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Higher Risk of Cardiovascular Events in Patients with Epilepsy

Article In Brief

Patients with epilepsy had a greater risk for major cardiovascular events than did the general population. Physicians should make patients with epilepsy aware of their cardiovascular risks and encourage them to make lifestyle changes to reduce them, the study author stressed.

Adults with epilepsy, regardless of the type of antiepileptic drug (AED) they were taking were more likely to experience major cardiovascular events than the general population, according to a retrospective study of patient records in Wales.

The researchers examined data on 10,241 cases and 35,145 matched controls over a period of 6.1 years: 31.1 percent of the patients received enzyme-inducing antiepileptic drugs (EIAEDs) and 68.9 percent took non-enzyme-inducing drugs (NEIAEDs.

“We found that people with epilepsy who take antiseizure medications have an increased risk of having a major cardiovascular event when compared with matched controls without epilepsy,” said the lead author William O. Pickrell, MD, a clinical associate professor at Swansea University Medical School Institute of Life Science in Wales, UK.

“However, when adjusting for potential confounding factors there did not appear to be a significant difference in the number of major cardiovascular events in the EIAED group when compared with patients treated with NEIAEDs,” Dr. Pickrell told Neurology Today. “We were unable to tell from our data whether people with epilepsy might do better or worse on a particular type of drug given a particular cardiovascular risk profile,” Dr. Pickrell said.

He said health care professionals need to “prioritize identification and treatment” of cardiovascular disease risk factors in epilepsy patients.

The study, published in the May 27 issue of Epilepsia, was not sufficiently powered to evaluate how lifestyle, family history, and other known cardiovascular risk factors may have affected the results. Even so, Dr. Pickrell said that physicians should make patients with epilepsy aware of their cardiovascular risks and encourage them to make lifestyle changes to reduce them.

“It is possible that people with epilepsy may have reduced physical activity, different diets, or increased rates of obesity. Stress, anxiety, and depression are also common with epilepsy, and could impact other cardiovascular risk factors,” Dr. Pickrell said. “Our data highlight the need for proactive management of modifiable cardiovascular risk factors in people with epilepsy.”

He said that further work is necessary to try and establish which groups of people with epilepsy are most at risk and whether there are any differences between individual AEDs and elevated cardiovascular risk.

Previous studies have found an increased risk of stroke and myocardial infarction among people with epilepsy. A recent systematic review found hazard ratios of 1.09-2.85 for stroke and 1.09-1.48 for myocardial infarction. In the current study, the adjusted hazard ratio for cardiovascular events in patients with epilepsy was 1.58.

Study Methodology

To assess the risks, the investigators conducted a retrospective matched cohort study of major cardiovascular events and survival rates in adult patients prescribed AEDs between 2003 and 2017. They applied an algorithm that has previously been shown to be 84 percent sensitive and 98 percent specific to identify people with epilepsy from primary care records.

Figure

“The first papers that really brought attention to the issue of elevated cholesterol with EIAEDs came out in 2009-2010, and half the cohort in this study came after that. Perhaps physicians became aware of the issue, checked lipids, and treated them—or maybe patients were being screened for hyperlipidemia anyway. Its very difficult to sort these things out without looking at the whole potential causal chain.”—DR. SCOTT MINTZER

The algorithm requires cases to have an epilepsy diagnosis code as well as two AED prescription codes within a six-month period. Individuals were classified as being in the EIAED group if they had at least two prescriptions of phenytoin, phenobarbital, carbamazepine, methylphenobarbital, or primidone.

The primary outcome was the first occurrence of a major cardiovascular event, after a diagnosis of epilepsy, within the study window. This was defined as a cardiac arrest, myocardial infarction, stroke, ischemic heart disease, clinically significant arrhythmia, thromboembolism, onset of heart failure, or cardiovascular death.

Cardiovascular event data were obtained from primary care records, hospital data, and death certificates, using previously validated case definitions.

Expert Commentary

Commenting on the study, Leah Blank, MD, MPH, assistant professor of neurology at the Icahn School of Medicine at Mount Sinai said that it may be necessary to follow an extremely large number of patients over many years to really detect any association between cardiovascular events and EIAEDs.

“It is possible that the study was insufficiently large to detect a small difference between groups,” Dr. Blank told Neurology Today. “Another possibility may be related to timing of the exposure to EIAEDs and timing of major cardiovascular events. In order to be included in the EIAED group, you only needed to have two prescriptions for an EIAED. If we believe that cardiovascular risk depends on longer-term exposure, some of these patients might not have been on EIAEDs long enough to produce an effect,” she said.

Dr. Blank also pointed out that the mean length of follow-up was six years, which she said may not have been long enough for the development of a major cardiovascular event, as the authors noted.

Also, the non-enzyme inducing group included participants who took valproic acid, which is believed to lead to changes, such as metabolic syndrome, that are associated with increased cardiovascular risk, and this might have led to a lack of difference between the two treatment groups, she said.

“Finally, there could also be an issue of over-adjustment. The authors adjusted for statins, which are prescribed to treat hyperlipidemia. Prior work suggests that the EIAED's pathway to causing a major cardiovascular event would be via abnormal lipids and atherosclerosis. This model may be adjusting for the mediator and therefore losing the association between EIAEDs and major cardiovascular events.”

Scott Mintzer, MD, medical director of the epilepsy monitoring unit at Thomas Jefferson University, agreed that the study was well done overall, but he added, “I think they made some decisions that might have made any ‘signal’ from the different types of drugs harder to see

“The first papers that really brought attention to the issue of elevated cholesterol with EIAEDs came out in 2009-2010, and half the cohort in this study came after that,” Dr. Mintzer told Neurology Today. “Perhaps physicians became aware of the issue, checked lipids, and treated them—or maybe patients were being screened for hyperlipidemia anyway. It's very difficult to sort these things out without looking at the whole potential causal chain.”

Figure

“The challenge here is that the study is retrospective and may be confounded by factors such as patients with cerebrovascular disease having higher rates of epilepsy due to related events such as stroke.”—DR. ORRIN DEVINSKY

As for whether elevated lipids and similar risk factors might have played a role in influencing cardiovascular events in the EIAED patients, he said: “If those patients were detected and treated, then any differences between the two kinds of drugs would have been mitigated. This would also serve to obscure important physiologic differences between the two types of drugs.”

Orrin Devinsky, MD, FAAN, director of the NYU Langone Hospital Epilepsy Center said the study supports others that have found epilepsy patients to be at higher risk of cardiovascular disease than control subjects.

“The challenge here is that the study is retrospective and may be confounded by factors such as patients with cerebrovascular disease having higher rates of epilepsy due to related events such as stroke.”

Other confounding factors that could have influenced the results include a history of drug abuse, head trauma, higher rates of both current and prior smoking, obesity, diabetes, and hypertension in the epilepsy patients, Dr. Devinsky said.

“Together, this suggests that factors other than epilepsy may be driving the increased risk,” he said. “Prospective, observational studies would be needed to help reduce some of these confounding factors. Unfortunately, it is impossible to do randomized studies to answer this question. The bottom line is that the findings are likely real, but quite possibly unrelated to epilepsy,” he told Neurology Today.

Link Up for More Information

• Lee-Lane E, Torabi F, Lacey A, et al. Epilepsy, antiepileptic drugs, and the risk of major cardiovascular events https://onlinelibrary.wiley.com/doi/10.1111/epi.16930?af=R. Epilepsia 2021; Epub 2021 May 27.
    • Brigo F, Lochner P, Nardone R, Manganotti P, Lattanzi S. Increased risk of stroke and myocardial infarction in patients with epilepsy: a systematic review of population-based cohort studies https://www.epilepsybehavior.com/article/S1525-5050(19)30239-2/fulltext. Epilepsy Behav 2019;104:106307.
    • Hsu SPC, Yeh C-C, Chou Y-C, et al. Stroke risk and outcomes in epilepsy patients: two retrospective cohort studies based on National Health Insurance in Taiwan https://www.atherosclerosis-journal.com/article/S0021-9150(18)31464-3/fulltext. Atheroscler 2019;280:147–54.
      • Brigo F, Lochner P, Nardone R, Manganotti P, Lattanzi S. Increased risk of stroke and myocardial infarction in patients with epilepsy: a systematic review of population-based cohort studies https://www.epilepsybehavior.com/article/S1525-5050(19)30239-2/fulltext. Epilepsy Behav 2019;104:106307.