Enzyme-Inducing Antiseizure Drug Use Is Associated with Long-Term Cardiovascular Disease in a Dose Dependent Fashion in Adults with Epilepsy

Abstract

Background: Enzyme-inducing antiseizure medications (eiASMs) have been associated with long-term risks of cardiovascular disease. The objective of this study was to quantify and model this putative hazard. Methods: We used the population-based the CALIBER © resource with linked primary and hospital data to isolate three cohorts, one comprising all adults meeting a case definition for epilepsy diagnosed after 1990, one comprising incident cases diagnosed after 1998 (hospital linkage date), and one limited to adults diagnosed with epilepsy at age ≥65. Exposure was receipt of four consecutive eiASMs following an epilepsy diagnosis and the outcome was incident cardiovascular disease (ischaemic heart disease or ischaemic or haemorrhagic stroke). The hazard of incident cardiovascular disease was evaluated using adjusted propensity matched survival analyses and weighted cumulative exposure models. Findings: Of 10,916,166 adults, we identified 50,888 (0.6%) period prevalent cases, of whom 31,466 (62%) were diagnosed on or after 1990 and were free of cardiovascular disease at baseline. In a propensity matched Cox proportional hazards model adjusted for age, sex, baseline socioeconomic status, and cardiovascular risk factors, the hazard of incident cardiovascular disease was 1.21 (95% confidence interval 1.06-1.39) for those receiving eiASMs. The absolute difference in cumulative hazard appeared to diverge significantly after 8-10 years. Median hazard ratio increased from 1.54 when taking a relative defined daily dose (rDDD) of an eiASM of 1 to 2.38 with a rDDD of 2 over a maximum of 25 years follow-up compared to those not receiving an eiASM. The hazard was elevated but attenuated when restricting analyses to incident cases or those diagnosed after age 65. Conclusions and relevance: There is a clinically meaningful hazard of incident cardiovascular disease in those receiving eiASMs. The effect is dose dependent and the absolute difference in hazard seems to reach clinical significance by approximately 10 years from first exposure. Funding Statement: This analysis was in part funded by the Canadian Frailty Network which is supported by the Government of Canada through the Networks Centres of Excellence (NCE) program, as well as through the University of Calgary. Declaration of Interests: All authors declare that they have no conflicts of interest. Ethics Approval Statement: The study was approved by the MHRA (UK) Independent Scientific Advisory Committee [17_064RA3], under Section 251 (NHS Social Care Act 2006).