In a study published in JAMA Neurology, researchers aimed to quantify and model the putative hazard of cardiovascular disease secondary to enzyme-inducing antiseizure medications. The study was conducted between January 1990 and March 2019, with a median follow-up of 9 years. The researchers linked primary care and hospital electronic health records at National Health Service hospitals in England and included adults with an epilepsy diagnosis after January 1, 1990.

The researchers used receipt of four consecutive enzyme-inducing antiseizure medications (eiASMs; carbamazepine, eslicarbazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, rufinamide, or topiramate) following an adult-onset (age >18 years) epilepsy diagnosis or repeated exposure in a weighted cumulative-exposure model.

Cohorts included all adults who met a case definition for epilepsy who were diagnosed after 1990, incident cases diagnosed after 1998, and adults who received the diagnosis at age 65 years or older. Incident cardiovascular disease, including ischemic heart disease or ischemic or hemorrhagic stroke, served as the outcome. The researchers evaluated risk for incident cardiovascular disease via adjusted propensity-matched analyses and weighted cumulative-exposure models.

The patient population comprised 10,916,166 adults. Of these, 50,888 (0.6%) had period-prevalent cases (median age, 32 years; 53% women), with 31,479 (62%) diagnosed on or after 1990 who were free of cardiovascular disease at baseline. The researchers used a propensity-matched Cox proportional-hazards model adjusted for age, gender, baseline socioeconomic status, and cardiovascular risk factors; this model revealed a hazard ratio (HR) for incident cardiovascular disease of 1.21 (95% CI, 1.06-1.39) among patients who received eiASMs.

The researchers noted that the absolute difference in cumulative risk diverged by more than 1% and was greater after 10 years. Patients whose exposure persisted beyond four prescriptions had a median HR increase from 1.54 when taking a relative defined daily eiASM dose of one to 2.38 when this dose was two throughout a maximum of 25 years of follow-up versus patients who did not receive an eiASM. Risk intensified but lessened when researchers restricted analyses to incident cases or patients diagnosed when older than age 65 years.

The researchers concluded that the hazard of incident cardiovascular disease is greater in patients receiving eiASMs. They also noted that the correlation is dose dependent and that the absolute difference in hazard seems to reach clinical significance by approximately 10 years from first exposure.

The researchers stated, "Short-term use does not appear to confer considerable risk, but caution should be used when taking these medications long term. Future studies are required to further elucidate pathological mechanisms and to evaluate whether proactively managing conventional risk factors, such as dyslipidemia and hypertension, using the minimal effective dose of the eiASM and using prophylactic interventions, such as folate supplementation, can help mitigate risk in patients that require these medications for long-term seizure control."

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