Safety of Antiseizure Medications During Direct Oral Anticoagulant Therapy in Epilepsy

Importance: Concomitant use of antiseizure medications (ASMs) and direct oral anticoagulants (DOACs) is common in epilepsy, but comparative safety data remain limited. Objective: To compare risks of thromboembolic events, major bleeding, and all-cause mortality across commonly used ASMs in adults with epilepsy receiving DOACs. Design, Setting, and Participants: This was a retrospective cohort study emulating a target trial for each ASM group against an active comparator; 1:1 propensity score matching in 4 cohorts emulated randomization to estimate the per-protocol outcome of sustained ASM monotherapy. Participant data were acquired from the TriNetX Global Collaborative Network, a federated, deidentified electronic health record platform of 165 health care organizations internationally. Included in the study were adults 18 years or older with epilepsy. Individuals were excluded if there was evidence of recent use of vitamin K antagonists (VKAs) or strong non-ASM cytochrome P450 3A4/P-glycoprotein modulators and if there was a history of major vascular events in the prior year. Participant follow-up began at a prespecified 90-day landmark. Data were analyzed January to March 2026. Exposures: ASM monotherapy with levetiracetam, valproate, moderate enzyme-inducing ASMs, or strong enzyme-inducing ASMs (eg, carbamazepine, phenytoin), each vs lamotrigine or lacosamide (1 pooled reference group of patients taking either drug; hereafter referred to as lamotrigine/lacosamide). Main Outcomes and Measures: The primary outcomes included primary thromboembolic composite (ischemic stroke, myocardial infarction, pulmonary or systemic/peripheral embolism), major bleeding, and all-cause mortality. Sensitivity analyses included patients treated with VKAs. Results: Of 2.29 million adults (≥18 years) with epilepsy, 40 932 were DOAC eligible, 26 962 had DOAC-ASM overlap within 6 months, 10 209 were monotherapy eligible, and 9529 initiators formed the analytic cohort. Among 9529 initiators (mean [SD] age, 63 [18] years; 4869 female [51%]), there were 5473 (57%) taking levetiracetam, 1395 (15%) taking strong enzyme-inducing ASMs, 1006 (11%) taking valproate, and 382 (4%) taking moderate enzyme-inducing ASMs. In matched analyses vs lamotrigine/lacosamide, levetiracetam was associated with higher thromboembolic risk (hazard ratio [HR], 1.98; 95% CI, 1.37-2.87) and higher all-cause mortality (HR, 1.60; 95% CI, 1.23-2.08), with comparable major bleeding. Strong enzyme-inducing ASMs were associated with higher thromboembolic risk (HR, 1.55; 95% CI, 1.02-2.36) but lower major bleeding (HR, 0.62; 95% CI, 0.46-0.83). Valproate was associated with higher mortality (HR, 1.49; 95% CI, 1.09-2.04) and higher intracranial major bleeding (HR, 3.01; 95% CI, 1.45-6.26). Approximately 28% of thromboembolic events were potentially preventable under a lamotrigine/lacosamide reference. In VKA-treated adults, thromboembolic risks were near null. Conclusions and Relevance: Results suggest that in adults with epilepsy who are treated with DOACs, ASM selection was associated with distinct thromboembolic, bleeding, and mortality risks, supporting ASM choice as a modifiable contributor to clinical outcomes.