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Association Between Antiseizure Medication Use and Cardiovascular Events in Older People With Epilepsy
TAKE-HOME MESSAGE
- This prospective cohort study evaluated the risk of cardiovascular events (CVEs) in older adults with epilepsy compared with those without epilepsy, focusing on the role of enzyme-inducing antiseizure medications (EIASMs). Using data from the Canadian Longitudinal Study on Aging, it found that individuals with a lifetime history of epilepsy were about twice as likely to experience new-onset CVEs, such as strokes, transient ischemic attacks, or myocardial infarctions. The analysis also revealed that nearly one-third of the increased risk of CVEs in people with epilepsy can be attributed to the use of EIASMs.
- The findings of this study highlight the importance of considering cardiovascular risk when prescribing EIASMs.
abstract
This abstract is available on the publisher's site.
Access this abstract nowIMPORTANCE
How epilepsy may promote cardiovascular disease remains poorly understood.
OBJECTIVE
To estimate the odds of new-onset cardiovascular events (CVEs) over 6 years in older people with vs without epilepsy, exploring how enzyme-inducing antiseizure medications (EIASMs) and traditional cardiovascular risk factors mediate these odds.
DESIGN, SETTING, AND PARTICIPANTS
This was a prospective cohort study using the comprehensive cohort of the Canadian Longitudinal Study on Aging (CLSA), with 6 years of follow-up (2015-2021, analysis performed in December 2023). The CLSA is an ongoing, national study of 51 338 adults aged 45 to 85 years at baseline who are recruited in Canada. The comprehensive cohort includes 30 097 individuals living near 1 of 11 data collection centers. Participation in the CLSA was voluntary; participation rate was 45%. Among those in the comprehensive cohort, individuals reporting no previous history of CVEs (ie, stroke, transient ischemic attack [TIA], or myocardial infarction [MI]) at baseline were excluded. No other exclusion criteria were applied. A total of 86% of participants completed follow-up.
EXPOSURE
Lifetime history of epilepsy.
MAIN OUTCOMES AND MEASURES
The primary outcome was new-onset CVEs over 6 years. Secondary outcomes were new-onset strokes, TIAs, and MIs. Logistic models were fitted for these outcomes as a function of epilepsy, age, sex, household income, and education level. Mediation analyses were conducted for strong EIASM use, weak EIASM use, Framingham score, Physical Activity Scale for the Elderly (PASE) score, and waist to hip ratio.
RESULTS
Among the 30 097 individuals in the comprehensive cohort, a total of 27 230 individuals (mean [SD] age, 62.3 [10.1] years; 14 268 female [52.4%]) were included, 431 with a lifetime history of epilepsy. New-onset CVEs were more likely in epilepsy, with an adjusted odds ratio of 2.20 (95% CI, 1.48-3.27). The proportion of the effect of epilepsy on new-onset CVEs was mediated as follows by each of the following variables: strong EIASM use, 24.6% (95% CI, 6.5%-54.6%), weak EIASM use, 4.0% (95% CI, 0.8%-11.0%), Framingham score, 1.4% (95% CI, -1.6% to 4.5%), PASE score, 3.3% (95% CI, 1.4%-6.8%), and waist to hip ratio, 1.6% (95% CI, 0.4%-3.7%).
CONCLUSIONS AND RELEVANCE
Results of this cohort study reveal that epilepsy was associated with new-onset CVEs. Nearly one-third of this association can be explained by EIASMs. These findings should be considered when choosing an antiseizure medication for a person at risk for cardiovascular disease.
Additional Info
Disclosure statements are available on the authors' profiles:
Antiseizure Medications and Cardiovascular Events in Older People With Epilepsy
JAMA Neurol 2024 Sep 30;[EPub Ahead of Print], J Li, NA Shlobin, RD Thijs, MP Sylvestre, CB Josephson, C Deacon, MR KeezerFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
The incidence and prevalence of epilepsy are highest among adults older than 60 years. In our rapidly aging population, we will be caring for an increasing number of older adults with epilepsy, including those with chronic epilepsy and people with late-onset epilepsy. Epilepsy, especially late-onset epilepsy, in older adults is more responsive to antiseizure medications (ASMs) compared with that in younger adults.1 However, there are some unique challenges in managing ASMs in this population, chiefly age-related comorbidities, polypharmacy, and frailty.2,3
More than a decade ago, evidence started to emerge that enzyme-inducing ASMs (EIASMs) like phenytoin or carbamazepine worsen cholesterol control and vascular risks, which is reversible when the patient is switched to newer-generation ASMs like lamotrigine or levetiracetam.4 Further research has confirmed these findings and found that EIASM use is associated with higher healthcare expenditures.5,6 Regardless, they remain the predominant ASM type used among this population in Western countries like the US, the UK, and Canada.6-8 Now, one can hope that the article by Li et al discussed here would catalyze a reversal in this prescribing trend.
A previous study by the same group of researchers used 30 years of data from England's National Health Services and found that the hazard of new cardiovascular diseases (CVD; including myocardial infarction, stable or unstable angina, transient ischemic attack, and ischemic or hemorrhagic stroke) is significantly higher among patients prescribed EIASMs.9 However, the risk of CVD increases with age in the general population. CVD serves as a common cause of late-onset epilepsy.1 Conversely, there is evidence to suggest that chronic epilepsy increases the CVD risk due to repeated seizure-related surges in catecholamines and hypoxemia, culminating in electrical and mechanical dysfunction.10 Li et try to tackle the problem of the "chicken or the egg" conundrum of increased CVD risk among older adults with epilepsy, specifically the role of EIASMs and typical CVD risk factors.
The investigators analyzed a prospective Canadian cohort of adults aged 45 years or older with 6 years of follow-up. They found that nearly a third of the heightened CVD risk among older adults with epilepsy could be attributed to EIASMs. Surprisingly, only 4% of the EIASM effect on CVD was mediated by incident dyslipidemia. This study has clear implications for clinical practice, particularly in medication selection for older patients with epilepsy who may already have cardiovascular risk factors. Clinicians managing epilepsy in older adults frequently balance seizure control with the patient's overall health status, including cardiovascular risk management. Given that many ASMs are associated with lipid abnormalities and other pro-atherogenic effects, this study suggests a re-evaluation of EIASM use in favor of non–enzyme-inducing ASMs (non-EIASMs), particularly in patients with a pre-existing cardiovascular risk. EIASMs, including carbamazepine, phenytoin, and phenobarbital, are shown to influence lipid levels and inflammatory markers like C-reactive protein, which contribute to atherosclerosis progression.11 The study's mediation analysis supports this, revealing that strong EIASM use is the predominant modifiable risk factor among those studied.
Additionally, the findings emphasize the role of lifestyle factors, such as physical activity and obesity, in mediating the risk of cardiovascular events (CVEs) in patients with epilepsy. Lower physical activity and higher waist-to-hip ratios were found to be associated with an increased CVE risk, underscoring the value of a comprehensive approach to managing epilepsy in older adults. Encouraging physical activity and weight management, alongside careful medication selection, may help reduce the long-term cardiovascular burden in this population.
Ultimately, the study underscores the importance of cross-specialty collaboration in managing older adults with epilepsy. Neurologists, cardiologists, and primary care providers should work together to monitor these patients' cardiovascular health, mainly when using EIASMs. This collaborative approach is crucial in cases where seizure control necessitates EIASM use, as clinicians might consider adjunct therapies or more frequent monitoring of lipid profiles and inflammatory markers to mitigate these risks. The necessity of this teamwork should be felt by all healthcare professionals involved in the care of older adults with epilepsy.
A formidable clinical challenge may arise when older adults with well-controlled epilepsy on EIASMs develop CVD, requiring a switch to non-EIASMs for secondary prophylaxis. This may require nuanced, informed decision-making with the patient and other care providers to balance the risk of breakthrough seizures against preventing future CVDs. Although there are not much data to inform counsel, a small study found a modest breakthrough seizure risk of approximately 15% associated with switching EIASMs in well-controlled patients compared with maintaining the same regimen.
In conclusion, the highlighted study provides compelling evidence that EIASMs contribute substantially to CVD risk. This evidence should motivate clinicians treating older adults with epilepsy to avoid the use of EIASMs and shift their practice toward non-EIASMs. Integrating these findings into clinical practice could lead to improved long-term outcomes and quality of life for older adults managing both epilepsy and cardiovascular risks.12
References