The Impact of Polypharmacy on the Effectiveness and Safety of Non-vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation

Maxim Grymonprez, Mirko Petrovic, Tine L De Backer, Stephane Steurbaut, Lies Lahousse

Research output: Contribution to journalArticlepeer-review


BACKGROUND:  Polypharmacy may affect outcomes in patients with atrial fibrillation (AF) using non-vitamin K antagonist oral anticoagulants (NOACs) or vitamin K antagonists (VKAs) due to interactions or reduced adherence, but comparative data are lacking. Therefore, the impact of polypharmacy on AF-related outcomes and benefit-risk profiles of NOACs in patients with polypharmacy were investigated.

METHODS:  AF patients initiating anticoagulation between 2013 and 2019 were included using Belgian nationwide data. Inverse probability of treatment weighted Cox regression was used to investigate outcomes.

RESULTS:  Among 254,478 AF patients, 167,847 (66.0%) used ≥5 drugs. Polypharmacy was associated with higher stroke or systemic embolism (stroke/SE) (adjusted hazard ratio [aHR]: 1.08, 95% confidence interval [CI]: 1.02-1.15), all-cause mortality (aHR: 1.45, 95% CI: 1.40-1.50), and major bleeding risks (aHR: 1.29, 95% CI: 1.23-1.35). Among patients with polypharmacy, NOACs were associated with lower stroke/SE (aHR: 0.68, 95% CI: 0.63-0.73), all-cause mortality (aHR: 0.80, 95% CI: 0.77-0.84), major bleeding (aHR: 0.92, 95% CI: 0.87-0.97), and intracranial bleeding risks (aHR: 0.77, 95% CI: 0.69-0.85), but higher gastrointestinal bleeding risks (aHR: 1.10, 95% CI: 1.01-1.19) compared to VKAs. Major bleeding risks were lower with apixaban (aHR: 0.79, 95% CI: 0.74-0.85), but nonsignificantly different with other NOACs compared to VKAs. Lower major bleeding risks were observed with dabigatran (aHR: 0.91, 95% CI: 0.85-0.97) and apixaban (aHR: 0.77, 95% CI: 0.73-0.81) compared to rivaroxaban, and with apixaban compared to dabigatran (HR: 0.83, 95% CI: 0.77-0.90) and edoxaban (HR: 0.77, 95% CI: 0.70-0.85).

CONCLUSION:  Polypharmacy was associated with increased thromboembolic, bleeding, and mortality risks in AF patients. NOACs had better benefit-risk profiles than VKAs in patients with polypharmacy.

Original languageEnglish
Pages (from-to)135-148
Number of pages14
JournalThrombosis and Haemostasis
Issue number2
Early online date27 Jun 2023
Publication statusPublished - Feb 2024

Bibliographical note

The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (


  • atrial fibrillation
  • polypharmacy
  • NOAC
  • Thromboembolism


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