Enzyme-Inducing Antiseizure Medications May Increase the Risk of Cardiovascular Disease

September 2022

The risk of cardiovascular disease (CVD) is higher in people with epilepsy than in the general population. Antiseizure medications may increase the risk of CVD, particularly enzyme-inducing antiseizure medications because they may promote dyslipidemia and hyperhomocysteinemia. To understand the risk of CVD in patients with epilepsy taking enzyme-inducing antiseizure medications, investigators conducted a large population-based cohort study in England.

The cohort data were obtained from CALIBER, a platform with curated electronic health records from primary care, hospitals, and a cause-specific mortality registry.

Patients were aged ≥18 years who had received a diagnosis of epilepsy from January 1990 to March 2019 and did not have CVD at the time of diagnosis. Patients were grouped into 1 of 3 cohorts: a study cohort of all incident cases of epilepsy, an incident cohort of cases of epilepsy diagnosed after 1998, and an older cohort of patients with epilepsy diagnosed at ≥65 of age. Patients were classified as exposed to enzyme-inducing antiseizure medications if they had 4 consecutive prescriptions for carbamazepine, eslicarbazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, rufinamide, or topiramate.

The primary outcome was incident CVD, which included ischemic heart diseases, ischemic stroke, or hemorrhagic stroke.

The investigators identified 31,479 patients who received a diagnosis of epilepsy after January 1, 1990, 7501 patients were diagnosed after 1998, and 3790 patients were aged ≥65 years at the time of diagnosis. The median age at diagnosis was 32 years. Of the whole study cohort, 37% were exposed to enzyme-inducing antiseizure medications.

When controlling for factors such as age, comorbidities, smoking, and socioeconomic status, the hazard for incident CVD was 21% higher for the patients taking enzyme-inducing antiseizure medications compared with a propensity-matched cohort of nonexposed patients (P = .003). The investigators found that other analyses supported a higher risk of incident CVD with enzyme-inducing antiseizure medications. The difference in cumulative hazard between exposure groups widened after the first 8 to 10 years of exposure to enzyme-inducing antiseizure medications. Furthermore, those taking higher doses of enzyme-inducing antiseizure medications had a greater risk of CVD than those taking lower doses.

The hazard for incident CVD for the other cohorts, patients who received a diagnosis of epilepsy after 1998 and patients who received a diagnosis of epilepsy at ≥65 years, were not significantly different between groups. In these cohorts, while the hazard ratio was slightly higher in the enzyme-inducing antiseizure medications groups compared with the unexposed groups, the effect sizes were small.

The investigators suggested that their results differed from a previous study that did not find an association between enzyme-inducing antiseizure medications and CVD1 because their study had a longer follow-up, a requirement for 4 prescriptions, and a larger number of patients.

“Future studies are required to further elucidate pathological mechanisms and to evaluate whether proactively managing conventional risk factors such as dyslipidemia and hypertension, using the minimal effective dose of the enzyme-inducing antiseizure medications and using prophylactic interventions such as folate supplementation can help mitigate risk in patients that require these medications for long-term seizure control,” the investigators suggested.


  1. Lee-Lane E, Torabi F, Lacey A, et al. Epilepsy, antiepileptic drugs, and the risk of major cardiovascular events. Epilepsia. 2021;62(7):1604-1616.


Josephson CB, Wiebe S, Delgado-Garcia G, et al. Association of enzyme-inducing antiseizure drug use with long-term cardiovascular disease. JAMA Neurol. 2021;78(11):1367-1374.

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