title: Polypharmacy and the Efficacy and Safety of Rivaroxaban Versus Warfarin in the Prevention of Stroke in Patients With Nonvalvular Atrial Fibrillation.
abstract: BACKGROUND
  Patients with atrial fibrillation (AF) often take multiple medications.
  
  
  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.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT00403767.
authors.affiliation: 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.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Piccini
authors.affiliation: 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.).
authors.forename: Anne S
authors.initials: AS
authors.lastname: Hellkamp
authors.affiliation: 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.).
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Washam
authors.affiliation: 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.).
authors.forename: Richard C
authors.initials: RC
authors.lastname: Becker
authors.affiliation: 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.).
authors.forename: Günter
authors.initials: G
authors.lastname: Breithardt
authors.affiliation: 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.).
authors.forename: Scott D
authors.initials: SD
authors.lastname: Berkowitz
authors.affiliation: 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.).
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Halperin
authors.affiliation: 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.).
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Hankey
authors.affiliation: 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.).
authors.forename: Werner
authors.initials: W
authors.lastname: Hacke
authors.affiliation: 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.).
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Mahaffey
authors.affiliation: 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.).
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Nessel
authors.affiliation: 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.).
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Singer
authors.affiliation: 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.).
authors.forename: Keith A A
authors.initials: KA
authors.lastname: Fox
authors.affiliation: 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.).
authors.forename: Manesh R
authors.initials: MR
authors.lastname: Patel
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000188:drug therapy*; D004311:Double-Blind Method; D065427:Factor Xa Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced / Q000175:diagnosis; D006801:Humans; D008297:Male; D008875:Middle Aged; D019338:Polypharmacy; D012189:Retrospective Studies; D000069552:Rivaroxaban / Q000008:administration & dosage* / Q000009:adverse effects; D020521:Stroke / Q000175:diagnosis / Q000517:prevention & control*; D016896:Treatment Outcome; D014859:Warfarin / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D014859:Warfarin; D000069552:Rivaroxaban
keywords: atrial fibrillation; factor Xa; pharmacokinetics; polypharmacy; rivaroxaban; warfarin