NOAC safe and effective in NVAF patients taking at least 5 other chronic medications

Influence of Polypharmacy on the Effectiveness and Safety of Rivaroxaban versus Warfarin in Patients with Nonvalvular Atrial Fibrillation

Literature - Martinez BK, Baker WL, Sood NA et al., - Pharmacotherapy. First published: 31 December 2018

Introduction and methods

Comorbidities are common in patients with nonvalvular atrial fibrillation (NVAF)[1]. A consequence of having multiple comorbidities is that patients with NVAF are at higher risk of thromboembolic events [2], and that they need multiple, chronic, non-anticoagulant medication [1, 3-6]. Polypharmacy is associated with a risk of drug-drug interactions [4], thrombotic events and major bleeding [5], and decreased time in therapeutic range (TTR) in patients receiving warfarin [7].

This study aimed to evaluate the comparative effectiveness and safety of rivaroxaban versus warfarin in patients with NVAF managed in routine clinical practice with varying degrees of polypharmacy. To this end, a retrospective claims analysis of United States Truven MarketScan data from November 2012 – March 2017 was performed. Truven MarketScan is a combination of a commercial and a Medicare supplemental database, and covers all age groups and both government and public organizations, which overall represent about 240 million lives.

Patients naïve for oral anticoagulants (OAC) in the 12 months preceding the day of the first qualifying rivaroxaban or warfarin dispensing (index date) were included. Included patients had at least 2 inpatient or outpatient ICD codes for AF (except codes suggesting valvular disease), had polypharmacy with ≥5 unique chronic medications. A secondary analysis was performed in individuals with substantial polypharmacy (≥10 chronic medications). Each eligible rivaroxaban user was propensity-score matched to a warfarin user, separately for the ≥5 and ≥10 polypharmacy analyses. The primary effectiveness outcome was stroke or systemic embolism (SSE) and major bleeding the primary safety outcome.

Main results

  • Of 128.786 patients with NVAF, 57.8% were taking ≥5 concomitant medications, and 7.6% ≥10. In 13.981 patients receiving rivaroxaban who were matched to warfarin users, the median follow-up was 1.7 years (IQR: 0.7-3.0). Median age was 71 (IQR: 62-80), median CHA2DS2-VASc was 3 (IQR: 2-4) and modified HAS-BLED was 2 (IQR: 1-3).
  • In patients taking ≥5 chronic medications, treatment with rivaroxaban as compared with warfarin, was associated with a significant 34% lower risk of SSE (HR: 0.66, 95%CI: 0.50-0.88), and 40% lower risk of ischemic stroke alone (HR: 0.60, 95%CI: 0.43-0.84).
  • No significant difference in major bleeding was seen between patients treated with rivaroxaban and warfarin (HR: 1.08, 95%CI: 0.92-1.28).
  • In patients with substantial polypharmacy (n=3530), median follow-up was 1.4 years (IQR: 0.6-2.7), median age was 72 years (IQR: 63-79) and median CHA2DS2-VASc was 4 (IQR: 3-5) and modified HAS-BLED was 2 (IQR: 2-3).
  • In patients taking ≥10 medications, rivaroxaban was not associated with significant reductions in SSE (HR: 0.44, 95%CI: 0.17-1.12) or ischemic stroke (HR: 0.62, 95%CI: 0.22-1.78). No significant difference in major bleeding was seen between treatment groups (HR: 1.07, 95%CI: 0.73-1.58).


These data suggest that rivaroxaban is associated with lower rates of SSE and ischemic stroke and similar rates of bleeding in patients with NVAF who take at least 5 non-OAC chronic medications, as compared with warfarin. No significant difference between treatment groups was seen in patients taking at least 10 chronic medications.


1. LaMori JC, Mody Sh, Gross HJ et al. Burden of comorbidities among patients with atrial fibrillation. Ther Adv Cardiovasc Dis 2013;7:53-62.

2. Proietti M, Raparelli V, Olshansky B, Lip GY. Polypharmacy and major adverse events in atrial fibrillation: observations from the AFFIRM trial. Clin Res Cardiol 2016;105:412-420.

3. Abdel-Aziz MI, Ali MA, Hassan AK, Elfaham TH. Warfarin-drug interactions: an emphasis on influence of polypharmacy and high doses of amoxicillin/clavulanate. J Clin Pharmacol 2016;56:39-46.

4. Masnoon N, Shakib S, Kalisch-Ellett L, Caughey GE. What is polypharmacy? A systematic review of definitions. BMC Geriatr 2017;17:230.

5. Jaspers Focks J, Brouwer MA, Wojdyla DM et al. Polypharmacy and effects of apixaban versus warfarin in patients with atrial fibrillation: post hoc analysis of the ARISTOTLE trial. BMJ 2016;353:i2868.

6. Piccini JP, Hellkamp AS, Washam JB et al. Polypharmacy and the efficacy and safety of rivaroxaban versus warfarin in the prevention of stroke in patients with nonvalvular atrial fibrillation. Circulation 2016;133:352-360.

7. Rose AJ, Hylek EM, Ozonoff A, Ash AS, Reisman JI, Berlowitz DR. Patient characteristics associated with oral anticoagulation control: results of the Veterans AffaiRs Study to Improve Anticoagulation (VARIA). J Thromb Haemost 2010;8:2182-2191.

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