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Journal Club

Journal Club. 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

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Journal Club

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  1. Journal Club Jim Hoehns, Pharm.D.

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

  3. 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

  4. 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 • EstClcr <30 ml/min • ACS or stroke within past 30 days • Use of dual antiplatelets • “High risk” of bleeding

  5. 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

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

  7. 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

  8. 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

  9. Afib Trials - Comparison

  10. Afib Trials - Comparison * Significantly different (P<0.05)

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