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Original Investigation
October 4, 2021

Association of Enzyme-Inducing Antiseizure Drug Use With Long-term Cardiovascular Disease

Author Affiliations
  • 1Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
  • 2Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
  • 3Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
  • 4O’Brien Institute for Public Health, University of Calgary, Calgary, Alberta, Canada
  • 5Centre for Health Informatics, University of Calgary, Calgary, Alberta, Canada
  • 6Clinical Research Unit, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
  • 7UCL Institute of Health Informatics, London, United Kingdom
  • 8Health Data Research, London, United Kingdom
  • 9Alan Turing Institute, London, United Kingdom
  • 10Department of Neurosciences, Université de Montreal, Montreal, Quebec, Canada
JAMA Neurol. 2021;78(11):1367-1374. doi:10.1001/jamaneurol.2021.3424
Key Points

Question  What is the risk of incident cardiovascular disease following persistent exposure to enzyme-inducing antiseizure medications (eiASMs)?

Findings  In this cohort study of 31 479 individuals, the hazard ratio of incident cardiovascular disease was higher for those receiving 4 consecutive prescriptions for eiASMs at diagnosis compared with non-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.

Meaning  This study found a dose-dependent hazard of incident cardiovascular disease associated with eiASMs.


Importance  Enzyme-inducing antiseizure medications (eiASMs) have been hypothesized to be associated with long-term risks of cardiovascular disease.

Objective  To quantify and model the putative hazard of cardiovascular disease secondary to eiASM use.

Design, Setting, and Participants  This cohort study covered January 1990 to March 2019 (median [IQR] follow-up, 9 [4-15], years). The study linked primary care and hospital electronic health records at National Health Service hospitals in England. People aged 18 years or older diagnosed as having epilepsy after January 1, 1990, were included. All eligible patients were included with a waiver of consent. No patients were approached who withdrew consent. Analysis began January 2021 and ended August 2021.

Exposures  Receipt of 4 consecutive 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.

Main Outcomes and Measures  Three cohorts were isolated, 1 of which comprised all adults meeting a case definition for epilepsy diagnosed after 1990, 1 comprised incident cases diagnosed after 1998 (hospital linkage date), and 1 was limited to adults diagnosed with epilepsy at 65 years or older. Outcome was incident cardiovascular disease (ischemic heart disease or ischemic or hemorrhagic stroke). Hazard of incident cardiovascular disease was evaluated using adjusted propensity-matched survival analyses and weighted cumulative exposure models.

Results  Of 10 916 166 adults, 50 888 (0.6%) were identified as having period-prevalent cases (median [IQR] age, 32 [19-50] years; 16 584 [53%] female), of whom 31 479 (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 ratio for incident cardiovascular disease was 1.21 (95% CI, 1.06-1.39) for those receiving eiASMs. The absolute difference in cumulative hazard diverges by more than 1% and greater after 10 years. For those with persistent exposure beyond 4 prescriptions, the median hazard ratio increased from amedian (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.

Conclusions and Relevance  The hazard of incident cardiovascular disease is higher in those receiving eiASMs. The association is dose dependent and the absolute difference in hazard seems to reach clinical significance by approximately 10 years from first exposure.

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