1. Jim Hoehns, Pharm.D.

3. Edoxaban Oral factor Xa inhibitor Bioavailability: 62% Tmax: 1-2 hrs Elimination: 50% renal Half-life: 9-11 hours

4. ENGAGE AF-TIMI 48 Randomized, double-blind, double-dummy trial N=21,105 patients with Afib Median follow-up: 2.8 years 1393 centers; 46 countries Treatment “High dose” edoxaban 60mg QD “Low dose” edoxaban 30mg QD Warfarin INR 2.0-3.0 Randomization: stratified according to CHADS 2 score and need for a reduced dose Dose-modification for edoxaban groups Half-dose if any present: Clcr 30-50 ml/min, weight <60 kg, or use of verapamil, amiodarone, dronedarone

5. ENGAGE - Methods Inclusion criteria Age ≥21 years ECG tracing of Afib within previous 12 months CHADS 2 of 2 or greater Exclusion criteria Afib due to reversible disorder Est Clcr <30 ml/min ACS or stroke within past 30 days Use of dual antiplatelets “High risk” of bleeding

6. ENGAGE - Methods Endpoints Primary efficacy: time to first stroke or systemic embolism Primary safety: major bleeding Analysis Modified ITT Noninferiority: upper boundary of 97.5% CI could not exceed 1.38 vs. warfarin Superiority testing: if met noninferiority criteria Power: If 672 endpoints, >87% power

7. ENGAGE - Results 21,105 patients randomized Reduced dose: 25% of patients Warfarin: mean TTR 68%

14. Observations High study drug discontinuation rate (33%) Similar rates among groups; would like more clarity re: symptomatic AE’s Low-dose edoxaban 30mg QD likely not tenable Met criteria for noninferiority Primary endpoint: warfarin 1.5%/yr vs. low-dose 1.61%/yr Significant increased risk of ischemic stroke vs. warfarin HR 1.41 (95% CI: 1.19-1.67, P<0.001) Warfarin: 1.25%/yr Low-dose edoxaban: 1.77%/yr

15. Summary Edoxaban: a new factor Xa inhibitor Will compete with dabigatran, rivaroxaban, and apixiban “high-dose” edoxaban 60mg QD Same lower risk of ICH and hemorrhagic stroke as other new anticoagulants Efficacy and bleeding data look very favorable Higher GI bleeding than warfarin

16. Afib Trials - Comparison CharicteristicDabigatranApixabanRivaroxaban Age (yrs)71.5 (mean)70 (median)73 (median) Prior VKA use50%57%62% CHADS 2 0-132%34% (1 only)0% 235%36%13% ≥333%30%87% Prior MI17%14%17% Prior stroke, TIA, or systemic embolism 20% 55%

17. Afib Trials - Comparison Dabigatra n (%/yr) Warfari n (%/yr) Apixiban (%/yr) Warfarin (%/yr) Rivaroxa. (%/yr) Warfarin (%/yr) Primary end (stroke/emb. ) 1.111.69*1.271.6*2.12.4 Hemorrhagi c stroke 0.10.38*0.240.47*0.410.71* Ischemic stroke 0.921.2*0.971.051.341.42 MI 0.740.53*?0.530.610.91.1 Death – any cause 3.644.133.523.94*4.54.9 Major bleeding 3.113.362.133.09*3.63.4 * Significantly different (P<0.05)