Pharmacokinetic studies reported lower direct oral anticoagulant (DOAC) levels with the co-use of cytochrome P450 or P-glycoprotein-inducing antiseizure medications. Whether the drug–drug interactions confer a clinical risk of thromboembolism was unclear.

In our population-based cohort study involving 8746 patients taking concurrent antiseizure medications and DOAC over a 5-year period, cytochrome P450/ P-glycoprotein-modulating antiseizure medications were associated with a 28% increase in the odds of ischemic stroke compared with DOAC users taking cytochrome P450/P-glycoprotein-neutral antiseizure medications. Among which, phenytoin users had a 39% increase in the odds of developing ischemic stroke.

In a subgroup analysis of 2173 patients with epilepsy taking DOAC, the use of phenytoin, valproate, or levetiracetam was not associated with ischemic stroke or venous thromboembolism.

While phenytoin or valproate use with DOAC was associated with increased mortality, levetiracetam in combination with DOAC was not associated with an increased risk of death.