Treatment with enzyme-inducing antiseizure medications (eiASMs) may be associated with a higher risk of incident cardiovascular disease (CVD) among adult patients with epilepsy, according to study findings published in JAMA Neurology.

Cardiovascular risk factors such as hypertension, dyslipidemia, type 2 diabetes, and atrial fibrillation tend to be more common at the time of adult-onset epilepsy. It’s been hypothesized that eiASMs, which are used for the treatment of epilepsy, can also contribute to cardiovascular disease risk. The objective of the current study was to compare the risk associated with eiASMs compared with non-eiASMs, explore the risks of eiASM in incident cases of epilepsy, and assess the risk of eiASM in patients diagnosed with epilepsy at 65 years or older who may be at greater risk for adverse events of long-term eiASM use.

The study was a review of adult patients from England who had been diagnosed with epilepsy after January 1, 1990, and to March 2019. Patients were categorized into 3 groups: the overall cohort of adults diagnosed with epilepsy after 1990 (n= 31,479), incident cases diagnosed after 1998 (n=7501), and adults diagnosed with epilepsy at age ≥65 years on or after January 1, 1990 (n=3790). Researchers evaluated the rate of incident CVD in adjusted propensity-matched survival analyses that controlled for age, sex, baseline socioeconomic status, and cardiovascular risk factors. Weighted cumulative exposure models were also used as part of the analyses.

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The median age of the patients at diagnosis was 32 years. All patients included in the final cohort were free of CVD at baseline. Most demographic features were similar between the patients exposed and not exposed to eiASMs; however, patients who received eiASMs following diagnosis had a longer follow-up of a median 2 years (P <.001).

In the adjusted propensity-matched Cox proportional hazards model, the hazard ratio (HR) for incident CVD was higher for patients who received eiASM (HR, 1.21; 95% CI, 1.06-1.39). While the absolute difference in cumulative hazard for incident CVD was slightly higher over the first 8 to 10 years, the researchers noted continued divergence by >1% from 10 to 25 years of the follow-up period.

In patients with persistent exposure (>4 prescriptions), the median HR increased from 1.54 (95% CI, 1.28-1.79) when receiving a relative defined daily dose of an eiASM of 1 to 2.38 (95% CI, 1.52-3.56) with a relative defined daily dose of 2 through 25 years of follow-up vs patients who didn’t receive an eiASM. The researchers added that the elevated hazard was attenuated when they restricted the analyses to incident cases or patients who were diagnosed when they were >65 years of age.

They noted that they were unable to determine whether all patients adhered to their eiASMs during the study period, further limiting the findings.

While short-term use of eiASMs “does not appear to confer considerable risk,” the researchers suggest “caution should be used when taking these medications long-term.”

Disclosure: Multiple authors declared affiliations with the pharmaceutical industry. Please refer to the original article for a full list of disclosures.


Josephson CB, Wiebe S, Delgado-Garcia G, et al. s. JAMA Neurol. Published online October 4, 2021. doi:10.1001/jamaneurol.2021.3424