Can Antiseizure Drugs Increase Cardiovascular Risk?

Enzyme-inducing antiseizure medications (EIASMs) increase the risk for new-onset cardiovascular events among older adults with epilepsy, a new study suggests.

In a prospective cohort study of more than 27,000 patients, the odds of a cardiovascular event were on average 2.2 times greater in patients with epilepsy compared with those without epilepsy. Almost one third of the association between epilepsy and cardiovascular events was mediated by the use of EIASMs.

“Our study may provide healthcare professionals further justification for avoiding EIASMs when clinically feasible,” senior author Mark R. Keezer, MD, PhD, head of the epilepsy group at Centre Hospitalier de l’Université de Montréal, told Medscape Medical News. 

“Future studies should begin to examine whether cardiovascular screening would be useful in people at greatest risk of cardiovascular disease,” he suggested.

The findings were published on September 30 in JAMA Neurology.

Study Findings

Epilepsy and cardiovascular disease have a strong cross-sectional association, but how epilepsy may promote cardiovascular disease remains poorly understood, said Keezer.

“My research program has always focused on the somatic comorbidities of epilepsy. During my PhD studies, I focused on premature mortality in epilepsy and was struck by the frequency with which people with epilepsy died of cardiovascular disease. This left me with a strong interest in understanding why this occurs, and this study is part of that search for answers,” he explained.

His team used data from the Canadian Longitudinal Study on Aging (CLSA), an ongoing, national, prospective study of 51,338 adults aged 45-85 years at study entry. They looked at results in the comprehensive cohort of the CLSA and included 27,230 people in their study. Participants were followed for 6 years (from 2015 to 2021). 

Statistical models helped estimate the proportion of the association between epilepsy and cardiovascular events that is mediated by the use of EIASMs. The models adjusted for age, sex, household income, and education level. Mediation analyses were conducted for strong EIASM use, weak EIASM use, Framingham risk score, Physical Activity Scale for the Elderly (PASE) score, and waist-to-hip ratio.

The primary outcome was new-onset cardiovascular events over 6 years. Secondary outcomes included new-onset stroke, transient ischemic attack, and myocardial infarction.

The mean age of the comprehensive cohort was 62.3 years. Slightly more than half (52.4%) of participants were female, and 431 participants had a lifetime history of epilepsy. 

New-onset cardiovascular events were more than twice as likely to occur in participants with epilepsy (adjusted odds ratio, 2.20). Results were similar for transient ischemic attack and myocardial infarction. After adjusting the data for age, sex, household income, and education level, the researchers found that strong EIASM use mediated 24.6% of the effect of epilepsy on new-onset cardiovascular events. 

Weak EIASM, PASE score, and waist-to-hip ratio were also significant mediators of new cardiovascular events as well, although with lesser effect sizes. Weak EIASM use mediated 4.0% of the effect of epilepsy on new-onset cardiovascular events. For PASE score, it was 3.3%, and for waist-to-hip ratio, it was 1.6%. The Framingham Risk Score and non-EIASM use did not have significant mediating effects.

A Striking Correlation

“As a clinician who manages patients with epilepsy, I find it quite striking to see how much stronger the correlation between EIASMs and cardiovascular events is, compared with the impact of conventional vascular risk factors,” Chantelle T. Hrazdil, MD, clinical assistant professor of neurology at the University of British Columbia in Vancouver, told Medscape Medical News.

“For me, this underscores the importance of aiming to minimize the long-term use of EIASMs in patients with epilepsy, both young and old,” Hrazdil said.

“Some of our newer medications are weaker enzyme inducers. It is encouraging to see that the odds ratio for cardiovascular events is substantially lower for those on weak EIASMs compared with those on strong EIASMs,” she added.

“In our publicly funded Canadian healthcare system, patients with epilepsy often end up on EIASMs at higher rates than our American and other developed nation counterparts, mainly due to cost factors,” Hrazdil noted.

“This study should be considered in the development of public drug coverage policies, which I would argue should be more generous when covering the newer weak and non-EIASMs,” she said.

The Canadian Longitudinal Study on Aging is funded by the government of Canada through the Canadian Institutes of Health Research and the Canadian Foundation for Innovation, as well as the provinces of Newfoundland, Nova Scotia, Quebec, Ontario, Manitoba, Alberta, and British Columbia. Keezer reported receiving grants from UCB, Eisai, Jazz Pharmaceuticals, and Paladin outside the submitted work. Hrazdil reported having no relevant financial relationships.