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

  • The median edoxaban concentrations were significantly lower in Asians without dose reduction (29.4 vs. 36.4 ng/mL) and in Asians with dose reduction (22.0 vs. 29.0 ng/mL), compared to non-Asians.
  • The median anti-FXa activities were similar for Asians vs. non-Asians without dosage reduction (0.6 vs. 0.6 IU/mL) but significantly lower in patients who required dosage reduction (0.3 vs. 0.5 IU/mL).
  • Older age and use of amiodarone were two significant factors associated with higher edoxaban trough concentrations, which were less frequent in Asians compared with non-Asians. Of note, Asian race was not an independent predictor of edoxaban trough concentration.

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

  • The edoxaban trough concentrations and anti-FXa activity were highly correlated in both Asians [r=0.99 (0.987–0.995)] and non-Asians [r=0.85 (0.84–0.87)].
  • In Asians, the risk of ischemic stroke exceeded the risk of major bleeding when the trough concentration of edoxaban was low (i.e. <15ng/mL).
  • In Asians, the risk of major bleeding increased steeply with increasing concentration of edoxaban, while the risk of ischemic stroke decreased gradually. In contrast, among non-Asians, the risk of major bleeding exceeded the risk of ischemic stroke across the range of edoxaban concentration achieved.

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

  • Stroke/SEEs was observed numerically less often in Asians treated with higher dose edoxaban, compared to Asian patients treated with warfarin (HR: 0.74, 95%CI: 0.51–1.08). Similarly, in non-Asian patients stroke/SEEs was less often seen in those treated with higher dose edoxaban compared to a warfarin (HR: 0.90, 95%CI: 0.76–1.07) (P-interaction=0.37).
  • The risk of hemorrhagic stroke and CV mortality tended to be reduced by higher dose edoxaban vs. warfarin in both Asians (HR: 0.67, 95%CI: 0.35-1.29 and HR: 0.78, 95%CI: 0.57-1.06, respectively) and non-Asians (HR: 0.50, 95%CI: 0.33-0.75 and HR: 0.88, 95%CI: 0.78-1.00, respectively) (each P-interaction >0.10).
  • The risks of other efficacy endpoints, including ischemic and fatal stroke, MI, and non-CV mortality, did not significantly differ between higher dose edoxaban and warfarin and no significant interactions with these associations were seen for being Asian or not (each P-interaction ≥0.10).
  • Both in Asians and non-Asians, the risk of ICH was lower for patients treated with higher dose edoxaban, compared with warfarin (HR: 0.57, 95%CI: 0.32– 1.00 and HR: 0.43, 95%CI: 0.30–0.62), respectively, P-interaction=0.41).
  • The risks of ICH, life-threatening or fatal bleeding, clinically relevant non-major bleeding, major/clinically relevant non-major bleeding and any bleeding, were significantly lower for patients treated with higher dose edoxaban, compared with warfarin, in both Asians and non-Asians (P-interaction >0.10).
  • In Asians, the risk of major bleeding was non-significantly lower with higher dose edoxaban, compared to warfarin (HR: 0.77, 95%CI: 0.56-1.06), while in non-Asians that risk was decreased with edoxaban (HR: 0.81, 95%CI: 0.70-0.93).
  • The risk for major GI bleeding tended to be increased in both Asians (HR: 1.27, 95%CI: 0.72-2.21) and non-Asians (HR: 1.23, 95%CI: 1.00-1.51) (P-interaction=0.92).
  • The primary net clinical outcome (stroke, SEEs, major bleeding, or all-cause death) was non-significantly better with higher dose edoxaban vs. warfarin in Asians (HR: 0.75, 95%CI: 0.62-0.92) than in non-Asians (HR: 0.92, 95%CI: 0.85-1.00) (P-interaction=0.063).
  • The secondary (disabling stroke, life-threatening bleeding, or all-cause death) and tertiary (stroke, SEE, life-threatening bleeding, or death from any cause) net clinical outcomes were significantly more favorable with higher dose edoxaban in Asians (HR: 0.70, 95%CI: 0.55-0.89 and HR: 0.92, 95%CI: 0.84-1.02, respectively, P-interaction=0.037), compared with non-Asians (HR: 0.70, 95%CI: 0.56-0.88 and HR: 0.91, 95%CI: 0.83-1.00, respectively, P-interaction=0.032).


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.


1. Hori M, Connolly SJ, Zhu J et al; RE-LY Investigators. Dabigatran versus warfarin: effects on ischemic and hemorrhagic strokes and bleeding in Asians and non-Asians with atrial fibrillation. Stroke 2013;44:1891–1896.

2. Wong KS, Hu DY, Oomman A et al; Executive Steering Committee and the ROCKET AF Study Investigators. Rivaroxaban for stroke prevention in East Asian patients from the ROCKET AF trial. Stroke 2014;45:1739–1747.

3. Goto S, Zhu J, Liu L et al; ARISTOTLE Investigators. Efficacy and safety of apixaban compared with warfarin for stroke prevention in patients with atrial fibrillation from East Asia: a subanalysis of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial. Am Heart J 2014;168:303–309.

4. Yamashita T, Koretsune Y, Yang Y et al. Edoxaban vs. warfarin in East Asian patients with atrial fibrillation—an ENGAGE AF-TIMI 48 subanalysis. Circ J 2016;80:860–869.

Find this article online at Eur Heart J

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