Warfarin is dependent on multiple hepatic
enzymes for metabolism while
apixaban is a substrate for
P-glycoprotein (P-gp) transport and hepatic
CYP3A4 metabolism. The aim of this analysis was to assess the impact of interacting medication use on the treatment effects of
apixaban versus
warfarin. Outcomes were compared between
apixaban and
warfarin using Cox proportional hazards modeling according to the use of interacting medications at randomization in ARISTOTLE (n = 18,201). Interacting medications for
apixaban were identified as combined P-gp and 3A4 inhibitors or inducers while interacting medications for
warfarin were defined as those highly probable for
warfarin potentiation or inhibition. At randomization, 5547 (30.5%) patients were on an interacting medication, including 2722 on
apixaban and 2825 on
warfarin. Patients using an interacting medication were more likely to be female, taking
aspirin, and have a history of prior
bleeding and were less likely to have a prior
stroke or
transient ischemic attack. No significant differences were observed on the treatment effect of
apixaban compared with
warfarin in patients on and off interacting medications for outcomes including the primary efficacy outcome of
stroke or systemic
embolism (P for interaction = 0.79) or the primary safety outcome of major
bleeding (P for interaction = 0.75). Use of interacting medications with
anticoagulants occurs often in patients with
atrial fibrillation. Despite the potential for altered exposure, interacting medication use was not associated with a significant change in the efficacy or safety of
apixaban compared with
warfarin in the ARISTOTLE trial.Trial registration ClinicalTrials.gov, NCT00412984.