To elucidate the risk of ischemic stroke and major bleeding in patients with different DOAC/AED combinations.

Clinical relevance of the drug-drug interactions between direct oral anticoagulants (DOAC) and antiepileptic drugs (AED) combinations is uncertain. Determining the thromboembolic and major bleeding risks in different DOAC/AED combinations may guide treatment selection for at-risk patients.

We performed a propensity-score weighted, territory-wide retrospective study involving patients in Hong Kong from 1^st January 2015 to 31^st December 2020. All patients who received concomitant DOAC (dabigatran, apixaban, rivaroxaban, edoxaban) and AEDs were identified. We compared the risks of thromboembolism and major bleeding among patients taking 1) DOAC and cytochrome P450 (CYP450) or P-glycoprotein (P-gp) non-modulating AEDs (gabapentin, pregabalin), and 2) DOAC with CYP450/P-gp modulating AEDs (phenytoin, lamotrigine, levetiracetam, valproate, and topiramate) in the primary analysis. Secondary analyses included between-AED and between-DOAC comparisons by Cox regression. Primary outcome was ischemic stroke, secondary outcomes were systemic arterial and venous thromboembolism, major bleeding and death.

8753 patients with DOAC/AED combination were identified with a median follow-up of 6 years. CYP450/P-gp inducing AEDs (phenytoin, levetiracetam) were associated with a higher risk of ischemic stroke (adjusted hazard ratio (aHR) 2.30, 95% CI 1.80-2.93, p<0.001) and major bleeding (aHR 1.81, 95% CI 1.40-2.33, p<0.001) compared to CYP450/P-gp non-modulating AEDs. Levetiracetam and valproate were associated with higher risk of ischemic stroke. Apixaban was associated with lower risk of ischemic stroke (aHR 0.57, 95% CI 0.37-0.89, p=0.01) compared to other DOACs.

Drug-drug interactions among DOACs and AEDs were clinically relevant. Compared to gabapentin and pregabalin, phenytoin, levetiracetam were associated with higher risk of ischemic stroke. Apixaban was associated with the lowest risk of ischemic stroke compared with other DOACs. Caution should be exercised on AED selection for DOAC patients. Further pharmacokinetic studies should elucidate the reasons behind these observations.