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Drug interaction as a predictor of direct oral anticoagulant drug levels in atrial fibrillation patients

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Abstract

Data are limited on the effects of drug interactions on direct-acting oral anticoagulant (DOAC) levels. We evaluated the effects of the use of interacting drugs on DOAC levels in patients with atrial fibrillation (AF). We reviewed data of AF patients tested for DOAC levels in 2013–2017. The primary outcomes were drug levels exceeding the expected steady-state range, and in the highest quartile. A multivariate analysis was performed to evaluate the correlation of treatment by the use of interacting drugs, CYP3A4 and P-glycoprotein (P-gp) inhibitors, with the primary outcomes. Overall, 147 patients underwent DOAC level measurement [dabigatran (n = 31), rivaroxaban (n = 29), apixaban (n = 87)]. Thirty-three (22.4%) had drug levels exceeding the expected range. Seventy-nine (53.7%) patients were treated with at least one interacting drug. In multivariate analysis, the concomitant use of interacting drugs was an independent predictor for drug levels exceeding the expected range (OR 3.3, 95% CI 1.20–9.05). The defined daily dose of the interacting drug correlated positively with DOAC levels (r = 0.29, P = 0.001). Co-treatment with interacting drugs was associated with extremely high levels of dabigatran, (OR 16.6, 95% CI 1.29–215.18) but not of the other DOAC examined. Concomitant use of interacting drugs is associated with high DOAC levels in patients with AF. Further investigation is warranted to establish the differences between specific DOAC, evaluate the effect on patient outcomes, and characterize the role of DOAC monitoring in this setting.

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Acknowledgements

We appreciate Ms. Cindy Cohen’s help in editing.

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Author notes

  1. Bruria Hirsh Raccah and Amihai Rottenstreich have contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology, Hadassah University Hospital, Jerusalem, Israel

    Bruria Hirsh Raccah

  2. Division of Clinical Pharmacy, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel

    Bruria Hirsh Raccah, Ilan Matok & Amichai Perlman

  3. Department of Hematology, Hadassah-Hebrew University Medical Center, POB 12000, 91120, Jerusalem, Israel

    Amihai Rottenstreich, Netanel Zacks & Yosef Kalish

  4. Division of Clinical Pharmacology, Department of Medicine, Hadassah University Hospital, Jerusalem, Israel

    Mordechai Muszkat

  5. Department of Medicine, Hadassah University Hospital, Jerusalem, Israel

    Amichai Perlman

Authors
  1. Bruria Hirsh Raccah
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  4. Mordechai Muszkat
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  5. Ilan Matok
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  7. Yosef Kalish
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Contributions

BHR contributed to conception, design, acquisition, analysis, and interpretation. AR contributed to conception, design, acquisition and interpretation. NZ contributed to design and analysis. MM contributed to conception and interpretation. IM contributed to design and analysis. AP contributed to design, analysis, and interpretation. YK contributed to conception, design and interpretation. All authors critically revised manuscript and gave final approval.

Corresponding author

Correspondence to Yosef Kalish.

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Conflict of interest

The authors do not have any conflicts of interest to disclose.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was approved by the local institutional review board of Hadassah Medical Center Helsinki Committee.

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Informed consent was waived by the by the institutional review board of Hadassah Medical Center.

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Hirsh Raccah, B., Rottenstreich, A., Zacks, N. et al. Drug interaction as a predictor of direct oral anticoagulant drug levels in atrial fibrillation patients. J Thromb Thrombolysis 46, 521–527 (2018). https://doi.org/10.1007/s11239-018-1738-7

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  • DOI: https://doi.org/10.1007/s11239-018-1738-7

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