More Evidence Epilepsy Tied to Risk for Major Cardiovascular Events

Erik Greb

July 07, 2021

More data link epilepsy to a significantly increased risk for major cardiovascular events, including stroke or arrhythmia.

In a large retrospective cohort study, risk for cardiovascular events was 58% greater among patients with epilepsy who underwent treatment with antiepileptic drugs (AEDs) in comparison with their peers who did not have epilepsy.

Interestingly, this associated risk did not differ significantly between enzyme-inducing AEDs and non-enzyme-inducing AEDs.

Although these findings add to those from previous studies on cardiovascular risk, they leave certain questions open for future investigation, the authors note.

Dr William Owen Pickrell

"Further research is needed in this area in order to help stratify cardiovascular risks for people with epilepsy and to determine what, if any, effects that individual antiseizure medications have," study investigator William Owen Pickrell, PhD, honorary associate clinical professor at Swansea University Medical School, Swansea, United Kingdom, told Medscape Medical News.

The findings were published online May 27 in Epilepsia.

Limited Research

The mortality rate among patients with epilepsy is higher than among the general population, and cardiovascular events associated with AEDs may contribute to this difference. Previous research has shown a link between AEDs and increased risk for stroke, myocardial infarction, and arrhythmia.

In addition, enzyme-inducing AEDs, most of which are older medications, have been associated with elevated levels of total cholesterol and low-density lipoprotein cholesterol. However, data regarding these drugs' effects on cardiovascular events are limited, the current investigators note.

For the study, investigators examined records from primary care and secondary care practices in Wales and identified patients who had been diagnosed with epilepsy from January 2003 through December 2017. Eligible participants were at least 18 years old, and at least 6 months of data were available before and after the date of diagnosis (n = 10,241; 52% men; mean age, 49.6 years).

The researchers also identified a control group of participants who had not been diagnosed with epilepsy (n = 35,145). Four control patients were matched to each case patient on the basis of age, gender, socioeconomic deprivation, and year of entry into the study.

A total of 5819 of these participants were matched to more than one case patient, resulting in a total of 40,964 control patients.

The study's primary outcome was a major cardiovascular event, which the investigators defined as cardiac arrest, myocardial infarction, stroke, ischemic heart disease, clinically significant arrhythmia, thromboembolism, onset of heart failure, or cardiovascular death. Data on these events were retrieved from healthcare records and death certificates.

"We used population-level, routinely collected data, which enabled us to study a large number of people with epilepsy and a large number of major cardiovascular events," said Pickrell. Using population-level data also reduced the risk for recruitment bias, he added.

In the group with epilepsy, 31% received enzyme-inducing AEDs, and 69% received non-enzyme-inducing AEDs.

Patients with epilepsy were more likely to be underweight or have obesity, diabetes, hypertension, and dyslipidemia. In addition, they were more likely than the control group to have had a prior stroke or to have been prescribed an antiplatelet, an anticoagulant, or a statin.

BMI Data Missing

Results showed that 2115 major cardiovascular events occurred among the group with epilepsy and AED use during a mean follow-up time of 6 years. Among the control group, 4457 major cardiovascular events occurred during a mean follow-up duration of 7 years.

The hazard ratio (HR) for cardiovascular events among the patients was 1.47 compared to the control group (95% CI, 1.45 – 1.50; P < .001). After adjusting for variables such as age, sex, socioeconomic deprivation, smoking, comorbidities, and time-dependent covariates, the HR for cardiovascular events increased to 1.58 (95% CI, 1.51 – 1.63; P < .001).

Patients who received enzyme-inducing AEDs were more likely to be between 18 and 64 years of age and were less likely to be 75 years or older compared with those who received non-enzyme-inducing AEDs.

The unadjusted HR for cardiovascular events was 1.12 (95% CI, 1.04 – 1.20; P = .004) for the p[atients who received non-enzyme-inducing AEDs in comparison with the patients who received enzyme-inducing AEDs. However, the adjusted HR for cardiovascular events did not differ significantly between the groups.

Pickrell noted that although body mass index (BMI) is a risk factor for cardiovascular events, the investigators were not able to account for it in the analysis because a large proportion of data on this variable were missing.

"It may be that differences in BMI could account for some of the increased risk of cardiovascular events in the epilepsy group," he said.

Questions Remain

Commenting on the study for Medscape Medical News, Joseph Sirven, MD, professor of neurology at the Mayo Clinic, Jacksonville, Florida, said the findings are consistent with those from previous research.

"This is yet another reminder that we need to watch for cardiovascular issues when using these meds," said Sirven, was not involved in the study.

A common mechanism of antiseizure drugs is sodium channel modulation. Because the heart has sodium channels, a relationship between antiseizure drugs and increased cardiovascular events is not surprising, he noted.

"Thus, the comparison between enzyme-inducing vs non-enzyme-inducing may not be as meaningful; rather, it's the mechanism of action," Sirven said.

Also commenting on the findings for Medscape Medical News, John-Paul Nicolo, MBBS, acting head of epilepsy at Royal Melbourne Hospital, in Melbourne, Australia, noted that although the investigators cite previous studies that showed no difference in risk between enzyme-inducing and non-enzyme-inducing AEDs, overall results on this question are mixed.

For example, a 2016 study in an older population (median age, 60 years) showed an increased risk for development of new comorbidities, especially cerebrovascular disease, among patients who used enzyme-inducing AEDs.

The current study included additional cardiovascular endpoints, such as arrhythmia and cardiac failure, that "may be indicative of different pathological processes and not necessarily of accelerated atherosclerosis, the putative mechanism for risk" that is associated with enzyme-inducing AEDs, said Nicolo.

Several Strengths, Weaknesses

Nicolo and Sirven noted several strengths of the study, including the size of the cohort and its overall originality.

"Moreover, the authors took particular care to have a case-control cohort group, which was wise," said Sirven.

In addition, the researchers' list of relevant covariates, which include risk factors for major cardiovascular events and data on the prescription of statins and anticoagulants, is comprehensive, Nicolo said.

However, in population-based studies, the accuracy of diagnostic codes for epilepsy and cardiovascular conditions is in question, he added.

"We know, for example, that a significant proportion of patients are prescribed AEDs for paroxysmal neurological symptoms that are nonepileptic in nature. This makes the differentiation between epilepsy-related risk and treatment-related risk more difficult," he said.

Furthermore, how the pathology of what caused the epilepsy affects or biases the data is unknown.

"Were these patients more likely to have stroke-related epilepsy or other causes that might affect the results?" Sirven asked. "If there is a higher representation of cerebrovascular pathologies in the cohort, then we are definitely going to see a higher cardiovascular risk."

"While the increased risk of cardiovascular events in epilepsy patients is well established, it remains unclear whether this is driven primarily by epilepsy-related risk or treatment-related risk," Nicolo added.

Because epilepsy is a heterogeneous condition and subclinical cerebrovascular disease is an important etiology in some patients who present with epilepsy later in life, more research is needed to clarify the effect of seizure frequency and epilepsy syndrome on cardiovascular risk, Nicolo concluded.

The study was funded by Health Data Research UK. Pickrell has received consulting fees from GPW Pharma and Arvelle therapeutics and an investigator grant from UCB Pharma. Sirven has reported no relevant financial relationships

Epilepsia. Published online May 27, 2021. Full article

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