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Prevalence and bleeding risk associated with the concomitant use of direct oral anticoagulants and antiarrhythmic drugs in patients with atrial fibrillation, based on the French healthcare insurance database

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Abstract

Purpose

Pharmacokinetic interactions exist between apixaban or rivaroxaban, and CYP3A4 and P-glycoprotein inhibitors such as amiodarone, verapamil and diltiazem. We aimed to estimate the prevalence of exposure to this drug-drug association (DDA) and to assess the bleeding risk associated in patients with atrial fibrillation (AF).

Methods

We conducted a cohort study using a representative 1/97th sample of the French healthcare insurance database between 2014 and 2019. Patients with AF receiving apixaban or rivaroxaban were included and followed-up until hospitalization for bleeding, death, discontinuation of apixaban or rivaroxaban, exposure to strong CYP3A4 inhibitor, or until December 31st 2019, whichever came first. Primary outcome was hospitalization for bleeding registered as primary diagnosis. The association between the exposure to the DDA and hospitalization for bleeding was evaluated as a time-dependent variable in Cox model.

Results

Between 2014 and 2019, the AF population under apixaban or rivaroxaban represented 10,392 patients. During the study period, the annual average prevalence of DDA exposure in this population was 38.9%. Among the 10,392 patients, 223 (2.1%) were hospitalized for bleeding, of which 75 (33.6%) received the association and 148 (66.4%) received apixaban or rivaroxaban alone. There was no association between DDA exposure and risk of hospitalization for bleeding (aHR = 1.19, [95% CI: 0.90, 1.58]). Age (HR 1.03 [1.02, 1.05]) and male gender (HR 1.72 [1.28, 2.30]) were associated with an increased risk of hospitalization for bleeding.

Conclusion

Exposure to antiarrhythmic drugs was not associated with an increased risk of hospitalization for bleeding in patients with AF under rivaroxaban or apixaban.

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Data availability

The data that support the findings of this study are available from a third party (data owner). Restrictions apply to the availability of these data, which were used under license for this study. Aggregated data are available from the authors with the permission of the third party.

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Funding

This project has received funding from the French National Agency for Medicines and Health Products Safety (ANSM) in the framework of the Scientific Interest Group EPI-PHARE. This publication represents the views of the authors and does not necessarily represent the position of the relevant health authorities.

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Authors and Affiliations

  1. Sorbonne Université, INSERM, Institut Pierre Louis d’épidémiologie et de Santé publique (IPLESP), Paris, France

    Laëtitia Gosselin, Ana-Maria Vilcu, Cécile Souty, Olivier Steichen, Titouan Launay, Clément Turbelin, Marianne Sarazin, Thierry Blanchon, Thomas Hanslik & Louise Rossignol

  2. Département de Médecine Générale, Université Paris Cité, Paris, France

    Laëtitia Gosselin & Louise Rossignol

  3. Assistance Publique - Hôpitaux de Paris (APHP), hôpital Tenon, Service de Médecine Interne, Paris, France

    Olivier Steichen

  4. INSERM, Université de Toulouse, Service de Pharmacologie médicale et clinique, CIC 1436, Centre Hospitalo-Universitaire de Toulouse (CHU Toulouse), Toulouse, France

    Cécile Conte & Maryse Lapeyre-Mestre

  5. Agence National de Sécurité du Médicaments et des produits de santé, Saint-Denis, 93200, France

    Béatrice Saint-Salvi

  6. Université de Versailles Saint-Quentin-en-Yvelines, UVSQ, UFR de Médecine, Versailles, France

    Thomas Hanslik

  7. Assistance Publique - Hôpitaux de Paris (APHP), hôpital Ambroise Paré, Service de Médecine Interne, Boulogne Billancourt, France

    Thomas Hanslik

Authors
  1. Laëtitia Gosselin
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Contributions

Conception and design of the study: AV, CS, OS, CC, BSS, MS, TB, TH, MLM, LR, LG. Data analysis: AV, LG. Drafting manuscript: LR, LG. All authors participated in data interpretation, reviewed and approved the final manuscript.

Corresponding author

Correspondence to Laëtitia Gosselin.

Ethics declarations

Ethics

National Institute for Health and Medical Research (INSERM) agreement for the research protocol was given in 2017–11-15. Neither ethics committee authorization nor request to national commissions for individual data protection is required according to French law to access this kind of anonymous and restricted-access database. Access to EGB is possible only through a secured connection to a specific server. Data are accessible online and are analyzed by the software SAS Enterprise Guide version 4.3 (Copyright © 2006–2010, SAS Institute Inc., Cary, NC, USA).

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The authors declared no competing interests for this work.

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Gosselin, L., Vilcu, AM., Souty, C. et al. Prevalence and bleeding risk associated with the concomitant use of direct oral anticoagulants and antiarrhythmic drugs in patients with atrial fibrillation, based on the French healthcare insurance database. Eur J Clin Pharmacol 79, 937–945 (2023). https://doi.org/10.1007/s00228-023-03501-8

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