Efficacy and Safety of Apixaban Compared With Warfarin in Patients With Atrial Fibrillation in Relation to Renal Function Over Time: Insights From the ARISTOTLE Randomized Clinical Trial

JAMA Cardiol. 2016 Jul 1;1(4):451-60. doi: 10.1001/jamacardio.2016.1170.


Importance: Renal impairment confers an increased risk of stroke, bleeding, and death in patients with atrial fibrillation. Little is known about the efficacy and safety of apixaban in relation to renal function changes over time.

Objectives: To evaluate changes of renal function over time and their interactions with outcomes during a median of 1.8 years of follow-up in patients with atrial fibrillation randomized to apixaban vs warfarin treatment.

Design, setting, and participants: The prospective, randomized, double-blind Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) clinical trial randomized 18 201 patients with atrial fibrillation to apixaban or warfarin. Serial creatinine measurements were available in 16 869 patients. Worsening of renal function was defined as an annual decrease in estimated glomerular filtration more than 20%. The relations between treatment, outcomes, and renal function were investigated using Cox regression models, with renal function as a time-dependent covariate.

Main outcomes and measures: Stroke or systemic embolism (primary outcome), major bleeding (safety outcome), and mortality were examined in relation to renal function over time estimated with both the Cockcroft-Gault and Chronic Kidney Disease Epidemiology Collaboration equations.

Results: Among 16 869 patients, the median age was 70 years and 65.2% of patients were men. Worsening in estimated glomerular filtration more than 20% was observed in 2294 patients (13.6%) and was associated with older age and more cardiovascular comorbidities. The risks of stroke or systemic embolism, major bleeding, and mortality were higher in patients with worsening renal function (HR, 1.53; 95% CI, 1.17-2.01 for stroke or systemic embolism; HR, 1.56; 95% CI, 1.27-1.93 for major bleeding; and HR, 2.31; 95% CI, 1.98-2.68 for mortality). The beneficial effects of apixaban vs warfarin on rates of stroke or systemic embolism and major bleeding were consistent in patients with normal or poor renal function over time and also in those with worsening renal function.

Conclusions and relevance: In patients with atrial fibrillation, declining renal function was more common in elderly patients and those with cardiovascular comorbidities. Worsening renal function was associated with a higher risk of subsequent cardiovascular events and bleeding. The superior efficacy and safety of apixaban as compared with warfarin were similar in patients with normal, poor, and worsening renal function.

Trial registration: clinicaltrials.gov Identifier: NCT00412984.

Publication types

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

MeSH terms

  • Aged
  • Anticoagulants / adverse effects*
  • Anticoagulants / therapeutic use
  • Atrial Fibrillation / drug therapy*
  • Double-Blind Method
  • Female
  • Humans
  • Kidney / drug effects
  • Kidney / physiopathology
  • Kidney Diseases / chemically induced*
  • Male
  • Prospective Studies
  • Pyrazoles / adverse effects*
  • Pyrazoles / therapeutic use
  • Pyridones / adverse effects*
  • Pyridones / therapeutic use
  • Treatment Outcome
  • Warfarin / adverse effects*
  • Warfarin / therapeutic use


  • Anticoagulants
  • Pyrazoles
  • Pyridones
  • apixaban
  • Warfarin

Associated data

  • ClinicalTrials.gov/NCT00412984