| Key points |
• We studied 10,241 people with epilepsy who were prescribed antiepileptic medications and 35,145 matched controls. • There was an increased risk of major cardiovascular events in people with epilepsy. • V There did not appear to be a difference when comparing enzyme-inducing and non-enzyme-inducing antiepileptic drugs. • Cardiovascular risk management is important in people with epilepsy. |
Epilepsy is a common neurological condition, and people with epilepsy have higher mortality rates than the general population. Although some of this increased risk may be explained by comorbid conditions or lifestyle factors, cardiovascular events associated with epilepsy or antiepileptic drugs (AEDs) may also contribute.
For most people with epilepsy, antiepileptic drugs (AEDs) are the mainstay of treatment. Previous studies have suggested a link between AEDs and an increased risk of cardiovascular events, such as stroke, myocardial infarction, and arrhythmia.
AEDs can be grouped into enzyme-inducing AEDs (EIFAEs; for example, phenytoin, phenobarbital, and carbamazepine) and non-enzyme-inducing AEDs (NEIFAEs), based on their action on the hepatic enzyme system. Older AEDs, which are primarily enzyme inducers , may be associated with more adverse effects and may alter metabolic pathways related to vascular risk.
EIFAEs are associated with elevated levels of total cholesterol and low-density lipoprotein cholesterol due to effects on enzymes involved in cholesterol synthesis. Other vascular risk markers may be affected by AEDs, such as homocysteine and C-reactive protein .
Despite evidence linking AEDs to lipid abnormalities, evidence of their effect on cardiovascular events is lacking. AEDs are long-term treatments and therefore it is important to fully understand the possible side effects.
This study aimed to evaluate whether people with epilepsy who take AEDs have a higher risk of experiencing a major cardiovascular event than people without epilepsy. The study also examined whether the risk of clinically relevant cardiovascular outcomes differed in those treated with EIFAE compared to NEIFAE.
| Objective |
This study was conducted to determine whether epilepsy and antiepileptic medications (including enzyme-inducing and non-enzyme-inducing medications) are associated with major cardiovascular events using data routinely collected at the population level.
| Methods |
Using routinely collected, anonymised healthcare data in Wales, UK, we conducted a retrospective matched cohort study (2003-2017) of adults with epilepsy prescribed an antiepileptic medication. Controls were matched with replacement on age, gender, deprivation quintile and year of study entry.
Participants were followed until the end of the study for the occurrence of a major cardiovascular event, and survival models were constructed to compare the time to a major cardiovascular event (cardiac arrest, myocardial infarction, stroke, ischemic heart disease, arrhythmia clinically significant, thromboembolism), occurrence of heart failure or cardiovascular death) for individuals in the case group versus the control group.
| Results |
There were 10,241 cases (mean age = 49.6 years, 52.2% men, mean follow-up = 6.1 years) matched with 35,145 controls. A total of 3180 (31.1%) cases received enzyme-inducing antiepileptic drugs and 7061 (68.9%) cases received non-enzyme-inducing antiepileptic drugs.
Cases were at increased risk of experiencing a major cardiovascular event compared to controls (adjusted hazard ratio = 1.58, 95% confidence interval [CI] = 1.51–1.63, p < 0.001).
There was no notable difference in major cardiovascular events between those treated with enzyme-inducing antiepileptic drugs and those treated with non-enzyme-inducing antiepileptic drugs (adjusted hazard ratio = 0.95, 95% CI = 0.86–1, 05, p = 0.300).
| Meaning |
People with epilepsy who are prescribed antiepileptic medications have an increased risk of major cardiovascular events compared to population controls.
Prescription of an enzyme-inducing antiepileptic drug is not associated with an increased risk of a major cardiovascular event compared to treatment with other antiepileptic drugs.
Our data emphasize the importance of cardiovascular risk management in the clinical care of people with epilepsy.
| Impact |
This study demonstrates that adults with epilepsy taking AEDs are more likely to experience major cardiovascular events than the general population after accounting for comorbidities and relevant treatments. Therefore, it is important that healthcare professionals and people with epilepsy prioritize the identification and treatment of cardiovascular disease and its risk factors. For example, making dietary changes, increasing physical activity levels, quitting smoking, and treating hypertension and hypercholesterolemia can reduce the risk of developing cardiovascular events.
Previous studies have shown that EIAEDs could increase cholesterol and lipid levels. However, this study does not support an increase in major cardiovascular events at the population level. This is important when switching from EIAED to NEIAED is being considered, as the risks of breakthrough seizures may not be outweighed by the benefits of switching from EIAED to NEIAED.
| Conclusions |
Overall, this study suggests that people with epilepsy who take AEDs are at significantly higher risk of experiencing major cardiovascular events than the general population. This is corroborated by other studies, which highlight the need for rigorous management of cardiovascular risk in people with epilepsy who have been prescribed AEDs.
Our study has not observed any significant difference in the rates of major cardiovascular events in prescribed EIAEDs and NEIAEDs, which warrants further investigation and may have important implications for treatment selection in clinical practice.
