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Non-vitamin K Antagonist Oral Anticoagulants (NOACs) Versus Warfarin in Patients with Atrial Fibrillation Using P-gp and/or CYP450-Interacting Drugs: a Systematic Review and Meta-analysis

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Abstract

Purpose

Non-vitamin K antagonist oral anticoagulants (NOACs) are excreted by P-glycoprotein (P-gp) and some are metabolized by CYP450 enzymes such as CYP3A4. Although fewer drug interactions are present with NOACs, it is unclear whether NOACs should also be preferred over vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) using pharmacokinetically interacting drugs. Therefore, the benefit-risk profile of NOACs versus VKAs was investigated in AF patients treated with P-gp and/or CYP450-interacting drugs.

Methods

Using PubMed and Embase, randomized controlled trials and observational studies on the effectiveness and safety of NOACs versus VKAs in AF patients using P-gp and/or CYP450-interacting drugs were included. A meta-analysis was performed, calculating relative risks (RR) and 95% confidence intervals (CI) with the Mantel–Haenszel method.

Results

Twelve studies were included, investigating 10,793 NOAC and 10,096 VKA users treated with P-gp/CYP3A4 inhibitors, whereas no studies on P-gp and/or CYP450-inducing drugs were identified. Compared to VKAs, NOACs were associated with a borderline non-significantly lower stroke or systemic embolism (stroke/SE) risk (RR 0.85, 95%CI (0.72–1.01)), significantly lower intracranial bleeding (RR 0.47, 95%CI (0.34–0.65)) and all-cause mortality risks (RR 0.87, 95%CI (0.79–0.95), but significantly higher gastrointestinal bleeding risk (RR 1.74, 95%CI (1.06–2.86)). Among AF patients using amiodarone, NOACs were associated with significantly lower stroke/SE (RR 0.71, 95%CI (0.54–0.93)) and intracranial bleeding risks (RR 0.51, 95%CI (0.29–0.88)), but significantly higher gastrointestinal bleeding risk (RR 2.15, 95%CI (1.24–3.72)) than VKAs.

Conclusion

The benefit-risk profile of NOACs compared to VKAs was preserved in AF patients using P-gp/CYP3A4 inhibitors, including amiodarone.

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Data Availability

The data underlying this article are available in the article and in its Supplementary information.

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Funding

This work was supported by grants from the Research Foundation Flanders (FWO) [Grant number 11C0820N to Maxim Grymonprez].

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Authors and Affiliations

  1. Department of Bioanalysis, Pharmaceutical Care Unit, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium

    Maxim Grymonprez, Kevin Vanspranghe & Lies Lahousse

  2. Centre for Pharmaceutical Research, Research Group of Clinical Pharmacology and Clinical Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Jette, Belgium

    Stephane Steurbaut

  3. Department of Hospital Pharmacy, UZ Brussel, Laarbeeklaan 101, 1090, Jette, Belgium

    Stephane Steurbaut

  4. Department of Cardiology, Ghent University Hospital, C. Heymanslaan 10, 9000, Ghent, Belgium

    Tine L. De Backer

  5. Department of Epidemiology, Erasmus Medical Center, Doctor Molewaterplein 40, 3015, Rotterdam, The Netherlands

    Lies Lahousse

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  1. Maxim Grymonprez
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  4. Tine L. De Backer
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  5. Lies Lahousse
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Contributions

Maxim Grymonprez and Lies Lahousse contributed to the concept and design of the meta-analysis. Maxim Grymonprez and Kevin Vanspranghe performed the literature search, data extraction, quality assessment, interpretation, and writing. Maxim Grymonprez performed the statistical analysis. Tine De Backer, Stephane Steurbaut, and Lies Lahousse revised the manuscript critically. All authors read and approved the final manuscript.

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Correspondence to Maxim Grymonprez.

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Grymonprez, M., Vanspranghe, K., Steurbaut, S. et al. Non-vitamin K Antagonist Oral Anticoagulants (NOACs) Versus Warfarin in Patients with Atrial Fibrillation Using P-gp and/or CYP450-Interacting Drugs: a Systematic Review and Meta-analysis. Cardiovasc Drugs Ther 37, 781–791 (2023). https://doi.org/10.1007/s10557-021-07279-8

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