oral anticoagulants: a comprehensive review of clinical trials. International Journal of ; 214: Ruff CT, Giugliano RP, Braunwald E, et al. Comparrison of the efficacy and safety of the new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014; 383: Connolly SJ, Ezekowitz MD, Yusuf S, et al, and the RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fi brillation. N Engl J Med 2009; 361: Patel MR, Mahaff ey KW, Garg J, et al, and the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: Granger CB, Alexander JH, McMurray JJ, et al, and the ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fi brillation. N Engl J Med 2011; 365: Giugliano RP, Ruff CT, Braunwald E, et al. Once-daily edoxaban versus warfarin in patients with atrial fi brillation. N Engl J Med 2013; 369: Summers RL, Sterling SA. Emergent Bleeding in Patients Receiving Oral Anticoagulants. Air Medical Journal. 2016; 35: Pollack CV, Reilly PA, Eikelboom J, et al. Idarucizumab for Dabigatran Reversal. N Engl J Med