ABSTRACT NUMBER: ESOC2026A1960 COMPARATIVE THROMBOEMBOLIC, BLEEDING AND MORTALITY RISKS WITH ANTISEIZURE MEDICATIONS DURING DIRECT ORAL ANTICOAGULANT THERAPY IN EPILEPSY

Abstract Background and aims Direct oral anticoagulants are often co-prescribed with antiseizure medications in epilepsy, but comparative outcome data are limited. We compared thromboembolic, major bleeding and mortality outcomes across common antiseizure medication monotherapies during direct oral anticoagulant therapy. Methods Target trial emulation in the TriNetX Global Collaborative Network (165 health care organizations). Adults with epilepsy initiating antiseizure medication monotherapy overlapping direct oral anticoagulant therapy were included after prespecified exclusions. Follow-up began at a ninety day landmark after antiseizure medication initiation. Levetiracetam, valproate, and enzyme-inducing antiseizure medications were propensity score matched one to one to lamotrigine or lacosamide. Cox models estimated hazard ratios with robust variance. Negative control analyses were performed in vitamin K antagonist cohorts. Results Among 9,529 initiators, levetiracetam (57 percent) was associated with higher thromboembolic risk versus lamotrigine or lacosamide (hazard ratio 1.98; 95 percent confidence interval 1.37 to 2.87) and higher all-cause mortality (1.60; 1.23 to 2.08), without higher major bleeding. Strong enzyme-inducing antiseizure medications showed higher thromboembolic risk (1.55; 1.02 to 2.36) but lower major bleeding (0.62; 0.46 to 0.83). Valproate was associated with higher mortality (1.49; 1.09 to 2.04), intracranial major bleeding (3.01; 1.45 to 6.26), and aspiration pneumonia (3.08; 1.53 to 6.18). In vitamin K antagonist users, thromboembolic hazard ratios were near one. Conclusions In adults with epilepsy receiving direct oral anticoagulants, antiseizure medication selection was associated with distinct benefit risk profiles, supporting antiseizure medication choice as a potentially modifiable contributor to net clinical outcomes. Conflict of interest Marian Galovic received fees and travel support from Arvelle, Advisis, Bial and Nestlé Health Science outside the submitted work. Eugen Trinka has received personal honoraria for lectures and educational activities from EVER Pharma, Marinus, Arvelle, Angelini, Alexion, Argenx, Medtronic, Biocodex, Bial-Portela & Ca, NewBridge, GL Pharma, GlaxoSmithKline, Boehringer Ingelheim, LivaNova, Eisai, Epilog, UCB, Biogen, Sanofi, STOKE Therapeutics, Jazz Pharmaceuticals, and Rapport; his institution has received research grants from Biogen, UCB Pharma, Eisai, Red Bull, Merck, Bayer, the European Union, FWF Österreichischer Fond zur Wissenschaftsforderung Bundesministerium für Wissenschaft und Forschung, and Jubiläumsfond der Österreichischen Nationalbank. Johan Zelano has received speaker / advisory board fees from UCB, Orion Pharma, Angelini Pharma, Eisai and Sanofi and has, as an employee of Sahlgrenska University Hospital (no personal compensation), been investigator/sub-investigator in clinical trials sponsored by UCB, SK life science, Bial, GW Pharma, and Angelini Pharma. Emilio Russo has received speaker fees or funding from and has participated on advisory boards for Angelini Pharma, Eisai, Ethypharm, GW Pharmaceuticals, Jazz Pharmaceuticals, Kolfarma and UCB Pharma. Kai Michael Schubert, Carolina Ferreira-Atuesta, Arunachalam Soma, Francesco Brigo, Gregory Y. H. Lip, Gashirai K Mbizvo: nothing to disclose.