Drug interaction as a predictor of direct oral anticoagulant drug levels in atrial fibrillation patients
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.
KeywordsDrug interaction Direct-acting oral anticoagulants Drug levels CYP3A4 inhibitors P-gp inhibitors
We appreciate Ms. Cindy Cohen’s help in editing.
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.
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 was waived by the by the institutional review board of Hadassah Medical Center.
- 13.Drug Safety and Availability, FDA Drug Safety Communication, New restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury. https://www.fda.gov/Drugs/DrugSafety/ucm256581.htm
- 14.Drug Development and Drug Interactions (2018) Table of substrates, inhibitors and inducers, pp 1–14. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm#table3-2
- 16.Dabigatran, Summary of product characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000829/WC500041059.pdf
- 17.Apixaban, highlights of prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202155s000lbl.pdf
- 18.Rivaroxaban, Prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022406s000lbl.pdf
- 19.Dabigatran, Prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022512s000lbl.pdf
- 22.Patel MR, Mahaffey KW, Garg J et al (2010) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 365:609–619Google Scholar
- 25.Center for Drug Evaluation and Research Application Number, 202439Orig1s000, medical review, rivaroxaban. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202439Orig1s000MedR.pdf
- 26.Center for Drug Evaluation and Research Application Number, 202155Orig1s000, medical review, apixaban. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202155Orig1s000MedR.pdf
- 27.Center for Drug Evaluation and Research Application Number: 22-512, medical review, dabigatran. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022512Orig1s000MedR.pdf