Interacting medication use and the treatment effects of apixaban versus warfarin: results from the ARISTOTLE Trial

Warfarin is dependent on multiple hepatic enzymes for metabolism while apixabanis a substrate for P-glycoprotein(P-gp) transport and hepatic CYP3A4metabolism. The aim of this analysis was to assess the impact of interactingmedication use on the treatment effects of apixabanversus warfarin. Outcomes were compared between apixabanand warfarin using Cox proportional hazards modeling according to the use of interactingmedications at randomization in ARISTOTLE (n = 18,201). Interactingmedications for apixabanwere identified as combined P-gp and 3A4 inhibitors or inducers while interactingmedications for warfarin were defined as those highly probable for warfarin potentiation or inhibition. At randomization, 5547 (30.5%) patients were on an interactingmedication, including 2722 on apixabanand 2825 on warfarin. Patients using an interactingmedication 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 apixabancompared with warfarin in patients on and off interactingmedications 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 interactingmedications with anticoagulants occurs often in patients with atrial fibrillation. Despite the potential for altered exposure, interactingmedication use was not associated with a significant change in the efficacy or safety of apixabancompared with warfarin in the ARISTOTLE trial.