Polypharmacy and the Efficacy and Safety of Rivaroxaban Versus Warfarin in the Prevention of Stroke in Patients With Nonvalvular Atrial Fibrillation

Jonathan P Piccini; Anne S Hellkamp; Jeffrey B Washam; Richard C Becker; Günter Breithardt; Scott D Berkowitz; Jonathan L Halperin; Graeme J Hankey; Werner Hacke; Kenneth W Mahaffey; Christopher C Nessel; Daniel E Singer; Keith A A Fox; Manesh R Patel

doi:10.1161/CIRCULATIONAHA.115.018544

Polypharmacy and the Efficacy and Safety of Rivaroxaban Versus Warfarin in the Prevention of Stroke in Patients With Nonvalvular Atrial Fibrillation

Circulation. 2016 Jan 26;133(4):352-60. doi: 10.1161/CIRCULATIONAHA.115.018544. Epub 2015 Dec 16.

Affiliations

¹ From Duke Clinical Research Institute, Durham, NC (J.P.P., A.S.H., M.R.P.); Duke Heart Center, Duke University Medical Center, Durham, NC (J.P.P., J.B.W., M.R.P.); University of Cincinnati College of Medicine, OH (R.C.B.); Hospital of the University of Münster, Germany (G.B.); Bayer HealthCare Pharmaceuticals, Whippany, NJ (S.D.B.); Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Medical Center, New York, NY (J.L.H.); School of Medicine and Pharmacology, University of Western Australia, Crawley, WA (G.J.H.); Ruprecht-Karls-University, Heidelberg, Germany (W.H.); Department of Medicine, Stanford University, Palo Alto, CA (K.W.M.); Janssen Pharmaceutical Research and Development, Raritan, NJ (C.C.N.); Massachusetts General Hospital and Harvard Medical School, Boston (D.E.S.); and University of Edinburgh and Royal Infirmary of Edinburgh, UK (K.A.A.F.). jonathan.piccini@duke.edu.
² From Duke Clinical Research Institute, Durham, NC (J.P.P., A.S.H., M.R.P.); Duke Heart Center, Duke University Medical Center, Durham, NC (J.P.P., J.B.W., M.R.P.); University of Cincinnati College of Medicine, OH (R.C.B.); Hospital of the University of Münster, Germany (G.B.); Bayer HealthCare Pharmaceuticals, Whippany, NJ (S.D.B.); Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Medical Center, New York, NY (J.L.H.); School of Medicine and Pharmacology, University of Western Australia, Crawley, WA (G.J.H.); Ruprecht-Karls-University, Heidelberg, Germany (W.H.); Department of Medicine, Stanford University, Palo Alto, CA (K.W.M.); Janssen Pharmaceutical Research and Development, Raritan, NJ (C.C.N.); Massachusetts General Hospital and Harvard Medical School, Boston (D.E.S.); and University of Edinburgh and Royal Infirmary of Edinburgh, UK (K.A.A.F.).

PMID: 26673560
DOI: 10.1161/CIRCULATIONAHA.115.018544

Abstract

Background: Patients with atrial fibrillation (AF) often take multiple medications.

Methods and results: We examined characteristics and compared adjusted outcomes between rivaroxaban and warfarin according to number of concomitant baseline medications and the presence of combined cytochrome P450 3A4 and P-glycoprotein inhibitors in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study. At baseline, 5101 patients (36%) were on 0 to 4 medications, 7298 (51%) were on 5 to 9, and 1865 (13%) were on ≥ 10. Although polypharmacy was not associated with higher risk of stroke or non-central nervous system embolism (adjusted hazard ratio, 1.02 for ≥ 10 versus 0-4 medications; 95% confidence interval, 0.76-1.38), it was associated with higher risks of the combined end point of stroke, non-central nervous system embolism, vascular death, or myocardial infarction (adjusted hazard ratio, 1.41 for ≥ 10 versus 0-4 medications; 95% confidence interval, 1.18-1.68) and nonmajor clinically relevant or major bleeding (adjusted hazard ratio, 1.47 for ≥ 10 versus 0-4 medications; 95% confidence interval, 1.31-1.65). There was no significant difference in primary efficacy (adjusted interaction P=0.99) or safety outcomes (adjusted interaction P=0.87) between treatment groups by number of medications. Patients treated with 0 to 4 medications had lower rates of major bleeding with rivaroxaban (adjusted hazard ratio, 0.71; 95% confidence interval, 0.52-0.95; interaction P=0.0074). There was no evidence of differential outcomes in those treated with ≥ 1 combined cytochrome P450 3A4 and P-glycoprotein inhibitors.

Conclusions: In a population of patients with atrial fibrillation, two thirds were on ≥ 5 medications. Increasing medication use was associated with higher risk of bleeding but not stroke. Rivaroxaban was tolerated across complex patients on multiple medications.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00403767.

Keywords: atrial fibrillation; factor Xa; pharmacokinetics; polypharmacy; rivaroxaban; warfarin.

Publication types

Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Anticoagulants / administration & dosage
Anticoagulants / adverse effects
Atrial Fibrillation / diagnosis
Atrial Fibrillation / drug therapy*
Double-Blind Method
Factor Xa Inhibitors / administration & dosage
Factor Xa Inhibitors / adverse effects
Female
Hemorrhage / chemically induced
Hemorrhage / diagnosis
Humans
Male
Middle Aged
Polypharmacy*
Retrospective Studies
Rivaroxaban / administration & dosage*
Rivaroxaban / adverse effects
Stroke / diagnosis
Stroke / prevention & control*
Treatment Outcome
Warfarin / administration & dosage*
Warfarin / adverse effects

Substances

Anticoagulants
Factor Xa Inhibitors
Warfarin
Rivaroxaban

Associated data

ClinicalTrials.gov/NCT00403767