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 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
KeywordsAtrial fibrillation Interacting medications Warfarin Apixaban
The authors gratefully acknowledge Dr. Steen Husted’s contributions to the current analysis and the ARISTOTLE trial. Elizabeth E. S. Cook of the Duke Clinical Research Institute provided editorial support.
This work and the ARISTOTLE trial were funded by Bristol-Myers Squibb and Pfizer, Inc.
Compliance with ethical standards
Conflict of interest
Washam: None. Hohnloser: Consulting/Lecture fees from Boehringer Ingelheim, St Jude Medical, Sanofi Aventis, Cardiome. Lopes: Research grants from Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer; Consultant/Advisory Board fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Medtronic, Merck, Portola, GlaxoSmithKline, Pfizer. Wojdyla: None. Vinereanu: Research grants from GlaxoSmithKline, Pfizer, Bristol-Myers Squibb. Alexander: Institutional research grants from Bristol-Myers Squibb, Boehringer Ingelheim, CryoLife, CSL Behring, the US Food and Drug Administration, the National Institutes of Health, Tenax Therapeutics, and VoluMetrix; Consulting fees/Honoraria from AstraZeneca, Bristol-Myers Squibb, Janssen Pharmaceuticals, Merck, Novo Nordisk Pharmaceuticals, Pfizer, Portola Pharmaceuticals, VA Cooperative Studies Program, and Zafgen. Gersh: Consultant/Advisory Board fees from Boston Scientific Corporation, Cardiovascular Research Foundation, Coretherapix, Duke Clinical Research Institute, Duke University, Icahn School of Medicine at Mount Sinai, Janssen Research and Development, Janssen Scientific Affairs, Kowa Research Institute, Inc., Medtronic, Mount Sinai St. Luke’s, Sirtex Medical Limited, Teva Pharmaceutical Industries, Thrombosis Research Institute. Hanna: Employee of Bristol-Myers Squibb at the time the trial was conducted. Horowitz: None. Hylek: Research grants from Bristol Myers Squibb/Pfizer, Janssen; Consulting fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, Janssen, Medtronic, Portola. Xavier: None. Verheugt: Consulting fees/Honoraria from Bayer Healthcare, Boehringer Ingelheim, BMS/Pfizer, Daiichi Sankyo. Wallentin: Institutional research grants from Bristol-Myers Squibb/Pfizer, AstraZeneca, Merck, Boehringer Ingelheim, and GlaxoSmithKline; Consulting fees from GlaxoSmithKline, Bristol-Myers Squibb/Pfizer, Abbott, AstraZeneca, and Boehringer Ingelheim. Granger: Research grants from Armetheon, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, GlaxoSmithKline, Janssen, Medtronic Foundation, Novartis, Pfizer, The Medicines Company; Consultant/Advisory Board fees from AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Gilead Sciences, Inc, GlaxoSmithKline, Hoffman LaRoche, Janssen, Medtronic, Novartis, Pfizer, The Medicines Company, Verseon.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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