Efficacy and safety of DOAC versus warfarin consistent across CHA2DS2-VASc scores

Edoxaban versus warfarin in patients with atrial fibrillation in relation to the risk of stroke: A secondary analysis of the ENGAGE AF-TIMI 48 study

Literature - De Groot JR, Ruff CT, Murphy SA et al., - Am Heart J. 2021 Jan 22;235:132-139. doi: 10.1016/j.ahj.2021.01.013.

Introduction and methods

The ENGAGE AF-TIMI 48 trial has shown that oral factor Xa inhibitor edoxaban is noninferior to well-managed warfarin in the prevention of stroke or systemic embolism (SEE) in patients with AF [1,2]. The risk of stroke and major bleeding varies between patients. The CHA2DS2-VASc score can predict this risk in patients with AF on anticoagulation [3]. This analysis investigated the efficacy and safety of edoxaban versus warfarin across CHA2DS2-VASc scores in the ENGAGE AF-TIMI 48 trial.

ENGAGE AF-TIMI 48 was a phase 3, multinational, double-blind, double-dummy, randomized trial in 21 105 patients with AF and CHADS2 scores ≥2. Patients were randomized to edoxaban 60 mg, edoxaban 30 mg or warfarin. The edoxaban dose was reduced by 50% in patients with weight ≤60 kg, creatinine clearance ≤50 mL/min, or when they used strong P-glycoprotein inhibitors. The primary efficacy endpoint was SSE and the principal safety endpoint was major bleeding. Median follow-up was 2.8 years. This analysis compared the approved edoxaban dose (60/30 mg) to warfarin in patients stratified according to CHA2DS2-VASc score: ≤3 (n=4159, 29.6%), 4 (n=4066, 28.9%), 5 (n=3165, 22.5%, and ≥6 (n=2681, 19.1%).

Main results

  • Rates of SSE and major bleeding increased with increasing CHA2DS2-VASc score in patients in the warfarin group.
  • The HR for SSE per CHA2DS2-VASc point increment was 1.29 (95%CI 1.21-1.38, P<0.001) in the warfarin group and 1.26 (95%CI 1.17-1.36, P<0.001) in the edoxaban group.
  • The HR for major bleeding per unit increase of CHA2DS2-VASc score was 1.20 (95%CI 1.13-1.27, P<0.001) in the warfarin group and 1.19 (95%CI 1.12-1.27, P<0.001) in the edoxaban group.
  • Edoxaban reduced SSE, major bleeding, intracranial hemorrhage (ICH), and CV death versus warfarin to a similar degree across the spectrum of CHA2DS2-VASc strata (P interaction =0.90, 0.96, 0.21, and 0.37, respectively).
  • Patients with increasing CHA2DS2-VASc score had higher rates of major bleeding, ICH, and CV death with warfarin. Thus, while the relative risk reductions remained similar, absolute reductions were greater with edoxaban compared to warfarin as CHA2DS2-VASc scores increased.
  • Edoxaban concentration, exogenous anti-FXa activity, and percentage of endogenous FXa inhibition at day 29 increased with increasing CHA2DS2-VASc score. Patients in high CHA2DS2-VASc categories tended to have lower body weights and lower creatinine clearance. These factors are known to increase edoxaban exposure.


The efficacy and safety profile of edoxaban versus warfarin was consistent across the spectrum of CHA2DS2-VASc scores. Stroke, embolic events, bleeding and CV mortality rates increased with increasing CHA2DS2-VASc score. While relative risk reductions remained similar, the absolute number of prevented events was greater with edoxaban as compared to warfarin in patients with higher CHA2DS2-VASc scores.


1. Ruff CT , Giugliano RP , Antman EM , et al . Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: design and rationale for the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF-TIMI 48). Am Heart J 2010;160:635–41 .

2. Giugliano RP , Ruff CT , Braunwald E , et al . Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093–104.

3. Lee KT , Chang SH , Yeh YH , et al . The CHA(2)DS(2)-VASc score predicts major bleeding in non-valvular atrial fibrillation patients who take oral anticoagulants. J Clin Med 2018;7(10) .

Find this article online at Am Heart J.

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