Complications Associated with the Use of Enzyme-inducing and Non-enzyme-inducing Anti-seizure Medications in the Japanese Population: A Retrospective Cohort Study

Objective: Enzyme-inducing anti-seizure medications (EIASMs) may contribute to the development of complications such as fracture and cardiovascular disease. The objective of the study was to determine whether the use of EIASMs is associated with a higher risk of fracture and cardiovascular outcome in young Japanese patients with epilepsy.

Method: Adult patients diagnosed with epilepsy and initiated a monotherapy with an anti-seizure medication (ASM) between 2008 and 2018 were included in the study. The primary outcomes were the occurrence of acute myocardial infarction (AMI) or stroke. The secondary outcome was fracture. We performed a propensity score-matched analysis (1:1) to control for imbalances in patient characteristics, and the matched hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models.

Result: Of the 7115 eligible patients, 626 (8.79%) initiated treatment with EIASMs. The median age of the patients was 44 years (interquartile range: 31-54 years), and 56.2% were male. Propensity score matching generated 626 matched pairs of patients treated with EIASMs and non-EIASMs. There were no significant differences in the risk of stroke (EIASM group: n = 28[4.47%], non-EIASM group: n = 22[3.51%], HR: 1.47, 95% CI: 0.79-2.72, p = 0.22) or fracture (EIASM group: n = 7[1.12%], non-EIASM group: n = 5[0.80%], HR: 1.00, 95% CI: 0.29-3.45, p = 1.00) between the two groups. The hazard ratio for the occurrence of AMI could not be calculated due to the small number of events (EIASM group: n = 0[0.00], non-EIASM group: n = 2[0.32]).

Significance: Our cohort study did not find increased risk of the occurrence of stroke, AMI, or fracture hospitalization with the use of enzyme-inducing ASMs. Although the findings suggested that exposure to EIASMs does not appear to increase the risk of complications in young patients, caution should be taken as patients with epilepsy tend to take medication in the long run.