DIRECT ORAL ANTICOAGULANTS in adults with epilepsy were associated with different thromboembolic, bleeding, and mortality outcomes depending on the antiseizure medication used, according to a large retrospective cohort study.
Researchers evaluated the comparative safety of commonly prescribed antiseizure medications in adults receiving direct oral anticoagulants.
Using data from an international electronic health record network, the team emulated a target trial and compared levetiracetam, valproate, moderate enzyme inducing antiseizure medications, and strong enzyme inducing antiseizure medications against a pooled reference group receiving lamotrigine or lacosamide.
From 2.29 million adults with epilepsy, 40,932 were eligible for direct oral anticoagulant treatment. A total of 9,529 treatment initiators were included in the final analysis. The mean age was 63 years, and 51% were female.
Higher Thromboembolic Risk Observed
In matched analyses, levetiracetam was associated with a greater risk of thromboembolic events compared with lamotrigine or lacosamide. It was also associated with increased all-cause mortality. Major bleeding risk was comparable between groups.
Strong enzyme inducing antiseizure medications, including carbamazepine and phenytoin, were likewise associated with higher thromboembolic risk. However, these therapies were linked to a lower risk of major bleeding.
The investigators estimated that approximately 28% of thromboembolic events may have been preventable if outcomes had matched those observed in the lamotrigine or lacosamide reference group.
Mortality and Bleeding Concerns with Valproate
Valproate showed a distinct risk profile. Compared with the reference group, valproate was associated with higher all-cause mortality, as well as a greater risk of intracranial major bleeding.
Notably, among adults treated with vitamin K antagonists, thromboembolic risks were reported to be near null.
The authors concluded that antiseizure medication choice represents a potentially modifiable factor influencing outcomes in adults with epilepsy receiving direct oral anticoagulants, highlighting the importance of treatment selection when balancing thromboembolic and bleeding risks.
Reference
Schubert KM et al. Safety of Antiseizure Medications During Direct Oral Anticoagulant Therapy in Epilepsy. JAMA Neurol. 2026;DOI:10.1001/jamaneurol.2026.2712
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