Efficacy and safety of apixaban compared with warfarin at different levels of predicted international normalized ratio control for stroke prevention in atrial fibrillation

Circulation. 2013 Jun 4;127(22):2166-76. doi: 10.1161/CIRCULATIONAHA.112.142158. Epub 2013 May 2.


Background: In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, apixaban compared with warfarin reduced stroke and systemic embolism, major bleeding, and mortality. We evaluated treatment effects in relation to 2 predictions of time in therapeutic range (TTR).

Methods and results: The trial randomized 18 201 patients with atrial fibrillation to apixaban 5 mg twice daily or warfarin for at least 12 months. For each patient, a center average TTR was estimated with the use of a linear mixed model on the basis of the real TTRs in its warfarin-treated patients, with a fixed effect for country and random effect for center. For each patient, an individual TTR was also predicted with the use of a linear mixed effects model including patient characteristics as well. Median center average TTR was 66% (interquartile limits, 61% and 71%). Rates of stroke or systemic embolism, major bleeding, and mortality were consistently lower with apixaban than with warfarin across center average TTR and individual TTR quartiles. In the lowest and highest center average TTR quartiles, hazard ratios for stroke or systemic embolism were 0.73 (95% confidence interval [CI], 0.53-1.00) and 0.88 (95% CI, 0.57-1.35) (Pinteraction=0.078), for mortality were 0.91 (95% CI, 0.74-1.13) and 0.91 (95% CI, 0.71-1.16) (Pinteraction=0.34), and for major bleeding were 0.50 (95% CI, 0.36-0.70) and 0.75 (95% CI, 0.58-0.97) (Pinteraction=0.095), respectively. Similar results were seen for quartiles of individual TTR.

Conclusions: The benefits of apixaban compared with warfarin for stroke or systemic embolism, bleeding, and mortality appear similar across the range of centers' and patients' predicted quality of international normalized ratio control.

Trial registration: ClinicalTrials.gov NCT00412984.

Keywords: anticoagulation; apixaban; atrial fibrillation; bleeding; stroke; warfarin.

Publication types

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

MeSH terms

  • Aged
  • Anticoagulants / administration & dosage
  • Anticoagulants / adverse effects
  • Atrial Fibrillation / drug therapy*
  • Atrial Fibrillation / mortality
  • Female
  • Fibrinolytic Agents / administration & dosage
  • Fibrinolytic Agents / adverse effects
  • Follow-Up Studies
  • Hemorrhage / chemically induced
  • Hemorrhage / mortality
  • Humans
  • International Normalized Ratio
  • Male
  • Middle Aged
  • Pyrazoles / administration & dosage*
  • Pyrazoles / adverse effects
  • Pyridones / administration & dosage*
  • Pyridones / adverse effects
  • Risk Factors
  • Stroke / mortality
  • Stroke / prevention & control*
  • Thromboembolism / mortality
  • Thromboembolism / prevention & control*
  • Treatment Outcome
  • Warfarin / administration & dosage*
  • Warfarin / adverse effects


  • Anticoagulants
  • Fibrinolytic Agents
  • Pyrazoles
  • Pyridones
  • apixaban
  • Warfarin

Associated data

  • ClinicalTrials.gov/NCT00412984