Jim Hoehns, Pharm.D. Edoxaban  Oral factor Xa inhibitor  Bioavailability: 62%  Tmax: 1-2 hrs  Elimination: 50% renal  Half-life: 9-11 hours 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 CHADS2 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 ENGAGE - Methods  Inclusion criteria  Age ≥21 years  ECG tracing of Afib within previous 12 months  CHADS2 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 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 ENGAGE - Results  21,105 patients randomized  Reduced dose: 25% of patients  Warfarin: mean TTR 68% 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 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 Afib Trials - Comparison Charicteristic Dabigatran Apixaban Rivaroxaban 71.5 (mean) 70 (median) 73 (median) 50% 57% 62% 0-1 32% 34% (1 only) 0% 2 35% 36% 13% ≥3 33% 30% 87% Prior MI 17% 14% 17% Prior stroke, TIA, or systemic embolism 20% 20% 55% Age (yrs) Prior VKA use CHADS2 Afib Trials - Comparison Dabigatra Warfari Apixiban Warfarin Rivaroxa Warfarin n n (%/yr) (%/yr) (%/yr) . (%/yr) (%/yr) (%/yr) Primary end (stroke/emb. ) 1.11 1.69* 1.27 1.6* 2.1 2.4 Hemorrhagi c stroke 0.1 0.38* 0.24 0.47* 0.41 0.71* Ischemic stroke 0.92 1.2* 0.97 1.05 1.34 1.42 MI 0.74 0.53*? 0.53 0.61 0.9 1.1 Death – any cause 3.64 4.13 3.52 3.94* 4.5 4.9 Major bleeding 3.11 3.36 2.13 3.09* 3.6 3.4 * Significantly different (P<0.05)