Cardiovascular outcomes of enzyme‐inducing anti‐seizure medications: A real‐world Asian cohort study

OBJECTIVE: To determine whether enzyme-inducing anti-seizure medications (EIASMs) are associated with differential risks of major adverse cardiovascular events (MACE) and all-cause mortality compared with non-enzyme-inducing anti-seizure medications (NEIASMs) in adults with epilepsy. METHODS: Using the Chang Gung Research Database (2010-2019), adults with epilepsy receiving at least 28 cumulative days of anti-seizure medication therapy within 180 days of the index date were classified as EIASMs or NEIASMs users. Stabilized inverse probability of treatment weighting (IPTW) addressed confounding by indication. Composite MACE encompassing myocardial infarction (MI), arrhythmia, heart failure, ischemic stroke, hemorrhagic stroke, and sudden cardiac death and all-cause mortality were co-primary endpoints evaluated using Cox proportional hazards and Fine-Gray competing risk models. RESULTS: Of 20 693 eligible patients, 10 571 received EIASMs and 10 122 received NEIASMs. After IPTW, all covariates were balanced (absolute standardized mean differences <0.1). Cox analysis demonstrated lower composite MACE (adjusted HR: 0.91, 95% CI: 0.85-0.99, p = 0.020) and all-cause mortality (adjusted HR: 0.95, 95% CI: 0.89-1.00, p = 0.048) with EIASM use, with individually lower rates of MI (adjusted HR: 0.83, p = 0.013) and arrhythmia (adjusted HR: 0.85, p = 0.029). Under Fine-Gray modeling, composite MACE was attenuated to nonsignificance (adjusted SHR 0.94, 95% CI: 0.87-1.01, p = 0.118), with directional consistency preserved. SIGNIFICANCE: In this large propensity score-weighted Asian cohort, EIASM use was not associated with excess cardiovascular risk. These findings challenge the assumption that EIASMs carry inherent cardiovascular disadvantage and support their use with appropriate monitoring when seizure control requires enzyme-inducing therapy.