# Stroke and Thrombotic Events Associated With Concomitant Use of Oral Anticoagulants and Antiepileptic Drugs in the United States and Japan

## TL;DR

This study found that using certain antiepileptic drugs with blood thinners increases the risk of stroke and blood clots.

## Contribution

The study provides evidence linking first-generation antiepileptic drugs with higher odds of anticoagulant treatment failure.

## Key findings

- First-generation AEDs increased odds of reporting adverse outcomes compared to control AEDs (ROR: 1.79).
- Dabigatran, rivaroxaban, and apixaban showed increased reporting of adverse outcomes when used with first-generation AEDs.
- Edoxaban and JADER scores were not associated with patient outcomes.

## Abstract

Introduction: Direct oral anticoagulants (DOACs) are substrates of efflux P-glycoprotein (P-gp) transporters, and the hepatic enzyme cytochrome P450 plays an important role. Antiepileptic drugs (AEDs) may reduce absorption or increase the metabolism of DOACs, thereby reducing their antithrombotic efficacy. However, there is no evidence that concurrent use of metabolic inducers in patients taking DOACs is associated with an increased risk of stroke or thrombotic events.

Methods: We analyzed adverse event cases submitted to the Food and Drug Administration Adverse Event Reporting System (FAERS) from January 2010 to June 2023 and the Japanese Adverse Drug Event Report (JADER) database to April 2023. We compared the proportion of cases reporting thromboembolic and ischemic adverse events with the concomitant use of DOACs and first-generation drugs, such as phenytoin, metabolically inducing AEDs, to the proportion of cases with DOACs and control AEDs, such as levetiracetam.

Results: Compared with control AEDs, first-generation AEDs were associated with increased odds of reporting outcomes (reporting odds ratio {ROR}: 1.79, 95% confidence interval {CI}: 1.52-2.10, p<0.0001). Dabigatran, rivaroxaban, and apixaban were also similarly associated with increased reporting of outcome (ROR: 1.74, 95% CI: 1.26-2.39, ROR: 1.58, 95% CI: 1.24-2.02, and ROR: 2.07, 95% CI: 1.48-2.90). Edoxaban and JADER scores were not associated with patient outcomes.

Conclusion: We observed an increase in the odds of reporting anticoagulation treatment failure among patients treated with DOACs and concomitant first-generation AEDs compared to those treated with control AEDs in the FAERS database. Care should be taken when administering dabigatran, apixaban, and rivaroxaban.