Journal of Thrombosis and Thrombolysis

, Volume 46, Issue 4, pp 521–527 | Cite as

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

  • Bruria Hirsh Raccah
  • Amihai Rottenstreich
  • Netanel Zacks
  • Mordechai Muszkat
  • Ilan Matok
  • Amichai Perlman
  • Yosef KalishEmail author


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.


Drug interaction Direct-acting oral anticoagulants Drug levels CYP3A4 inhibitors P-gp inhibitors 



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

Author 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.

Compliance with ethical standards

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.

Informed consent

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

Supplementary material

11239_2018_1738_MOESM1_ESM.docx (27 kb)
Supplementary material 1 (DOCX 27 KB)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of CardiologyHadassah University HospitalJerusalemIsrael
  2. 2.Division of Clinical Pharmacy, Institute for Drug Research, School of Pharmacy, Faculty of MedicineHebrew University of JerusalemJerusalemIsrael
  3. 3.Department of HematologyHadassah-Hebrew University Medical CenterJerusalemIsrael
  4. 4.Division of Clinical Pharmacology, Department of MedicineHadassah University HospitalJerusalemIsrael
  5. 5.Department of MedicineHadassah University HospitalJerusalemIsrael

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