IMPORTANCE: In the Apixaban for Reduction of Stroke and Other Thromboembolic 
Complications in Atrial Fibrillation (ARISTOTLE) trial, the standard dose of 
apixaban was 5 mg twice daily; patients with at least 2 dose-reduction 
criteria-80 years or older, weight 60 kg or less, and creatinine level 1.5 mg/dL 
or higher-received a reduced dose of apixaban of 2.5 mg twice daily. Little is 
known about patients with 1 dose-reduction criterion who received the 5 mg twice 
daily dose of apixaban.
OBJECTIVE: To determine the frequency of 1 dose-reduction criterion and whether 
the effects of the 5 mg twice daily dose of apixaban on stroke or systemic 
embolism and bleeding varied among patients with 1 or no dose-reduction 
criteria.
DESIGN, SETTING, AND PARTICIPANTS: Among 18 201 patients in the ARISTOTLE trial, 
17 322 were included in this analysis. Annualized event rates of stroke or 
systemic embolism and major bleeding and hazard ratios (HRs) and 95% CIs were 
evaluated. Interactions between the effects of apixaban vs warfarin and the 
presence of 1 or no dose-reduction criteria were assessed. The first patient was 
enrolled in the ARISTOTLE trial on December 19, 2006, and follow-up was 
completed on January 30, 2011. Data were analyzed from January 2015 to May 30, 
2016.
MAIN OUTCOMES AND MEASURES: Analysis of major bleeding included events during 
study drug treatment. Analysis of stroke or systemic embolism was based on 
intention to treat.
RESULTS: Of the patients with 1 or no dose-reduction criteria assigned to 
receive the 5 mg twice daily dose of apixaban or warfarin, 3966 had 1 
dose-reduction criterion; these patients had higher rates of stroke or systemic 
embolism (HR, 1.47; 95% CI, 1.20-1.81) and major bleeding (HR, 1.89; 95% CI, 
1.62-2.20) compared with those with no dose-reduction criteria (n = 13 356). The 
benefit of the 5 mg twice daily dose of apixaban (n = 8665) compared with 
warfarin (n = 8657) on stroke or systemic embolism in patients with 1 
dose-reduction criterion (HR, 0.94; 95% CI, 0.66-1.32) and no dose-reduction 
criterion (HR, 0.77; 95% CI, 0.62-0.97) were similar (P for interaction = .36). 
Similarly, the benefit of 5 mg twice daily dose of apixaban compared with 
warfarin on major bleeding in patients with 1 dose-reduction criterion (HR, 
0.68; 95% CI, 0.53-0.87) and no dose-reduction criterion (HR, 0.72; 95% CI, 
0.60-0.86) were similar (P for interaction = .71). Similar patterns were seen 
for each dose-reduction criterion and across the spectrum of age, body weight, 
creatinine level, and creatinine clearance.
CONCLUSIONS AND RELEVANCE: Patients with atrial fibrillation and isolated 
advanced age, low body weight, or renal dysfunction have a higher risk of stroke 
or systemic embolism and major bleeding but show consistent benefits with the 5 
mg twice daily dose of apixaban vs warfarin compared with patients without these 
characteristics. The 5 mg twice daily dose of apixaban is safe, efficacious, and 
appropriate for patients with only 1 dose-reduction criterion.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00412984.