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An association between epilepsy and cardiovascular events (CVEs) in older people was likely largely due to the use of enzyme-inducing antiseizure medications (EIASM), according to a prospective cohort study from Canada.

Among over 27,000 participants, new-onset CVEs were more likely in those with epilepsy than those without (adjusted OR 2.20, 95% CI 1.48-3.27), with the relative contribution to this association highest for "strong" EIASM use (24.6%), reported Mark Keezer, MD, PhD, of Centre de Recherche du Centre Hospitalier de l'Université de Montréal, and colleagues in .

"Our study suggests that enzyme-inducing antiseizure medications increase the risk of cardiovascular events," Keezer told MedPage Today. "Future studies will need to study whether this should lead to screening for cardiovascular disease in certain people at greater risk. Our study may also provide healthcare professionals further justification for avoiding enzyme-inducing antiseizure medications, when clinically feasible."

There is a strong association between epilepsy and cardiovascular disease, at least partly because of the overlap in risk factors, Keezer and co-authors noted. Stroke can cause epilepsy, and even in populations without cerebrovascular disease, the risk of developing cardiovascular disease is high, they pointed out. Previous research has suggested that potential damage to the heart and coronary vasculature by repeat seizures may contribute to this connection, along with EIASM use.

The strength of this research is that data were derived prospectively in a cohort that didn't develop epilepsy as a result of a cardiovascular event, noted Jacqueline French, MD, of New York University in New York City, who wasn't involved with the study.

It also used a database with "more complete background information on subjects, which reduces the likelihood of confounders being responsible for the findings," French told MedPage Today.

"The authors did an excellent job of excluding socioeconomic factors that could have contributed both to the selection of (usually less costly) enzyme-inducing ASMs by healthcare providers, and also to the increased cardiovascular risk," French added. "Nonetheless, similar biases cannot be completely ruled out."

For this study, Keezer and team used data from 27,230 participants in the ongoing (CLSA) with 6 years of follow-up from 2015 to 2021. The CLSA includes adults ages 45 to 85 and excludes residents of long-term care facilities and those with cognitive impairment, among others.

Participants were included in this analysis if they reported no previous history of CVEs (stroke, transient ischemic attack, or myocardial infarction) at baseline. Mean age was 62.3, 52.4% were women, and 94.4% were white. In total, 431 had a lifetime history of epilepsy. Of those included, 86% completed follow-up.

The primary outcome was new-onset CVEs over 6 years, and new-onset strokes, transient ischemic attacks, or myocardial infarctions separately were secondary outcomes. To understand how mediator variables influenced relationships between epilepsy and CVEs, the researchers ran mediation analyses for strong EIASM use, weak EIASM use, , , and waist-to-hip ratio.

"Strong EIASM use" included use of carbamazepine, phenytoin, phenobarbital, and primidone, while "weak EIASM use" included use of drugs like oxcarbazepine, eslicarbazepine, topiramate, and rufinamide. Of the CVEs, strong EIASM use appeared to have the largest effect on myocardial infarction, with a proportion-mediated value of 59.1%.

Apart from the mediating effect of strong EIASM use, "more than two-thirds of this association may be due to other factors, such as more prevalent [cardiovascular risk factors] or a direct effect of epilepsy on [cardiovascular disease]," Keezer and colleagues wrote. Weak EIASM use, PASE score, and waist-to-hip ratio also played a role, with proportion-mediated values of 4.0%, 3.3%, and 1.6%, respectively.

The authors noted that they were limited by self-reported data, and by potential effects of the 14% of participants lost to follow-up. They also did not differentiate between ischemic stroke and hemorrhagic stroke, and noted that participants may have begun or stopped EIASM during follow-up, but EIASM data were only available for baseline use.

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