Received: 15 June 2023 | Accepted: 12 October 2023

DOI: 10.1111/ene.16116

ORIGINAL ARTICLE

Epilepsy and the risk of adverse cardiovascular events:

A nationwide cohort study

Josephine Mayer1,2 | Ameenathul M. Fawzy1 | Arnaud Bisson1,3 | Marco Pasi4 |

Alexandre Bodin3 | Pascal Vigny5 | Julien Herbert5 | Anthony G. Marson2 |
Gregory Y. H. Lip1,6 | Laurent Fauchier3

Abstract
1
Liverpool Centre for Cardiovascular
Science, University of Liverpool, Liverpool
John Moores University, and Liverpool Background and purpose: Epilepsy is associated with higher morbidity and mortality
Heart and Chest Hospital, Liverpool, UK compared to people without epilepsy. We performed a retrospective cross-sectional and
2
Walton Centre NHS Foundation Trust,
longitudinal cohort study to evaluate cardiovascular comorbidity and incident vascular
Department of Pharmacology and
Therapeutics, Institute of Systems, events in people with epilepsy (PWE).
Molecular, and Integrative Biology,
Methods: Data were extracted from the French Hospital National Database. PWE
University of Liverpool, Liverpool, UK
3
Department of Cardiology, Tours
(n = 682,349) who were hospitalized between January 2014 and December 2022 were
Regional University Hospital, Hospital matched on age, sex, and year of hospitalization with 682,349 patients without epilepsy.
Trousseau, Tours, France
4
Follow-up was conducted from the date of first hospitalization with epilepsy until the
Department of Neurology, Hospital
Bretonneau, Tours, France date of each outcome or date of last news in the absence of the outcome. Primary out-
5
Clinical Data Centre, Public Health come was the incidence of all-cause death, cardiovascular death, myocardial infarction,
and Prevention Unit, Tours University
hospitalization for heart failure, ischaemic stroke (IS), new onset atrial fibrillation, sus-
Hospital, Tours, France
6
Danish Centre for Health Services tained ventricular tachycardia or fibrillation (VT/VF), and cardiac arrest.
Research, Department of Clinical Results: A diagnosis of epilepsy was associated with higher numbers of cardiovascular
Medicine, Aalborg University, Aalborg,
Denmark risk factors and adverse cardiovascular events compared to controls. People with epi-
lepsy had a higher incidence of all-cause death (incidence rate ratio [IRR] = 2.69, 95% con-
Correspondence
Gregory Y. H. Lip, Liverpool Centre for fidence interval [CI] = 2.67–2.72), cardiovascular death (IRR = 2.16, 95% CI = 2.11–2.20),
Cardiovascular Science, Institute of Life heart failure (IRR = 1.26, 95% CI = 1.25–1.28), IS (IRR = 2.08, 95% CI = 2.04–2.13), VT/
Course and Medical Sciences, William
Henry Duncan Building, 6 West Derby VF (IRR = 1.10, 95% CI = 1.04–1.16), and cardiac arrest (IRR = 2.12, 95% CI = 2.04–2.20).
Street, Liverpool L7 8TX, UK. When accounting for all-cause death as a competing risk, subdistribution hazard ratios
Email: gregory.lip@liverpool.ac.uk
for ischaemic stroke 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 signifi-
cantly higher in PWE. Targeting cardiovascular health could help reduce excess morbidity
and mortality in PWE.

KEYWORDS
cardiovascular diseases, comorbidity, epilepsy, incidence, stroke

Gregory Y. H. Lip and Laurent Fauchier are joint senior authors.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.

Eur J Neurol. 2024;31:e16116.  wileyonlinelibrary.com/journal/ene | 1 of 10

https://doi.org/10.1111/ene.16116
2 of 10 | MAYER et al.

I NTRO D U C TI O N people) from birth (or immigration) to death (or emigration). This
process allows the determination of each hospital's budget, in 1546
Epilepsy is a common neurological condition, with lifetime preva- French health care facilities for both public and private hospitals.
lence reported to be 7.60/1000 persons [1]. Mortality in patients Each hospitalization is encoded in a standardized dataset, which
with epilepsy (PWE) has remained unchanged since the 1950s and is includes information about the patient (age and sex), hospital, stay
significantly higher compared to the general population [2, 3]. Only (date of admission, date of discharge, and modes of discharge), pa-
a small proportion of deaths in people with epilepsy are believed to thologies, and procedures. Routinely collected medical informa-
be directly attributable to seizures, with the majority being second- tion includes the principal diagnosis and secondary diagnoses. In
ary to epilepsy-related causes such as structural brain abnormali- the PMSI system, identified diagnoses are coded according to the
ties, stroke, neoplasms, and sudden unexpected death in epilepsy International Classification of Diseases, Tenth Revision (ICD-10).
(SUDEP) [2–4]. Epilepsy-unrelated causes such as cardiovascular All medical procedures are recorded according to the national no-
disease are contributory, and studies have indicated a higher risk of menclature, Classification Commune des Actes Medicaux. The PMSI
cardiovascular events such as stroke, myocardial infarction (MI), and contains individual anonymized information on each hospitalization
sudden cardiac death in PWE. Cardiovascular-related deaths may that is linked to create a longitudinal record of hospital stays and
account for approximately one quarter of deaths in PWE [2, 3, 5]. diagnoses for each patient. The reliability of PMSI data has already
The relationship between cardiovascular disease and epilepsy been assessed [13, 14], and this database has previously been used
is complex. The concept of the "epileptic heart" was proposed by to study patients with cardiovascular conditions [15–17]. There were
Verrier et al. [4] to explicate the changes that occur in the myocar- no missing data, as the information was based on codes [15, 18].
dium and coronary vasculature as a result of the recurrent catechol- The study was conducted retrospectively and, as patients were
aminergic surges and hypoxemia that occur with seizure activity in not involved in its conduct, there was no impact on their care.
patients with chronic epilepsy. Over time, these cardiotoxic insults Ethical approval was not required, as all data were anonymized. The
are believed to cause mechanical and electrical dysfunction, con- French Data Protection Authority granted access to the PMSI data.
sequently increasing the risk of adverse cardiovascular outcomes Procedures for data collection and management were approved by
such as arrhythmias and sudden cardiac death. It is hypothesized the Commission Nationale de l'Informatique et des Libertés, the in-
that there may be potential overlap between the latter and SUDEP dependent national ethical committee protecting human rights in
[4]. Epilepsy is also a symptom of cardiovascular disease. Stroke is a France, which ensures that all information is kept confidential and
common cause of adult onset epilepsy [6], and seizures in later life anonymous, in compliance with the Declaration of Helsinki (authori-
may be a presentation of subclinical cerebrovascular disease [7]. zation number 1897139).
Other factors that influence cardiovascular health in PWE include Patients with epilepsy aged >18 years were identified from hos-
lifestyle behaviors such as higher rates of smoking and socioeco- pital records if they had been admitted between 1 January 2014
nomic deprivation, which has been associated with higher mortal- and 31 December 2022 for any cause, and had been coded with
ity in PWE [5, 8]. In addition, some antiseizure medications may be a diagnosis of epilepsy (ICD-10 G40 and G41). Patient information
linked to accelerated atherosclerosis [9–11], but whether this trans- (demographics, comorbidities, medical history, and events during
lates to adverse cardiovascular outcomes in PWE is less clear [12]. hospitalization or follow-up) was obtained using data collected in
At present, there are a limited number of studies specifically the hospital records. For each hospital stay, combined diagnoses at
exploring cardiovascular outcomes such as mortality, arrhythmias, discharge were obtained. Each variable was identified using ICD-10
and cardiac arrest in PWE, despite the clinical implications. Thus, to codes (see Table S1). For each patient with a history of epilepsy, a
gain a better understanding of the epidemiology of cardiovascular hospitalized patient matched on age, sex, and year of inclusion with
disease and outcomes in these patients, we performed a retrospec- no epilepsy was selected. Matching was performed using propensity
tive cross-sectional and longitudinal cohort study to evaluate car- scores, which were calculated using logistic regression with epilepsy
diovascular comorbidity and incident vascular events in hospitalized as the dependent variable. The propensity score included age and
patients with epilepsy. sex. For each patient with epilepsy, a propensity score-matched
patient with no epilepsy was selected (1:1) using the one-to-one
nearest neighbour method (with a caliper of 0.01 of the SD of the
M E TH O D S propensity score on the logit scale) and no replacement.
The occurrence of cardiovascular outcomes was reviewed within
This study was carried out using the national hospitalization database this period (1 January 2014 to 31 December 2022) and compared
Programme de Médicalisation des Systèmes d'Information (PMSI), with hospitalized patients with no epilepsy matched for age, sex,
which includes data on hospital care for the entire French population and year of inclusion. Primary outcome was the incidence and risk
from January 2014 to December 2022. This was inspired by the US of all-cause death, cardiovascular death, and major cardiovascular
Medicare system and was implemented in 2004 so that all medical events. We considered major cardiovascular events to be new MI,
activity is recorded in a database, computed, and rendered anony- excluding patients with prior MI; hospitalization for heart failure;
mous. It includes more than 98% of the French population (67 million ischaemic stroke; new atrial fibrillation (AF), excluding patients with
EPILEPSY AND CARDIOVASCULAR EVENTS | 3 of 10

prior AF diagnosis; and sustained ventricular tachycardia or fibrilla- Patients with epilepsy hospitalized Matched patients by gender, age
in French hospitals 2014–2022 and year of inclusion hospitalized
tion (VT/VF). The endpoints were evaluated with follow-up starting N = 682,349 in French hospitals 2014–2022
from the date of hospitalization from any cause with a new or ex- N = 682,349

isting diagnosis of epilepsy (or date of first hospitalization, matched

with the year of inclusion, for patients with no epilepsy) until the date
Cross sectional analysis
of each specific outcome or date of last news in the absence of the
outcome. Information on outcomes during follow-up was obtained HF, MI, sustained cardiac HF, MI, sustained cardiac
arrhythmia or ischemic stroke arrhythmia or ischemic stroke
by analyzing the PMSI codes for each patient. Outcomes were iden- before or at index date before or at index date
n = 180,012 (26.4%) n = 64,517 (9.5%)
tified using their respective ICD-10 codes (see Table S1). The mode of
death (cardiovascular or noncardiovascular) was identified based on
the main diagnosis during hospitalization resulting in death. To check Longitudinal analysis, FU 1.9±2.3 years
for the persistence of associations after removal of cerebrovascular
Death, HF, MI, sustained cardiac Death, HF, MI, sustained cardiac
disease, a subanalysis was conducted excluding patients with prior arrhythmia or ischemic stroke arrhythmia or ischemic stroke
ischaemic stroke and intracranial hemorrhage from the analysis. after index date after index date
n = 211,254 (31.0%) n = 115,844 (17.0%)

F I G U R E 1 Flow chart of the matched study population. FU,

Statistical analysis follow-up; HF, heart failure; MI, myocardial infarction.

Qualitative variables are described as frequency and percentage

and quantitative variables as mean and SD. Comparisons were made as AF, VT/VF, and previous cardiac arrests, although the latter only
using χ2 tests for categorical variables and the Student t-test for comprised a small proportion of the cohort. Noncardiovascular co-
continuous variables. The analysis for clinical outcomes during the morbidities such as lung pathologies, malignancy, and thyroid and
whole follow-up in the groups of interests was performed using the inflammatory diseases were also more common in PWE. In addi-
Mantel–Haenszel method to estimate standardized incidence rates tion, PWE had a higher prevalence of poorer lifestyle-related fac-
and incidence rate ratios (IRRs) with 95% confidence intervals (CIs). tors including poor nutrition, obesity, smoking, and alcohol-related
A competing risk analysis was performed using the Fine and Gray disorders.
model with subdistribution hazard ratios (SHRs) used to denote the
risk of a particular outcome. The competing risk included noncardio-
vascular death for cardiovascular death, and all-cause death for non- Cross-sectional analysis
lethal clinical outcomes. There was no competing risk analysis for
all-cause death. All comparisons with p < 0.05 were considered sta- In the cross-sectional analysis, which looked at events at or before
tistically significant. All analyses were performed using Enterprise the index date, 180,012 events of heart failure, MI, sustained cardiac
Guide 7.1, (SAS Institute, Cary, NC, USA). arrhythmia, and ischaemic stroke had occurred in the epilepsy group,
and 64,517 events had occurred in the control group at the time of
inclusion in the study.
R E S U LT S

A total of 682,349 hospitalized epilepsy patients were identified. Longitudinal analysis

They were matched on a 1:1 basis with 682,349 patients without
epilepsy, according to age, gender, and year of first hospitalization Over a mean follow-up duration of 1.9 ± 2.3 years, 327,098 incident
within the time period. The study patient flow is shown in Figure 1. events were observed in both groups; 211,254 events in the epi-
lepsy group and 115,844 events in the control group. The incidence
rates for each of these outcomes are presented in Table 2. Figure 2
Baseline characteristics demonstrates the cumulative incidence function curves for the
outcomes.
Baseline characteristics and prevalent disease are demonstrated in
Table 1. The mean age of the epilepsy and matched control group
was 61.4 ± 20.5 years, with a range of 18–114 years. There was a All-cause death
slight male predominance of 52.8% (n = 360,485).
Cardiovascular risk factors and comorbidities such as hyperten- A total of 147,335 events were observed in the epilepsy group,
sion, dyslipidaemia, diabetes, coronary artery disease, valvulopathy, and 56,638 events were observed in the control group, with cor-
heart failure, and ischaemic stroke were more prevalent in the ep- responding incidence rates of 11.31%/year and 4.20%/year, IRR
ilepsy group. They were also more likely to have arrhythmias such 2.63 (95% CI = 2.67–2.72). SHR for all-cause death was 2.50 (95%
4 of 10 | MAYER et al.

TA B L E 1 Baseline medical diagnoses observed in patients with epilepsy compared to matched controls with no epilepsy.

Characteristic No epilepsy, n = 682,349 Epilepsy, n = 682,349 p Total, n = 1,364,698

Age, years, mean ± SD 61.4 ± 20.5 61.4 ± 20.5 1 61.4 ± 20.5

Age, years, median (IQR) 64.0 (47.0–78.0) 64.0 (47.0–78.0)
Sex, male, n (%) 360,485 (52.8) 360,485 (52.8) 1 720,970 (52.8)
Cardiovascular risk factors and lifestyle behaviors, n (%)
Hypertension 105,082 (15.4) 257,382 (37.7) <0.0001 362,464 (26.6)
Diabetes mellitus 43,943 (6.4) 103,649 (15.2) <0.0001 147,592 (10.8)
Chronic kidney disease 8734 (1.3) 37,052 (5.4) <0.0001 45,786 (3.4)
Smoker 18,492 (2.7) 75,058 (11.0) <0.0001 93,550 (6.9)
Dyslipidaemia 29,682 (4.4) 90,207 (13.2) <0.0001 119,889 (8.8)
Obesity 29,546 (4.3) 72,465 (10.6) <0.0001 102,011 (7.5)
Alcohol-related diagnoses 14,398 (2.1) 95,529 (14.0) <0.0001 109,926 (8.1)
Poor nutrition 23,405 (3.4) 120,708 (17.7) <0.0001 144,112 (10.6)
Cardiovascular outcomes, n (%)
Heart failure 29,750 (4.4) 86,522 (12.7) <0.0001 116,272 (8.5)
Previous MI 8188 (1.2) 14,056 (2.1) <0.0001 22,245 (1.6)
Atrial fibrillation 33,640 (4.9) 91,435 (13.4) <0.0001 125,075 (9.2)
Previous VF/sustained VT 1474 (0.2) 5356 (0.8) <0.0001 6830 (0.5)
Previous cardiac arrest 1760 (0.3) 10,372 (1.5) <0.0001 12,132 (0.9)
Ischaemic stroke 8052 (1.2) 60,524 (8.9) <0.0001 68,576 (5.0)
Other cardiovascular-related disorders, n (%)
History of pulmonary oedema 1494 (0.2) 7574 (1.1) <0.0001 9068 (0.7)
Valve disease 9962 (1.5) 29,409 (4.3) <0.0001 39,372 (2.9)
Aortic stenosis 4852 (0.7) 13,101 (1.9) <0.0001 17,953 (1.3)
Aortic regurgitation 1467 (0.2) 5868 (0.9) <0.0001 7335 (0.5)
Mitral regurgitation 3480 (0.5) 11,941 (1.8) <0.0001 15,421 (1.1)
Dilated cardiomyopathy 4510 (0.7) 16,445 (2.4) <0.0001 20,955 (1.5)
Coronary artery disease 33,503 (4.9) 70,828 (10.4) <0.0001 104,331 (7.6)
Previous PCI 4183 (0.6) 12,896 (1.9) <0.0001 17,079 (1.3)
Previous CABG 21 (0.0) 1788 (0.3) <0.0001 1809 (0.1)
Previous pacemaker or ICD 6496 (1.0) 21,767 (3.2) <0.0001 28,263 (2.1)
Vascular disease 23,200 (3.4) 68,098 (10.0) <0.0001 91,298 (6.7)
Intracranial bleeding 4272 (0.6) 60,320 (8.8) <0.0001 64,591 (4.7)
Noncardiovascular pathology, n (%
Lung disease 21,835 (3.2) 109,790 (16.1) <0.0001 131,625 (9.6)
Sleep apnea syndrome 9826 (1.4) 31,388 (4.6) <0.0001 41,214 (3.0)
COPD 10,645 (1.6) 41,487 (6.1) <0.0001 52,131 (3.8)
Liver disease 6557 (1.0) 37,461 (5.5) <0.0001 44,018 (3.2)
Thyroid diseases 16,240 (2.4) 53,019 (7.8) <0.0001 69,258 (5.1)
Inflammatory disease 11,805 (1.7) 34,390 (5.0) <0.0001 46,195 (3.4)
Anaemia 20,470 (3.0) 92,731 (13.6) <0.0001 113,202 (8.3)
Previous cancer 43,807 (6.4) 112,110 (16.4) <0.0001 155,917 (11.4)
Cognitive impairment 19,038 (2.8) 97,098 (14.2) <0.0001 116,136 (8.5)

Note: Values are n (%) or mean ± SD.

Abbreviations: CABG, coronary artery bypass graft; COPD, chronic obstructive pulmonary disease; ICD, implantable cardioverter defibrillator; IQR,
interquartile range; MI, myocardial infarction; PCI, percutaneous coronary intervention; VF, ventricular fibrillation; VT, ventricular tachycardia.
 EPILEPSY AND CARDIOVASCULAR EVENTS | 5 of 10

CI = 2.47–2.52), demonstrating a nearly threefold higher risk in the

<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
epilepsy group.

p
hazard ratio (95%

0.83 (0.78–0.89)
0.97 (0.95–0.98)

0.58 (0.57–0.59)
0.63 (0.61–0.65)
1.59 (1.55–1.63)

1.73 (1.58–1.89)
1.79 (1.75–1.83)
2.50 (2.47–2.52)
Subdistribution

Cardiovascular death

A total of 26,277 and 12,605 cardiovascular deaths occurred in the

epilepsy and control groups, respectively. The incidence (IRR = 2.16,
CI)

95% CI = 2.11–2.20) and risk (SHR = 1.79, 95% CI = 1.75–1.83) of car-

diovascular death were significantly higher in the epilepsy group.
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001

<0.0001
0.002
p

Heart failure
0.85 (0.83–0.88)

2.12 (2.04–2.20)
2.08 (2.04–2.13)
1.26 (1.25–1.28)

0.75 (0.74–0.76)
2.70 (2.67–2.72)
2.16 (2.11–2.20)

1.10 (1.04–1.16)
Incidence rate
ratio (95% CI)

Incident heart failure events in the epilepsy and control cohorts were
58,506 and 48,474, respectively. The incidence of heart failure was sig-
nificantly higher in the epilepsy group (IRR = 1.26, 95% CI = 1.25–1.28).
In the competing risk analysis, the risk of incident heart failure was sig-
nificantly lower in the epilepsy group (SHR = 0.97, 95% CI = 0.93–0.98).
11.31 (11.26–11.37)
Incidence, %/year

Abbreviations: AF, atrial fibrillation; CI, confidence interval; MI, myocardial infarction; VT/VF, ventricular tachycardia or fibrillation.
0.66 (0.65–0.68)
0.66 (0.65–0.67)

2.32 (2.30–2.35)
2.02 (1.99–2.04)

1.91 (1.88–1.93)

0.19 (0.18–0.19)
4.75 (4.71–4.78)
TA B L E 2 Incident outcomes in the age- and sex-matched population according to history of epilepsy or no epilepsy.

Myocardial infarction
(95% CI)

Fewer incident MIs were observed in the epilepsy group compared

to the control group (7043 vs. 8223). The incidence (IRR = 0.89, 95%
147,335

8505
26,277
58,506

24,209
29,309
2422
8591
Events,

CI = 0.86–0.91) and risk (SHR = 0.63, 95% CI = 0.61–0.65) of MI were

Epilepsy, n = 682,349

significantly lower in the control group compared to the epilepsy

n

group.
(patient- years)
Person-time

1,302,399

1,262,210
1,302,399
1,232,982
1,291,671
1,270,941

1,299,423
1,300,037

Ischaemic stroke

A total of 24,209 ischaemic stroke events were observed in the epi-

Incidence, %/year

0.31 (0.30–0.32)
0.91 (0.90–0.93)
3.76 (3.73–3.80)
0.77 (0.76–0.79)
4.20 (4.17–4.24)

0.17 (0.16–0.18)
0.94 (0.92–0.95)

3.10 (3.07–3.14)

lepsy group, and 12,198 events were observed in the control group.
The incidence of ischaemic stroke was twofold higher in the epilepsy
(95% CI)

group (IRR = 2.08, 95% CI = 2.04–2.13), and subdistribution haz-

ard demonstrated significantly increased risk in the epilepsy group
(SHR = 1.59, 95% CI = 1.55–1.63).
Events,

56,638
12,605
48,474
10,317

2285
4209
12,198
40,096
No epilepsy, n = 682,349

Atrial fibrillation
(patient- years)

A total of 29,309 patients had AF in the epilepsy group, and 40,096

Person-time

1,347,819
1,347,819

1,347,182
1,288,611
1,334,162
1,334,393
1,291,626
1,345,082

in the control group had incident AF. The incidence (IRR 0.75, 95%
CI = 0.74–0.76) and risk (SHR = 0.58, 95% CI = 0.57–0.59) of incident
AF were significantly lower in the epilepsy cohort compared to the
nonepilepsy cohort.
Cardiovascular death

Ischaemic stroke
All-cause death

Cardiac arrest

Ventricular tachycardia or fibrillation

Heart failure

Incident AF
Incident MI
Outcome

VT/VF

VT/VF events in the epilepsy and control groups were 2422

and 2285, respectively, with an IRR of 1.10 (95% CI = 1.04–1.16)
6 of 10 | MAYER et al.
EPILEPSY AND CARDIOVASCULAR EVENTS | 7 of 10

F I G U R E 2 (a) Cumulative incidence function curves for clinical outcomes with censoring for competing events in patients with and
without history of epilepsy: all-cause death (left upper panel), cardiovascular death (right upper panel), hospitalization for heart failure (left
lower panel), and myocardial infarction (right lower panel). (b) Cumulative incidence function curves for clinical outcomes with censoring
for competing events in patients with and without history of epilepsy: ischaemic stroke (left upper panel), atrial fibrillation (AF; right upper
panel), incident ventricular tachycardia or fibrillation (VT/VF; left lower panel), and incident cardiac arrest (right lower panel). CI, confidence
interval; HR, hazard ratio; SHR, subdistribution hazard ratio.

indicating a higher rate of ventricular arrhythmias in the epilepsy attention, including the possibility of shared mechanisms between
group. The SHR of 0.834 (95% CI = 0.780–0.893) was shown to be cardiac and brain health. Our findings reflect results from other ob-
significantly lower in this cohort after accounting for the competing servational studies that have identified a higher prevalence of car-
event of all-cause death. diac comorbidities, vascular risk factors, poorer lifestyle behaviors,
and increased rates of cardiac mortality, morbidity, and stroke in
PWE [12, 19–25].
Cardiac arrests The cross-sectional analysis of the epilepsy group differed
significantly for cardiovascular risk factors, outcomes, and poorer
A total of 8591 cardiac arrests were observed in the epilepsy group, lifestyle behaviors. These factors are likely contributory to the
and 4209 were observed in the control group. Incidence of cardiac high incident rates of cardiovascular outcomes. The risk of car-
arrests was twofold higher in the epilepsy group (IRR = 2.12, 95% diovascular disease, however, has remained elevated in other ob-
CI = 2.04–2.20), and risk was also significantly elevated (SHR = 1.73, servational cohorts even after adjustment for patients with prior
95% CI = 1.58–1.89) compared to controls. stroke and vascular risk factors [12, 21, 25, 26], providing evidence
towards an additional contribution of epilepsy-related factors to
adverse cardiovascular outcomes. In this study, when we removed
Exploratory analysis patients with prior stroke diagnoses to remove bias towards an
association with cardiovascular disease, PWE still had elevated
Ischaemic stroke and intracranial hemorrhage are the most com- incident rates of heart failure, ischaemic stroke, VT/VF, and car-
mon vascular disease-related causes of epilepsy. We performed diovascular death.
a subgroup analysis excluding patients with a prior history of is- Poorer lifestyle behaviors and socioeconomic factors [8, 27] are
chaemic stroke and intracranial hemorrhage (Table 3). The base- likely to be important contributors to cardiovascular health in PWE.
line comorbidities of the groups are outlined in Table S2. Results In the cross-sectional analysis in this study, PWE had significantly
were similar to our primary analysis, with elevated incidence of higher levels of smoking, poor diet, obesity, and alcohol-related dis-
cardiovascular death (IRR = 1.72, 95% CI = 1.67–1.77), heart failure orders. Terman et al. identified elevated cardiovascular risk in PWE,
(IRR = 1.26, 95% CI = 1.25–1.28), ischaemic stroke (IRR = 1.76, 95% which was attenuated after adjusting for lifestyle factors, suggesting
CI = 1.71–1.80), VT/VF (IRR = 1.08, 95% CI = 1.01–1.15), and cardiac targeting these may be an appropriate strategy to improve vascular
arrest (IRR = 2.18, 95% CI = 2.10–2.28) in PWE compared to controls, health in this group of patients [28].
whereas the incident rate and risk of MI and AF remained higher in There are likely to be differing mechanisms underlying the asso-
the control group. ciation of adverse cardiovascular outcomes in those with epilepsy
from a young age compared to those with late onset unprovoked ep-
ilepsy, where a shared vasculopathy may be contributory [7, 29], but
DISCUSSION data regarding mechanisms within different etiologies are scarce.
Contrasting with previous reports [21], in this French population
In this large population-based observational study of associated we did not identify an increased incidence of MI in PWE. The in-
comorbidity and incident vascular outcomes in PWE, we observed cidence of MI has been reported as 24% higher in PWE compared
that in hospitalized patients, a diagnosis of epilepsy was associated to those with lower limb fracture in a South Carolina-based study
with (i) an increased prevalence of cardiovascular risk factors such [22], and a correlation between number of hospitalizations with
as hypertension, diabetes, and dyslipidaemia; (ii) a higher prevalence epilepsy, a proxy for seizure frequency, and risk of MI in PWE has
of cardiovascular comorbidities; (iii) a higher prevalence of poorer been previously described [30]. In this study, where the mean par-
lifestyle behaviors, including smoking, obesity, alcohol use, and poor ticipants' age was 61.4 ± 20.5 years, there was a higher prevalence
diet; and (iv) a significantly higher incidence of death from all causes of AF (13.4%) compared to the figures reported in some of the other
including cardiovascular death, heart failure, ischaemic stroke, VT/ studies [31]. When patients with prior AF diagnoses were removed
VF, and cardiac arrest. from analysis, the incident rate was lower in the epilepsy group. It
To our knowledge, this is the largest study of comorbidity and is well known that the incidence of AF increases with age, and it is
incident cardiovascular outcomes in PWE. This work does not imply possible that these figures may differ depending on the age of the
causation, but generates a number of hypotheses that warrant study population [32]. Furthermore, given that cardiac arrhythmias
 8 of 10 | MAYER et al.

can masquerade as epilepsy, an element of AF underreporting may

<0.0001
<0.0001
<0.0001

<0.0001
<0.0001
<0.0001
<0.0001
0.04
also be present in PWE [33]. AF may also be more frequently di-
agnosed in the community [34]. Conversely, an association with a

p
hazard ratio (95% diagnosis of AF and the subsequent development of epilepsy (hazard

0.60 (0.59–0.62)
0.83 (0.77–0.90)
2.51 (2.49–2.54)

0.64 (0.61–0.66)
1.37 (1.33–1.42)
0.98 (0.97–1.00)
1.47 (1.43–1.51)

1.76 (1.59–1.91)
Subdistribution

ratio = 1.51, 95% CI = 1.35–1.69, p < 0.001) has also been previously
reported [35].
In this study, there was an unexpected lower incidence of MI and
TA B L E 3 Incident outcomes in the age- and sex-matched population according to history of epilepsy with no history of stroke or intracranial bleeding, or no epilepsy.

AF in PWE. As patients with prior diagnoses were excluded from the

CI)

incident analysis for MI and AF, the cohorts may not have reflected
the cross-sectional analysis. Furthermore, there are unknown medi-
<0.0001
<0.0001

<0.0001
<0.0001
<0.0001
<0.0001
<0.0001

cation and procedural factors (e.g., secondary prevention for stroke

0.02
and heart failure management) that may modify patients' subse-
p

quent MI or AF risk. In addition, patients were not matched on co-

morbidities, which may lead to bias. As we do not know the details of
0.85 (0.82–0.87)
2.66 (2.63–2.69)

1.26 (1.25–1.28)

0.77 (0.76–0.79)

2.18 (2.10–2.28)
1.08 (1.01–1.15)
1.72 (1.67–1.77)

1.76 (1.71–1.80)
Incidence rate
ratio (95% CI)

cardiovascular disease deaths, the high risk of cardiovascular-related

deaths may be attributed to other aetiologies such as ischaemic
stroke, cardiac arrest, or heart failure. There are also a number of
other limitations in the study relating to the difficulty in obtaining
an unbiased comparison of two clinically complex cohorts discussed
10.00 (9.95–10.06)
Incidence, %/year

Abbreviations: AF, atrial fibrillation; CI, confidence interval; MI, myocardial infarction; VT/VF, ventricular tachycardia or fibrillation.
0.62 (0.60–0.63)

0.64 (0.63–0.65)
1.32 (1.30–1.34)
4.35 (4.31–4.38)

2.22 (2.19–2.25)

below. Further studies examining this risk in those without a pre-

1.32 (1.29–1.34)

0.17 (0.17–0.18)

existing cardiovascular history may help clarify these relationships.

(95% CI)

Strengths and limitations

6975
14,839
24,599
1981
7299
47,185
114,379
15,030
Events,

The strengths of the study include the size of the analysis and the
n

coverage of the French hospitalized population. This study has a

Epilepsy, n = 571,532

number of limitations due to the retrospective design and use of a

(patient- years)

large national dataset. There is a selection bias into the cohort, as

Person-time

both epilepsy and cardiovascular outcomes may lead to hospitali-

1,134,256
1,124,269
1,108,888
1,140,863
1,141,261
1,143,369
1,143,369
1,085,943

zations, which may result in biased associations between epilepsy

and cardiovascular outcomes. There is a lack of detail regarding
epilepsy diagnosis such as etiology and length of epilepsy diagno-
Incidence, %/year

0.29 (0.28–0.30)

sis, and we cannot ascertain the finer details of the relationship

2.87 (2.83–2.90)
0.75 (0.74–0.77)
3.76 (3.73–3.80)

3.44 (3.41–3.48)

0.16 (0.15–0.17)
0.76 (0.75–0.78)

0.73 (0.71–0.74)

of epilepsy with cardiovascular outcomes. A high death rate was

seen in PWE in the cohort; this may reflect that the cohort only
(95% CI)

included hospitalized patients, which may result in a high num-

ber of those with symptomatic epilepsy. As diagnoses were based
on clinical codes, they are subject to misclassification error, and
Events,

31,069
8419

1809
3302
8133
42,446
8617
37,262

therefore patients who may otherwise not have met diagnostic

No epilepsy, n = 571,532

criteria for epilepsy may be included in the analysis; however, the

ICD-10 clinical codes for epilepsy have been demonstrated to
(patient- years)

have high accuracy in health care administrative datasets [36]. The

Person-time

1,084,524
1,126,190
1,127,880
1,117,661
1,119,326
1,128,364
1,128,364
1,082,357

consequences of antiseizure medication use are unaccounted for,

and these are likely to contribute to poorer cardiovascular health
in PWE via effects on cardiac electrophysiology and accelerated
atherosclerotic disease [9, 12, 37]. Patients in the reference group
Cardiovascular death

were not censored if they were subsequently diagnosed with epi-

Ischaemic stroke

lepsy, although these numbers are likely to be small. We were not

All-cause death

Cardiac arrest
Heart failure

able to adjust for shared-risk factors or account for informative

Incident AF
Incident MI
Outcome

censorship. Furthermore, the population studied is a hospitalized

VT/VF

population and does not consider PWE managed in the commu-

nity, or illness or death that occurred in a nonhospital setting. We
EPILEPSY AND CARDIOVASCULAR EVENTS | 9 of 10

used the Fine and Gray model to produce subdistribution hazard DATA AVA I L A B I L I T Y S TAT E M E N T
ratios; this method has a number of limitations, and results should The data used in this study may be available from the corresponding
be interpreted with caution given that patients who died "un- author upon reasonable request.
naturally" remain in the at-risk pool, and therefore a competing
event may falsely protect individuals from the event of interest I N S T I T U T I O N A L R E V I E W B OA R D S TAT E M E N T
[38]. Given the limitations, we only conclude an association be- The study was conducted in accordance with the Declaration of
tween epilepsy and adverse cardiovascular events in hospitalized Helsinki, and approved by an independent national ethics commit-
patients that requires further investigation. tee. Ethical approval was not required, as the study was retrospec-
tive and conducted using anonymized data without direct patient
involvement.
CO N C LU S I O N S
I N FO R M E D C O N S E N T
The prevalence and incident rates of cardiovascular outcomes were Informed consent was not required, as the study was conducted
significantly higher in hospitalized PWE. As cardiovascular disease retrospectively using anonymized data and without direct patient
contributes a significant proportion of morbidity and mortality in involvement.
this population, improving cardiovascular health is an attractive tar-
get to reduce premature deaths in PWE. ORCID
Josephine Mayer https://orcid.org/0000-0002-9662-2845
AU T H O R C O N T R I B U T I O N S Gregory Y. H. Lip https://orcid.org/0000-0002-7566-1626
Josephine Mayer: Writing – original draft; writing – review and Laurent Fauchier https://orcid.org/0000-0002-9267-1658
editing; methodology. Ameenathul M. Fawzy: Writing – original
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