Research Summary

Antiseizure Drug Choice Linked to Thromboembolic Risk During DOAC Therapy

Edited by:
Ashton L. Stahl

Key Highlights

  • Levetiracetam was associated with higher thromboembolic risk and mortality, with comparable major bleeding.
  • Strong enzyme-inducing antiseizure medications were associated with higher thromboembolic risk but lower major bleeding.
  • Valproate was associated with higher mortality and intracranial major bleeding.
  • The analysis included 9529 adults with epilepsy receiving direct oral anticoagulants and antiseizure monotherapy.

Antiseizure medication selection was associated with distinct thromboembolic, bleeding, and mortality risks among adults with epilepsy receiving direct oral anticoagulants (DOACs). Compared with lamotrigine or lacosamide, levetiracetam and strong enzyme-inducing antiseizure medications were associated with higher thromboembolic risk in a retrospective cohort study emulating target trials.

The researchers used de-identified electronic health records from the TriNetX Global Collaborative Network, encompassing 165 healthcare organizations internationally. Four cohorts underwent 1:1 propensity score matching to compare levetiracetam, valproate, moderate enzyme-inducing medications, or strong enzyme-inducing medications with a pooled lamotrigine/lacosamide reference group. Analyses estimated outcomes during sustained antiseizure monotherapy, with follow-up beginning at a prespecified 90-day landmark.

Study Findings

The analytic cohort comprised 9529 initiators, with a mean age of 63 years; 51% were women. Levetiracetam accounted for 57% of treatment, strong enzyme-inducing medications for 15%, valproate for 11%, and moderate enzyme-inducing medications for 4%. Compared with lamotrigine/lacosamide, levetiracetam was associated with higher thromboembolic risk (hazard ratio [HR], 1.98; 95% CI, 1.37-2.87) and mortality (HR, 1.60; 95% CI, 1.23-2.08), while major bleeding was comparable.

Strong enzyme-inducing medications, including carbamazepine and phenytoin, 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 intracranial major bleeding (HR, 3.01; 95% CI, 1.45-6.26). The investigators estimated that approximately 28% of thromboembolic events were potentially preventable under a lamotrigine/lacosamide reference. In sensitivity analyses involving adults treated with vitamin K antagonists, thromboembolic risks were near null.

Clinical Implications

According to the researchers, these differing outcome associations suggest antiseizure medication choice may be a potentially modifiable contributor to clinical outcomes during DOAC therapy.

Reference

Schubert KM, Ferreira-Atuesta C, Soma A, et al. Safety of antiseizure medications during direct oral anticoagulant therapy in epilepsy. JAMA Neurol. 2026;83(10):1002-1012. doi:10.1001/jamaneurol.2026.2712