Polypharmacy in patients with AF is associated with a higher risk of bleeding in ROCKET AF

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

Literature - Piccini JP et al., Circulation 2016

Piccini JP, Hellkamp AS, Washam JB, et al.
Circulation 2016;133:352-360.


Patients with atrial fibrillation (AF) usually suffer from comorbidities that force them to take multiple medications. Polypharmacy however, is associated with risks, such as decreased adherence, increased risk of adverse events, drug-drug interactions and lower quality of life [1-2].
This study evaluated the prevalence of polypharmacy and its impact on ischemic and hemorrhagic events in patients with AF, as well as the efficacy and safety of rivaroxaban versus warfarin according to the number of concomitant medications and the presence of combined CYP3A4 and P-glycoprotein inhibitors.
For this purpose, the study population of 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) was used [3]. Patients with non-valvular AF were randomised to receive either 20 mg rivaroxaban once daily (only 15 mg if creatinine clearance was 30-29 mL/min), or dose-adjusted warfarin.
While drug-drug interactions in warfarin-treated patients on multiple medications are common and associated with an increased risk of bleeding [4], rivaroxaban, with fewer drug-drug interactions, is affected by strong cytochrome P450 3A4 (CYP3A4) inducers and inhibitors and by medications with P-glycoprotein inhibition or induction.

Main results

• At baseline
  • 5101 patients (36%) were on 0 - 4 medications
  • 7298 (51%) were on 5 - 9 medications
  • 1865 (13%) were on ≥10 medications
• Polypharmacy
  • was not associated with higher risk of stroke or non–central nervous system (CNS) embolism (adjusted HR: 1.02 for ≥10 vs. 0–4 medications; 95% CI: 0.76–1.38)
  • was associated with a higher risk of the combined end point of stroke, non–CNS embolism, vascular death, or myocardial infarction (adjusted HR: 1.41 for ≥10 vs. 0–4 medications; 95% CI: 1.18–1.68)
  • was associated with a higher risk of non-major clinically relevant or major bleeding (adjusted HR: 1.47 for ≥10 vs. 0–4 medications; 95% CI: 1.31–1.65)
• The risk of major bleeding with rivaroxaban compared with warfarin in patients treated with
  • 0-4 medications was: HR: 0.71; 95% CI: 0.52–0.95
  • 5-9 medications was: HR: 1.23; 95% CI: 1.01–1.49
  • ≥10 medications was: HR: 1.17; 95% CI: 0.87–1.56
• There was no evidence of differential outcomes in those treated with ≥1 combined cytochrome P450 3A4 and P-glycoprotein inhibitors.


Polypharmacy in patients with AF was associated with a higher risk of bleeding. The risk of major bleeding with rivaroxaban compared with warfarin was reduced in patients taking fewer than 5 medications, but not in patients taking 5 or more medications. The risk of stroke was not increased due to multiple medications in the latter patient group. Treatment effect was not affected by use of combined CYP3A4 and P-glycoprotein inhibitors.

Find this article online at Circulation


1. Leendertse AJ, Egberts AC, Stoker LJ, et al. HARM Study Group. Frequency of and risk factors for preventable medication-related hospital admissions in the Netherlands. Arch Intern Med. 2008;168:1890–1896
2. Fincke BG, Miller DR, Spiro A 3rd. The interaction of patient perception of overmedication with drug compliance and side effects. J Gen Intern Med. 1998;13:182–185
3. ROCKET AF Study Investigators. Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation: rationale and design of the ROCKET AF study. Am Heart J. 2010;159:340–347
4. Teklay G, Shiferaw N, Legesse B, et al. Drug-drug interactions and risk of bleeding among inpatients on warfarin therapy: a prospective observational study. Thromb J. 2014;12:20

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