OBJECTIVE:  To determine whether the treatment effect of apixaban versus 
warfarin differs with increasing numbers of concomitant drugs used by patients 
with atrial fibrillation.
DESIGN:  Post hoc analysis performed in 2015 of results from ARISTOTLE (apixaban 
for reduction in stroke and other thromboembolic events in atrial 
fibrillation)-a multicentre, double blind, double dummy trial that started in 
2006 and ended in 2011.
PARTICIPANTS:  18 201 ARISTOTLE trial participants.
INTERVENTIONS:  In the ARISTOTLE trial, patients were randomised to either 5 mg 
apixaban twice daily (n=9120) or warfarin (target international normalised ratio 
range 2.0-3.0; n=9081). In the post hoc analysis, patients were divided into 
groups according to the number of concomitant drug treatments used at baseline 
(0-5, 6-8, ≥9 drugs) with a median follow-up of 1.8 years.
MAIN OUTCOME MEASURES:  Clinical outcomes and treatment effects of apixaban 
versus warfarin (adjusted for age, sex, and country).
RESULTS:  Each patient used a median of six drugs (interquartile range 5-9); 
polypharmacy (≥5 drugs) was seen in 13 932 (76.5%) patients. Greater numbers of 
concomitant drugs were used in older patients, women, and patients in the United 
States. The number of comorbidities increased across groups of increasing 
numbers of drugs (0-5, 6-8, ≥9 drugs), as did the proportions of patients 
treated with drugs that interact with warfarin or apixaban. Mortality also rose 
significantly with the number of drug treatments (P<0.001), as did rates of 
stroke or systemic embolism (1.29, 1.48, and 1.57 per 100 patient years, for 
0-5, 6-8, and ≥9 drugs, respectively) and major bleeding (1.91, 2.46, and 3.88 
per 100 patient years, respectively). Relative risk reductions in stroke or 
systemic embolism for apixaban versus warfarin were consistent, regardless of 
the number of concomitant drugs (Pinteraction=0.82). A smaller reduction in 
major bleeding was seen with apixaban versus warfarin with increasing numbers of 
concomitant drugs (Pinteraction=0.017). Patients with interacting (potentiating) 
drugs for warfarin or apixaban had similar outcomes and consistent treatment 
effects of apixaban versus warfarin.
CONCLUSIONS:  In the ARISTOTLE trial, three quarters of patients had 
polypharmacy; this subgroup had an increased comorbidity, more interacting 
drugs, increased mortality, and higher rates of thromboembolic and bleeding 
complications. In terms of a potential differential response to anticoagulation 
therapy in patients with atrial fibrillation and polypharmacy, apixaban was more 
effective than warfarin, and is at least just as safe.Trial 
registration ARISTOTLE trial, ClinicalTrials.gov NCT00412984.