Ischemic and Thrombotic Events Associated with Concomitant Xa-inhibiting Direct Oral Anticoagulants and Antiepileptic Drugs: Analysis of the FDA Adverse Event Reporting System (FAERS)
- 91 Downloads
Factor Xa-inhibiting direct oral anticoagulants (FXa-DOACs) undergo hepatic metabolism via cytochrome P-450 (CYP450). Concomitant use of rifampicin, an inducer of these enzymes, with FXa-DOACs, has been shown to decrease FXa-DOAC concentrations in healthy subjects. Several common antiepileptic drugs (AEDs) are known to induce CYP450 enzymes as well. However, little is known regarding the impact of this potential interaction on treatment outcomes with FXa-DOACs.
We analyzed adverse event cases submitted to the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) from January 2013 to December 2018. We compared the proportion of cases reporting thromboembolic and ischemic adverse events (TAIAEs) with the concomitant use of FXa-DOACs and enzyme-inducing AEDs to the proportion of cases with FXa-DOACs and other AEDs.
During this period, 9693 adverse event cases reported concomitant use of FXa-DOACs and AEDs. Almost all reports (> 99%) involved the use of rivaroxaban or apixaban. Compared with other AEDs, enzyme-inducing AEDs were associated with an 86% increase in the odds of reporting TAIAEs [reporting odds ratio (ROR) 1.86, 95% confidence interval (CI) 1.61–2.15; p < 0.0001]. In secondary separate analyses of rivaroxaban and apixaban, enzyme-inducing AEDs were similarly associated with increased reporting of a TAIAE (ROR 1.79, 95% CI 1.50–2.12, and ROR 1.88, 95% CI 1.41–2.48, respectively).
Using real world data, we observed an increase in the odds of reporting anticoagulation treatment failure among patients treated with FXa-DOACs and concomitant enzyme-inducing AEDs compared to those treated with other AEDs.
Compliance with Ethical Standards
No external funding was used in the preparation of this article.
Conflict of interest
A Perlman is a doctoral student at the Hebrew University of Jerusalem and an employee at K-health Inc. The work presented in this article is not related to his work at K-health. M. Wanounou, R. Goldstein, L. Choshen Cohen, D. Singer, and M. Muszkat declare that they have no potential conflicts of interest that might be relevant to this work.
- 15.Di Gennaro L, Lancellotti S, De Cristofaro R, De Candia E. Carbamazepine interaction with direct oral anticoagulants: help from the laboratory for the personalized management of oral anticoagulant Therapy. J Thromb Thrombolysis. 2019;48:528. https://doi.org/10.1007/s11239-019-01866-1.CrossRefPubMedGoogle Scholar
- 20.Center for Drug Evaluation and Research. National Drug Code Directory. U.S. Food and Drug Administration. 2019. https://www.fda.gov/drugs/drug-approvals-and-databases/national-drug-code-directory. Accessed 13 June 2019.
- 21.Cytochrome P-450 CYP3A4 inducers. DrugBank. 2019. https://www.drugbank.ca/categories/DBCAT003896. Accessed 13 June 2019.
- 24.Medication Guides. accessdata.fda.gov. 2019. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=medguide.page. Accessed 13 June 2019.
- 25.Medicines. European Medicines Agency. 2019. https://www.ema.europa.eu/en/medicines. Accessed 13 June 2019.