Edoxaban vs. warfarin in vitamin K antagonist experienced and naive patients with atrial fibrillation†

Eur Heart J. 2015 Jun 14;36(23):1470-7. doi: 10.1093/eurheartj/ehv014. Epub 2015 Feb 16.


Aims: Edoxaban is an oral, once-daily factor Xa inhibitor that is non-inferior to well-managed warfarin in patients with atrial fibrillation (AF) for the prevention of stroke and systemic embolic events (SEEs). We examined the efficacy and safety of edoxaban vs. warfarin in patients who were vitamin K antagonist (VKA) naive or experienced.

Methods and results: ENGAGE AF-TIMI 48 randomized 21 105 patients with AF at moderate-to-high risk of stroke to once-daily edoxaban vs. warfarin. Subjects were followed for a median of 2.8 years. The primary efficacy endpoint was stroke or SEE. As a pre-specified subgroup, we analysed outcomes for those with or without prior VKA experience (>60 consecutive days). Higher-dose edoxaban significantly reduced the risk of stroke or SEE in patients who were VKA naive [hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.56-0.90] and was similar to warfarin in the VKA experienced (HR 1.01, 95% CI 0.82-1.24; P interaction = 0.028). Lower-dose edoxaban was similar to warfarin for stroke or SEE prevention in patients who were VKA naive (HR 0.92, 95% CI 0.73-1.15), but was inferior to warfarin in those who were VKA experienced (HR 1.31, 95% 1.08-1.60; P interaction = 0.019). Both higher-dose and lower-dose edoxaban regimens significantly reduced the risk of major bleeding regardless of prior VKA experience (P interaction = 0.90 and 0.71, respectively).

Conclusion: In patients with AF, edoxaban appeared to demonstrate greater efficacy compared with warfarin in patients who were VKA naive than VKA experienced. Edoxaban significantly reduced major bleeding compared with warfarin regardless of prior VKA exposure.

Keywords: Atrial fibrillation; Edoxaban; Novel oral anticoagulant; Warfarin.

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Anticoagulants / therapeutic use*
  • Atrial Fibrillation / complications*
  • Double-Blind Method
  • Factor Xa Inhibitors / therapeutic use*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Pyridines / therapeutic use*
  • Risk Factors
  • Stroke / prevention & control*
  • Thiazoles / therapeutic use*
  • Treatment Outcome
  • Warfarin / therapeutic use*


  • Anticoagulants
  • Factor Xa Inhibitors
  • Pyridines
  • Thiazoles
  • Warfarin
  • edoxaban