OBJECTIVES

: All direct oral anticoagulants (DOACs) are substrates of the efflux P-glycoprotein (P-gp) transporters. The hepatic enzyme cytochrome P450 also plays an important role in the metabolism of apixaban and rivaroxaban. Antiepileptic drugs (AEDs) may reduce absorption or and increase metabolism of DOACs and cause reduced antithrombotic efficacy of these drugs. Some case reports suggest that stroke and systemic embolism were caused with concomitant treatment AEDs-DOACs. However, there are no evidence whether concurrent use of metabolic inducers in patient taking DOACs was associated with increased risk of stroke and thrombotic events.

METHODS

: We analyzed adverse event cases submitted to the Food and Drug Administration Adverse Event Reporting System from January 2010 to June 2019. We compared the proportion of cases reporting thromboembolic and ischemic adverse events with the concomitant use of DOACs and first-generation, metabolic inducing AEDs to the proportion of cases with DOACs and control AEDs. First generation AEDs were defined as phenytoin, phenobarbital, carbamazepine, and topiramate. Control AEDs were defined agents as lamotrigine and levetiracetam.

RESULTS

: During this observation, 214 thromboembolic and ischemic event cases reported in concomitant use of DOACs and AEDs. Compared with control AEDs, first generation AEDs were associated with increases in the odds of reporting outcomes [reporting odds ratio (ROR) 4.7, 95% confidence interval (CI) 3.3-6.6, p<0.0001]. In secondary analyses of dabigatran, rivaroxaban, and apixaban, inducing AEDs were similarly associated with increased reporting of outcome (ROR 2.2, 95%CI 1.3-4.0, ROR 7.3, 95%CI 4.3-12.7, and ROR 6.2, 95%CI 2.8-14.0). Edoxaban was not associated with the outcomes.

CONCLUSIONS

: 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.