Physicians' Academy for Cardiovascular Education

Greater net clinical benefit of NOAC vs. warfarin in Asians with AF compared with non-Asians

Clinical outcomes, edoxaban concentration, and anti-factor Xa activity of Asian patients with atrial fibrillation compared with non-Asians in the ENGAGE AF-TIMI 48 trial

Literature - Chao TF, Chen SA, Ruff CT et al. - Eur Heart J 2018; 0, 1–11

Introduction and methods

Large RCTs of patients with atrial fibrillation (AF) treated with non-vitamin K antagonist oral anticoagulants (NOACs) versus warfarin have shown a higher risk for intracranial hemorrhage (ICH) and ischemic stroke in Asian patients, compared to non-Asians [1-3]. However, these trials did not include adjustments for baseline differences between the two races. Also, the relationship between edoxaban concentration, anti-factor Xa (anti-FXa) activity and clinical outcomes in Asians versus non-Asians have not been documented. A previous paper reported consistent efficacy and safety of edoxaban in both East-Asian and all other countries [4], however, the safety and efficacy of edoxaban compared to warfarin for patients with Asian race remains unknown.

This post-hoc analysis of the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) study therefore compared the baseline characteristics, risks of thromboembolic and bleeding events, and the edoxaban concentration and anti-FXa activity of patients of Asian race, regardless of country of enrolment, to those in non-Asians.

The phase 3 multinational, double-blind, double-dummy, and non-inferiority ENGAGE AF-TIMI 48 trial (n=21.105) randomized Asian (n=2.909) and non-Asian (n=18.195) patients across 46 countries with documented AF in the prior 12 months and a CHADS₂ score ≥2 to warfarin titrated to an INR of 2.0-3.0, a higher dose regimen of edoxaban (60 mg/day), or a lower dose edoxaban regimen (30 mg/day), and followed them for a median of 2.8 years (IQR: 2.4-3.2), which was longer than other major NOAC vs. warfarin trials in patients with AF. In patients with an estimated creatinine clearance 30–50 mL/min, body weight ≤60kg, or in those requiring concomitant use of verapamil, quinidine, or dronedarone, the edoxaban dose was reduced by 50%.

Main results

Edoxaban concentration and anti-FXa activity in Asians vs. non-Asians

Edoxaban trough concentration and events in Asians vs. non-Asians

Efficacy, safety and net clinical outcomes with edoxaban vs. warfarin in Asians vs. non-Asians


In Asians with AF, higher dose edoxaban (60/30 mg) vs. warfarin was associated with comparable efficacy, favorable safety, and even better net secondary and tertiary clinical outcomes, compared with non-Asians. These findings appear to be due to the lower trough edoxaban concentration and anti-FXa activity in Asians with AF, especially after the protocol-driven dose reduction of edoxaban.


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Find this article online at Eur Heart J

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