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Drug-drug interactions with metronidazole and itraconazole in patients using acenocoumarol

  • Pharmacoepidemiology and Prescription
  • Published:
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Abstract

Purpose

Various population-based cohort studies have shown that antimicrobial agents increase the risk of overanticoagulation in patients using coumarins. In this study, we assessed this association in hospitalized patients.

Methods

We included all patients hospitalized in the Spaarne Gasthuis (Haarlem/Hoofddorp, the Netherlands), who started using an antimicrobial agent during acenocoumarol treatment or vice versa between 1 January 2015 and 1 July 2019. Patients were followed from start of concomitant therapy until 48 h after termination of the concomitant therapy or discharge, whichever came first. We analyzed the association between the antimicrobial agents and the risk of overanticoagulation, defined as an interpolated INR above 6, using Cox regression analysis. We corrected for multiple testing with the Bonferroni correction. Patients who started using acenocoumarol and amoxicillin/clavulanic acid were used as reference group.

Results

In the study population, sixteen antimicrobial agents were started frequently concomitantly with acenocoumarol treatment. We included 2157 interaction episodes in 1172 patients. Patients who started using the combination of co-trimoxazole (HR 3.76; 95% CI 1.47–9.62; p = 0.006), metronidazole (HR 2.55; 95% CI 1.37–4.76; p = 0.003), or itraconazole (HR 4.11; 95% CI 1.79–9.45; p = 0.001) concomitantly with acenocoumarol treatment had an increased risk of overanticoagulation compared with patients using acenocoumarol and amoxicillin/clavulanic acid concomitantly. The associations for metronidazole (p = 0.045) and itraconazole (p = 0.015) remained statistically significant after correction for multiple testing.

Conclusion

Co-trimoxazole, metronidazole, and itraconazole increase the risk of overanticoagulation in patients using acenocoumarol. These combinations should be avoided if possible or otherwise acenocoumarol doses should be reduced and INR measured more frequently.

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Availability of data and material

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

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Authors and Affiliations

  1. Pharmacy Foundation of Haarlem Hospitals, Boerhaavelaan 24, 2035 RC, Haarlem, The Netherlands

    Matthijs L. Becker, Renate C.A.E. van Uden & Thijs J. Giezen

  2. Department of Clinical Pharmacy, Spaarne Gasthuis, Haarlem / Hoofddorp, The Netherlands

    Matthijs L. Becker, Renate C.A.E. van Uden & Thijs J. Giezen

  3. Department of Hematology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Karina Meijer

  4. Department of Internal Medicine, Spaarne Gasthuis, Haarlem / Hoofddorp, The Netherlands

    Ilse Houtenbos

  5. Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Patricia M.L.A. van den Bemt

Authors
  1. Matthijs L. Becker
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  2. Renate C.A.E. van Uden
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  3. Thijs J. Giezen
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Contributions

M.L.B., R.C.A.E.v.U., and I.H. contributed to the study conception and design. Material preparation and data collection was performed by M.L.B., and analysis was performed by M.L.B., R.C.A.E.v.U., T.J.G., K.M., and P.M.L.A.v.d.B. The first draft of the manuscript was written by M.L.B., and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Matthijs L. Becker.

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Conflict of interests

K. Meijer reports travel support from Baxter; grants, travel support, and speaker fees from Bayer; grants and speaker fees from Sanquin; grants from Pfizer; speaker fees from Boehringer Ingelheim; speaker fees from BMS; speaker fees from Aspen; consulting fees from Uniqure; and grants from Federatie van Nederlandse Trombosediensten, all outside the submitted work. The other authors have no conflicts of interest.

Ethics approval

Ethical approval was waived by the local Institutional Review Board of the Spaarne Gasthuis in view of the retrospective nature of the study, and all the procedures being performed were part of the routine care.

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Becker, M.L., van Uden, R.C., Giezen, T.J. et al. Drug-drug interactions with metronidazole and itraconazole in patients using acenocoumarol. Eur J Clin Pharmacol 76, 1457–1464 (2020). https://doi.org/10.1007/s00228-020-02930-z

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  • DOI: https://doi.org/10.1007/s00228-020-02930-z

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