Cardiovascular events and mortality in adults with late onset seizures: Focus on enzyme‐modulating antiseizure medications

OBJECTIVE: Using a Dutch insurance claims registry, we examine whether people with epilepsy have an increased risk of major ischemic cardiovascular events or death compared to people without epilepsy. We also assess whether this risk differs between users of enzyme-modulating and non-enzyme-modulating antiseizure medications (ASMs). METHODS: This nationwide study included adults ≥50 years old in the VEKTIS registry. Incident seizure cases were matched 2:1 to controls by age, sex, and region. ASM prescriptions (≥6 months) were classified as enzyme-modulating or non-enzyme-modulating. The primary outcome was a composite event over 5-year follow-up. Cox models adjusted for age, sex, and baseline cardiovascular medications. RESULTS: We matched 8728 cases to 17 445 controls (56% male, median age = 67 years, range = 50-102). During follow-up, 6895 events occurred. Seizure disorder was associated with a higher cardiovascular risk than controls (hazard ratio [HR] = 2.30, 95% confidence interval [CI] = 2.19-2.41, p < .001), particularly early after diagnosis. Older age and cardiovascular medication use increased risk, whereas female sex was protective. Among 1758 participants with seizures treated with ASM, 656 events occurred. The enzyme-modulating ASM group showed a nonsignificant trend toward higher risk than the non-enzyme-modulating ASM group (HR = 1.14, 95% CI = .97-1.34, p = .12). Time-varying models suggested a lower risk with current enzyme-modulating ASM exposure compared with non-enzyme-modulating ASMs (HR = .80, 95% CI = .70-.92, p = .001). There was an increased risk with cumulative exposure (HR = 1.41 per year of past enzyme-modulating ASM exposure, 95% CI = 1.30-1.54, p < .001). SIGNIFICANCE: People with seizures face higher cardiovascular risk, especially shortly after diagnosis. Although short-term analyses showed no clear differences between ASM categories, longer term and cumulative exposure to enzyme-modulating ASMs was associated with modestly increased risk. Findings are generalizable to routine care, although further work is needed to clarify time- and drug-specific cardiovascular effects.