100% of People Who Confuse Correlation With Causation Eventually Die

Abstract

Epilepsy and the Risk of Adverse Cardiovascular Events: A Nationwide Cohort Study

Mayer J, Fawzy AM, Bisson A, Pasi M, Bodin A, Vigny P, Herbert J, Marson AG, Lip GYH, Fauchier L. Eur J Neurol. 2024;31(3):e16116. doi: 10.1111/ene.16116

Background and purpose: Epilepsy is associated with higher morbidity and mortality compared to people without epilepsy. We performed a retrospective cross-sectional and longitudinal cohort study to evaluate cardiovascular comorbidity and incident vascular events in people with epilepsy (PWE). Methods: Data were extracted from the French Hospital National Database. PWE (n = 682 349) who were hospitalized between January 2014 and December 2022 were matched on age, sex, and year of hospitalization with 682 349 patients without epilepsy. Follow-up was conducted from the date of first hospitalization with epilepsy until the date of each outcome or date of last news in the absence of the outcome. The primary outcome was the incidence of all-cause death, cardiovascular death, myocardial infarction, hospitalization for heart failure, ischaemic stroke (IS), new-onset atrial fibrillation, sustained ventricular tachycardia or fibrillation (VT/VF), and cardiac arrest. Results: A diagnosis of epilepsy was associated with higher numbers of cardiovascular risk factors and adverse cardiovascular events compared to controls. PWE had a higher incidence of all-cause death (incidence rate ratio [IRR] = 2.69, 95% confidence interval [CI] = 2.67-2.72), cardiovascular death (IRR = 2.16, 95% CI = 2.11-2.20), heart failure (IRR = 1.26, 95% CI = 1.25-1.28), IS (IRR = 2.08, 95% CI = 2.04-2.13), VT/VF (IRR = 1.10, 95% CI = 1.04-1.16), and cardiac arrest (IRR = 2.12, 95% CI = 2.04-2.20). When accounting for all-cause death as a competing risk, subdistribution hazard ratios for IS of 1.59 (95% CI = 1.55-1.63) and for cardiac arrest of 1.73 (95% CI = 1.58-1.89) demonstrated higher risk in PWE. Conclusions: The prevalence and incident rates of cardiovascular outcomes were significantly higher in PWE. Targeting cardiovascular health could help reduce excess morbidity and mortality in PWE.

Commentary

Epilepsy is associated with high mortality. In fact, people suffering more than 3 grand mal seizures a year have approximately a 23% risk of dying from their epilepsy each decade.^1,2 And yet, there is significant underutilization of effective treatments for epilepsy, whether from the socioeconomic disadvantage of many people with epilepsy (PWE), ignorance of indications for referral to specialty centers, lack of medical infrastructure, or status quo bias. ³ There is a significant gap in care and funding for epilepsy care compared to that for cancer or other diseases with similar morbidity and mortality. Despite evidence that up to 40% of mortality is avoidable and that the majority of people in the advanced economies, even with nationalized health care, receive inadequate care, ⁴ there has not been increased utilization of effective treatments over the past 2 decades.^5,6

One of the potential causes of higher mortality associated with epilepsy has been cardiovascular disease. This has been theorized to be due to brain-induced cardiac arrhythmias, but some studies have also shown the risk of stroke and myocardial infarction (MI) to be higher, suggesting other mechanisms. In this article, ⁷ Mayer et al study the rates of mortality from cardiovascular disease in PWE using a national database, following all patients admitted to hospitals in France between 2014 and 2022. PWE were compared with patients without epilepsy, matching by date, age, and sex. Analysis was limited to those over 18 years of age and the average age was 61.4 ± 20.5 years. In a longitudinal analysis with an average of 1.9 ± 2.3 years of follow-up, PWE had a 31% risk of the composite outcome of death, heart failure, sustained cardiac arrhythmia, or ischemic stroke after the index admission, as opposed to a 17% risk in the matched group without epilepsy. Of note, cardiovascular deaths were more likely in the epilepsy group, with significantly higher risks of heart failure, ischemic stroke, and cardiac arrest, but lower risks of MI and incident arrhythmias. Results were not much different when patients with a prior history of ischemic stroke or intracranial hemorrhage were excluded from the epilepsy cohort.

As the authors note, this study should not be interpreted to suggest that epilepsy causes cardiovascular disease. The groups were different at baseline: 26% of the PWE had baseline cardiovascular disease at or before the index admission, as opposed to only 9.5% in the comparison group. There was more than double, and often more than triple, the prevalence of hypertension, diabetes mellitus, chronic kidney disease, tobacco use, dyslipidemia, obesity, alcohol-related diagnoses, and malnutrition in the epilepsy cohort. Therefore, it is not surprising that they had a higher risk of cardiovascular mortality. While many think of epilepsy being a disease of young people, the bimodal distribution of epilepsy by age is weighted towards older people, at least in France.

Despite the large size of this database, there are several limitations based on the nature of the administrative data. PWE who had not been hospitalized were not included. Even among those hospitalized patients in the database, the primary indication for hospitalization was not defined. The cause of the patient's epilepsy or frequency of seizures was unknown. Seizure medications that might be associated with heart failure were not examined.

The association between cardiovascular disease and epilepsy has been known for some time.^4,8 Thus, this study is mainly confirmatory, although the large, population-based cohort makes this a valuable contribution. Now the question is: how do we apply this knowledge to patient care to ameliorate cardiovascular risk for patients with epilepsy? This starts with educating patients and providers about cardiovascular risk. These data and others ⁹ suggest the possibility of targeted intervention around risk modification. Specifically, cardiac toxicity of seizure medications in patients with underlying cardiovascular risk factors or disease should be closely monitored. ¹⁰ It also raises important questions for future investigation. Should more aggressive antiplatelet therapy for stroke prevention be considered in PWE? Should there be a different threshold for cardiac monitoring or demand pacemaker placement in PWE? It will be important for investigators to further examine this and other data sets for answers that will guide clinical care.