Calgary, Alberta—A large population study has found that the risk of incident cardiovascular disease increases following persistent exposure to enzyme-inducing antiseizure medications (eiASMs).

In the cohort study of 31,479 patients, as reported in JAMA Neurology, the hazard ratio of incident cardiovascular disease was higher for those receiving four consecutive prescriptions for eiASMs at diagnosis compared with those not using eiASMs.

“When consistently taking eiASMs for the duration of follow-up, the median hazard was associated with an increase in incident cardiovascular disease for those with a higher defined daily dose compared with no eiASM throughout a maximum of 25 years follow-up,” note the Canadian authors from the University of Calgary and colleagues.

Researchers undertook the study because eiASMs have been posited to be associated with long-term risks of cardiovascular disease. The cohort study, conducted from January 1990 to March 2019 (median [interquartile range, or IQR] follow-up, 9 [4-15], years), linked primary care and hospital electronic health records at National Health Service hospitals in England.

Included were patients aged 18 years or older diagnosed with epilepsy after January 1, 1990. Analysis began in January 2021 and ended in August 2021.

With epilepsy diagnosed as adults, participants received four consecutive eiASMs—carbamazepine, eslicarbazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, rufinamide, or topiramate—or repeated exposure in a weighted cumulative exposure model.

Patients were divided into three cohorts, and all adults met a case definition for epilepsy diagnosed after 1990, a second including incident cases diagnosed after 1998 (hospital linkage date), and a third that was limited to adults diagnosed with epilepsy at age 65 years or older.

The researchers were watching for incident cardiovascular disease, including ischemic heart disease or ischemic or hemorrhagic stroke.

Of the 10.9 million participants, 50,888 (0.6%) were identified as having period-prevalent cases (median [IQR] age, 32 [19-50] years; 16,584 [53%] female); ultimately, 31,479 (62%) were diagnosed on or after 1990 and were free of cardiovascular disease at baseline.

The researchers calculated that the hazard ratio for incident cardiovascular disease was 1.21 (95% CI, 1.06-1.39) for those receiving eiASMs, adding, “The absolute difference in cumulative hazard diverges by more than 1% and greater after 10 years.”

They explain, “For those with persistent exposure beyond four prescriptions, the median hazard ratio increased from a median (IQR) of 1.54 (1.28-1.79) when taking a relative defined daily dose of an eiASM of 1 to 2.38 (1.52-3.56) with a relative defined daily dose of 2 throughout a maximum of 25 years’ follow-up compared with those not receiving an eiASM. The hazard was elevated but attenuated when restricting analyses to incident cases or those diagnosed when older than 65 years.”

The authors conclude that the hazard of incident cardiovascular disease is higher in patients receiving eiASMs, although the association is dose-dependent and the absolute difference in hazard appears to reach clinical significance by about 10 years from first exposure.

Background information in the article points out that epilepsy patients have a high risk of cardiovascular disease in general. Compared with the general population, the authors state, the prevalence ratios of ischemic heart disease (1.35; 95% CI, 1.2-1.5), transient ischemic attack (4.9; 95% CI, 4.4.-5.5), ischemic stroke (7.5; 95% CI, 5.7-9.9), and hemorrhagic stroke (10.6; 95% CI, 6-17) are increased in those with epilepsy. “This may be associated in part with epilepsy itself, sedentary behaviors, high rates of cigarette smoking, lower socioeconomic status, obesity, and poor self-reported health,” they suggest.

On the other hand, the researchers explain that ASMs, especially eiASMs, also seem to contribute to the issue. They point out that regular use of eiASMs can lead to dyslipidemia and hyperhomocysteinemia, which can exacerbate atherosclerosis.

The authors note that their results are in contrast with another 2021 study, published in Epilepsia in July, that found no association between eiASMs and cardiovascular disease.

The difference, they write, can be partially explained by longer follow-up in the more recent study, adding, “The absolute cumulative hazard remains similar between eiASMs and non-eiASMs until approximately 8 to 10 years from first prescription The prior study has a mean (SD) follow-up of 6.05 (4.31) years (maximum, 15 years), meaning the analysis was restricted to a period in which the cumulative hazards were relatively comparable.”

In addition, the researchers say, the more recent study was larger, with more than 30,000 patients, compared with about 10,000 in the earlier study.

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