Polypharmacy Effects in Patients with Nonvalvular Atrial Fibrillation on Rivaroxaban or Warfarin

Kaity Bader, Pharm.D., Apple Valley Medical Clinic, Fairview Physician Associates

Background: Patients with nonvalvular atrial fibrillation (NVAF) often have concomitant conditions requiring additional chronic medications. Polypharmacy and the associated drug-drug interactions may increase the risk of thrombotic events or bleeding events. In the Rivaroxaban Versus Warfarin in Nonvalvular Atrial Fibrillation (ROCKET AF) trial, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism (SSE) and no significant difference for the risk of major bleeding was found. Baseline data for concomitant cardiovascular medications were reported, but this trial did not specifically measure or analyze polypharmacy. The question remains whether polypharmacy has an effect on the safety and efficacy of anticoagulants in patients with NVAF.

Objective: The Influence of Polypharmacy on the Effectiveness and Safety of Rivaroxaban Versus Warfarin in Patients with Nonvalvular Atrial Fibrillation study sought to evaluate the safety and efficacy of rivaroxaban versus warfarin in patients with NVAF who are experiencing polypharmacy in a real-world setting.

Study Design: This study was a retrospective analysis of claims data.  Truven MarketScan, a database combining data from commercial and Medicare supplement products, was utilized.  Patients included in the analysis needed to meet the following inclusion criteria: two or more international classification of diseases (ICD) codes for atrial fibrillation, have polypharmacy (taking five or more concomitant chronic medications), have insurance coverage, and be oral anticoagulant (OAC) naive for 12 months prior to the dispense date of either rivaroxaban or warfarin. Patients who had a history of venous thromboembolism (VTE) were excluded. A second analysis reviewed patients with substantial polypharmacy, defined as concomitant medications being ten or more. Each eligible patient taking rivaroxaban was matched 1:1 with a patient taking warfarin using propensity score matching. The primaryefficacy outcome was the combination of SSE. The primary safety outcome was major bleeding.  Patients were followed until SSE combined or major bleeding event, OAC discontinuation or switch, termination of insurance, or end-of-study follow-up.  Results were reported as hazard ratios with p-value <0.05 as statistically significant.

Results: A total of 13,981 patients taking rivaroxaban (15 or 20 mg) were matched to 13,981 patients taking warfarin. Overall, the baseline characteristics between groups were well balanced. The median age was 71 years with a median follow-up of 1.7 years. Median CHADS2VASC and modified HAS-BLED scores were three and two respectively. The primary efficacy outcomes of SSE for rivaroxaban versus warfarin resulted in a HR of 0.66 [95% CI 0.50 - 0.88] favoring rivaroxaban.  There was no major difference for thesafetyoutcome of major bleeding with HR 1.08 [95% CI 0.92 - 1.28]. In the subanalysis of patients with 10 or more concomitant medications, a total of 3530 patients were analyzed. There was no statistically significant difference between rivaroxaban and warfarin for either outcome.  Polypharmacy drug interactions were seen most commonly with warfarin inhibitors and inducers, particularly diltiazem and amiodarone.

Conclusions: In patients with NVAF taking five or more chronic medications, rivaroxaban may be more effective in preventing SSE events than warfarin. However, this study is limited by the retrospective design and further prospective randomized trials are recommended to confirm results.  Additionally, the median duration was only 1.7 years, meaning results do not consider long term efficacy. It should also be noted that INR results for patients on warfarin and adherence to either medication were not tracked or analyzed.

Key Point: When polypharmacy and drug-drug interactions are concerning in NVAF patients requiring anticoagulation therapy, rivaroxaban may be more effective in preventing SSE events than warfarin.


  1. Martinez BK, Baker WL, Sood NA, et al. Influence of polypharmacy on the effectiveness and safety of rivaroxaban versus warfarin in patients with nonvalvular atrial fibrillation [published online December 31, 2018]. Pharmacotherapy. doi: 10.1056/NEJMoa1808721.

  2. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-91. doi: 10.1056/NEJMoa1009638.