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Randomized Controlled Trial
. 2016 Jun 15:353:i2868.
doi: 10.1136/bmj.i2868.

Polypharmacy and effects of apixaban versus warfarin in patients with atrial fibrillation: post hoc analysis of the ARISTOTLE trial

Jeroen Jaspers Focks  1 , Marc A Brouwer  2 , Daniel M Wojdyla  3 , Laine Thomas  3 , Renato D Lopes  3 , Jeffrey B Washam  4 , Fernando Lanas  5 , Denis Xavier  6 , Steen Husted  7 , Lars Wallentin  8 , John H Alexander  3 , Christopher B Granger  3 , Freek W A Verheugt  2
Affiliations
Randomized Controlled Trial

Polypharmacy and effects of apixaban versus warfarin in patients with atrial fibrillation: post hoc analysis of the ARISTOTLE trial

Jeroen Jaspers Focks et al. BMJ. .

Abstract

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.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: JJF has received consulting fees/honorariums from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, and Daiichi Sankyo; MAB has received consulting fees/honorariums from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, and Daiichi Sankyo; DMW, LT, FL, and JBW have nothing to report; RDL reports consulting fees/honorariums from Bristol-Myers Squibb, Bayer, Boehringer Ingelheim, Merck, Pfizer, and Portola, and research grants from Bristol-Myers Squibb and GlaxoSmithKline; DX reports research grants to his institution from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Cadila Pharma, Pfizer, and Sanofi-Aventis; SH reports consulting fees/honorariums from AstraZeneca, Bayer, Boehringer Ingelheim, and Pfizer, and research grants from GlaxoSmithKline; LW reports consulting fees/honorariums from Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, and Pfizer, and research grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Merck/Schering-Plough, Pfizer, and Roche Diagnostics; JHA reports consulting fees/honorariums from Bristol-Myers Squibb, CSL Behring, Portola, and Somahlution, and research grants from Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Regado Biosciences, Sanofi, Tenax Therapeutics, and Vivus Pharmaceuticals; CBG reports consulting fees/honorariums from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Gilead Sciences, GlaxoSmithKline, Hoffman LaRoche, Janssen, Medtronic, Novartis, Pfizer, Sanofi-Aventis, Takeda, and The Medicines Company, and research grants from Armetheon, AstraZeneca, Bayer, Boehringer Ingelheim, and Bristol-Myers Squibb; FWAV reports consulting fees/honorariums from AstraZeneca, BMS/Pfizer, Bayer, Daiichi-Sankyo, and Boehringer-Ingelheim.

Figures

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Fig 1 Association between randomised treatment and main outcomes, by number of concomitant drugs used at baseline by ARISTOTLE trial participants
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Fig 2 Treatment comparisons for efficacy, safety, and net benefit outcomes between apixaban and warfarin according to the number of concomitant drugs used by ARISTOTLE trial participants at baseline
See this image and copyright information in PMC

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