ANTISEIZURE medications combined with direct oral anticoagulants yield distinct vascular and mortality outcomes in adult epilepsy. In a target trial emulation investigating 9,529 adults, researchers evaluated clinical safety profiles across common antiseizure strategies in patients receiving concurrent direct oral anticoagulants. Compared with a low-interaction active reference of lamotrigine or lacosamide, individual drug classes demonstrated marked divergence in thromboembolic events, major hemorrhage, and all-cause mortality over follow-up.
Levetiracetam, despite being widely considered a low-interaction agent in routine practice, was associated with an elevated thromboembolic hazard ratio of 1.98 and a 60% increase in all-cause mortality, while displaying major bleeding rates comparable to the reference cohort. Strong enzyme-inducing antiseizure medications, such as carbamazepine and phenytoin, exhibited a 55% increase in thromboembolic hazard alongside a 38% reduction in major bleeding risk. This inverse pattern aligns with enhanced cytochrome P450 and P-glycoprotein induction, which accelerates direct oral anticoagulant clearance, impairing antithrombotic efficacy while reducing systemic bleeding. In contrast, valproate therapy demonstrated a threefold increase in major intracranial hemorrhage and a 49% rise in all-cause mortality, accompanied by heightened risk of noncerebral embolic events. Moderate enzyme inducers showed no statistically significant differences in primary vascular or bleeding end points.
Counterfactual population modeling indicated that approximately 28% of observed thromboembolic events were potentially preventable if all patients had initiated the lamotrigine or lacosamide reference strategy. Notably, levetiracetam accounted for 71% of these excess ischemic events, while strong enzyme inducers contributed 16%. In a sensitivity analysis of patients receiving vitamin K antagonists, thromboembolic and mortality hazards were near null across all drug groups, reinforcing that observed risks represent drug-specific pharmacokinetic interactions with direct oral anticoagulants.
These observational findings underscore that co-prescribing antiseizure medications and DOACs requires careful clinical risk assessment. Clinicians should consider prioritizing agents with low interaction potential, including lamotrigine and lacosamide, for patients requiring oral anticoagulation. When clinical necessity dictates the use of higher-risk anticonvulsants, switching from direct oral anticoagulants to vitamin K antagonists with regular international normalized ratio monitoring may safeguard clinical outcomes.
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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