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

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.