Enzyme-inducing antiseizure medications linked to vascular disease

Patients who received enzyme-inducing antiseizure medications had increased risk for incident cardiovascular disease, according to results of a cohort study published in JAMA Neurology.

“Regular use of [enzyme-inducing antiseizure medications (eiASMs)] can lead to dyslipidemia and hyperhomocysteinemia, which can lead to atherosclerosis,” Colin B. Josephson, MD, MSc, of Cumming School of Medicine at the University of Calgary in Canada, and colleagues wrote. “Use of eiASMs is theorized to increase risk for vascular disease.

“A 2020 systematic review postulated that the proatherogenic properties of eiASMs could partially explain the higher rates of vascular disease in epilepsy but that further evidence is required to confirm this hypothesis,” they added.

Researchers aimed to address this research gap by quantifying and modeling the putative risk for cardiovascular disease related to eiASM use. They conducted the study between January 1990 and March 2019, with a median follow-up of 9 years. They linked primary care and hospital electronic health records at National Health Service hospitals in England and included adults with an epilepsy diagnosis after Jan. 1, 1990.

Researchers used receipt of four consecutive eiASMs – carbamazepine, eslicarbazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, rufinamide or topiramate – after an adult-onset 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. Josephson and colleagues assessed risk for incident cardiovascular disease via adjusted propensity-matched analyses and weighted cumulative exposure models.

The patient population consisted of 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. A propensity-matched Cox proportional hazards model adjusted for age, sex, baseline socioeconomic status and cardiovascular risk factors revealed an HR for incident cardiovascular disease of 1.21 (95% CI, 1.06-1.39) among those who received eiASMs.

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 hazard ratio increase from a median of 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 vs. those who did not receive an eiASM. Risk increased but attenuated when researchers restricted analyses to incident cases or patients diagnosed when older than age 65 years.

“Short-term use does not appear to confer considerable risk, but caution should be used when taking these medications long term,” Josephson and colleagues wrote. “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.”