Effects of epilepsy and selected antiepileptic drugs on risk of myocardial infarction, stroke, and death in patients with or without previous stroke: a nationwide cohort study

ORIGINAL REPORT

Effects of epilepsy and selected antiepileptic drugs on risk ofmyocardial infarction, stroke, and death in patients with or withoutprevious stroke: a nationwide cohort study

Jonas Bjerring Olesen1*, Steen Zabell Abildstrøm2,3, Jesper Erdal4, Gunnar H. Gislason1, Peter Weeke1,Charlotte Andersson1, Christian Torp-Pedersen1 and Peter Riis Hansen1

1Department of Cardiology, Copenhagen University Hospital, Gentofte, Denmark2National Institute of Public Health, Copenhagen, Denmark3Department of Cardiology, Copenhagen University Hospital, Bispebjerg, Denmark4Department of Neurology, Copenhagen University Hospital, Herlev, Denmark

ABSTRACTPurpose Patients with epilepsy have increased morbidity and mortality. We evaluated the risk of myocardial infarction (MI), stroke, anddeath associated with epilepsy and examined if this risk was modified by treatment with antiepileptic drugs (AEDs).Methods A cohort consisting of the Danish population was followed from January 1997 to December 2006. The risk of MI, stroke, car-diovascular death, and all-cause death associated with epilepsy was estimated by multivariable Cox proportional hazard models stratified foroccurrence of previous stroke. AED use was determined at baseline, and risks associated with exposure to individual AEDs were examinedin patients with epilepsy.Results In patients without previous stroke, AED-treated epilepsy was associated with an increased risk of MI (hazard ratio [HR], 1.09;95%CI, 1.00–1.19), stroke (HR, 2.22; 95%CI, 2.09–2.36), cardiovascular death (HR, 1.64; 95%CI, 1.57–1.72), and all-cause death (HR,1.92; 95%CI, 1.86–1.97). Compared with carbamazepine monotherapy, valproate was associated with a decreased risk of MI (HR, 0.72;95%CI, 0.59–0.87) and stroke (HR, 0.86; 95%CI, 0.76–0.96), oxcarbazepine and phenobarbital with increased risk of cardiovascular death(HR, 1.10; 95%CI, 1.02–1.19 and HR, 1.08; 95%CI, 1.00–1.17, respectively) and all-cause death (HR, 1.11; 95%CI, 1.05–1.18 and HR,1.18; 95%CI, 1.12–1.25, respectively), and oxcarbazepine with increased risk of stroke (HR, 1.21; 95%CI, 1.10–1.34), in patients withepilepsy.Conclusions Patients with epilepsy exhibit increased risk of MI, stroke, cardiovascular death, and all-cause death. Compared with carba-mazepine monotherapy, valproate may decrease, and oxcarbazepine and phenobarbital may increase, the risk of adverse cardiovascularevents in these patients. Copyright © 2011 John Wiley & Sons, Ltd.

key words—epilepsy; antiepileptic; epidemiology; myocardial infarction; stroke

Received 9 October 2010; Revised 31 March 2011; Accepted 4 May 2011

INTRODUCTION

Patients with epilepsy have increased morbidity andmortality from ischemic heart disease and cerebrovas-cular disease.1,2 Whether this association is caused bya common risk factor (e.g., previous stroke) or if thepathogenesis of epilepsy in itself can increase the risk

of ischemic heart disease and cerebrovascular diseaseremains to be determined. Circulating markers of oxi-dative stress are increased in patients with epilepsy andmay be associated with subclinical atherosclerosis.3

Moreover, previous pharmacological studies have sug-gested that antiepileptic drugs (AEDs) modulate ather-othrombotic risk factors.4–8 For example, a range ofAEDs have been linked to increased levels of homo-cysteine,3,4,7,8 treatment with liver enzyme-inducingAEDs can increase levels of cholesterol and athero-genic lipoproteins,4 carbamazepine can decrease thy-roid hormone concentrations,5,6 and valproate has

*Correspondence to: J. B. Olesen, Department of Cardiology — Post 635,Copenhagen University Hospital Gentofte, Niels Andersens Vej 65, 2900Hellerup, Denmark. E-mail: [email protected]

Copyright © 2011 John Wiley & Sons, Ltd.

pharmacoepidemiology and drug safety 2011; 20: 964–971Published online 18 July 2011 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/pds.2186

been associated with weight gain, insulin resistance,and the metabolic sundrome.4,9 Investigations of therisk of ischemic heart disease and stroke associatedwith individual AEDs are therefore warranted andmay have important consequences for optimal cardio-vascular (CV) risk control in these patients. We there-fore conducted a nationwide study, aiming toinvestigate the effect of epilepsy on myocardial infarc-tion (MI), stroke, CV death, and all-cause death inpatients with or without previous stroke. Furthermore,we investigated the risk associated with individualAEDs in patients with epilepsy.

METHODS

Patients and Registers

All Danish citizens have a unique and permanent civilregistration number by which individual-level linkageof information from nationwide administrative regis-ters is possible. All admissions and discharge diagno-ses from Danish hospitals since 1978 are registered inthe Danish National Patient Register. Each hospitali-zation is registered by one primary and if appropriateone or more secondary diagnoses, which are codedaccording to the International Classification of Dis-eases, the 8th revision (ICD-8) until 1993 and the10th revision (ICD-10) since 1994. The Danish Regis-ter of Medicinal Product Statistics (prescription regis-ter) holds complete and accurate information on allprescriptions dispensed from Danish pharmaciessince 1995.10 Drugs are registered according to the in-ternational Anatomical Therapeutical Chemical (ATC)classification system. Primary and contributing causesof death are registered in the National Causes of DeathRegister based on evaluation of death certificates andthe cancer registers. The Integrated Database for theDanish Labour Market provides information on sub-ject income, highest education level, and socioeco-nomic status.

Study population

The main study cohort comprised all Danish citizensalive and aged10years or older on January 1, 1997.The cohort was followed from January 1, 1997, toDecember 31, 2006 (i.e., patients who were alivewere censored at this date). Patients with epilepsy(ICD-8: 345; ICD-10: G40–G41) diagnosed beforeJanuary 1, 1997, were identified from the DanishNational Patient Register. To examine the associa-tion between the study end points and the individualAEDs, a second study cohort was identified,

comprising patients with epilepsy that had a claimedprescription of any AED from January 1, 1995, toDecember 31, 1996.

Study end points

Information was retrieved on MI, stroke, CV mortality,and all-cause mortality, during the 10-year study pe-riod. MI was defined by either a discharge diagnosisof MI (ICD-10: I21–I22) in the Danish National PatientRegister or by death from MI in the National Causes ofDeath Register. Stroke (primary ischemic) was also de-fined by its respective diagnoses (ICD-10: I63–I64) inthe Danish National Patient Register or the NationalCauses of Death Register. CV mortality was definedas death from a CV cause (ICD-10: I0–I99) registeredin the National Causes of Death Register. All causemortality was defined as death from any cause beforeDecember 31, 2006. Analyses were carried out sepa-rately for the four outcomes; that is, patients experienc-ing two or more of the outcomes during follow-upcontributed with an outcome in more than one of theanalyses. For each outcome analysis, however, patientsexperiencing this particular outcome were not followedbeyond the date of the event. In the analysis of MI andstroke, patients that died from other causes were cen-sored at the time of death.

Medical treatment

Baseline AED use was determined by identifying allclaimed prescriptions in the prescription register fromJanuary 1, 1995, to December 31, 1996, for the followingAEDs (ATC code): carbamazepine (N03AF01), oxcar-bazepine (N03AF02), valproate (N03AG01), phenytoin(N03AB02), phenobarbital (N03AA02), lamotrigine(N03AX09), clonazepam (N03AE01), and clobazam(N05BA09). Gabapentin, primidone, and tiagabinewere also marketed in Denmark in this period; but be-cause of infrequent usage and low persistence rates,these drugs were not included in the study. Pregabalin,levetiracetam, and topiramate were not marketed inDenmark at the time of baseline exposure.Baseline use of concomitant medications at any time

in the period from January 1, 1995, to December 31,1996, was also identified for the following drugs: beta-blockers (C07), ACE inhibitors (C09), spironolactone(C03D), loop diuretics (C03C), statins (C10AA), calciumchannel blockers (C08), digoxin (C01A), vitamin-Kantagonists (B01AA), antiplatelet drugs (B01AC), anti-depressants (N06A), antipsychotics (N05A), and anti-diabetic drugs (A10).

risk of cardiovascular disease with epilepsy and antiepileptic drugs 965

Copyright © 2011 John Wiley & Sons, Ltd. Pharmacoepidemiology and Drug Safety, 2011; 20: 964–971DOI: 10.1002/pds

Comorbidity and socioeconomic status

Information on a previous discharge diagnosis ofMI (ICD-8: 410; ICD-10: I21–I22), stroke (ICD-8:430–438; ICD-10: I60–I69), and psychiatric disease(ICD-8: 290–315; ICD-10: F00–F99) was obtained fromthe Danish National Patient Register. The Charlson’sComorbidity Index,11 modified for ICD-10,12,13 wasused to define comorbidity. In order to further enhancethe discriminative power of this index, we included ap-propriate discharge diagnoses from all hospitalizationsobtained up to one year before January 1, 1997, asdone previously.14–16 Socioeconomic status was de-fined by the individual average annual gross incomeduring the five-year period from 1992 to 1996.Patients were divided into tertiles according to theirincome, as described previously.17 Information oncivil status (i.e., living alone or not) was obtained onJanuary 1, 1997.

Statistical analyses

To estimate the risk of MI, stroke, CV death, and all-cause death associated with epilepsy, we used multi-variable Cox proportional hazard models. The totalDanish population aged10years or older on January1, 1997, was entered into the analysis. A significantinteraction was found between previous stroke andepilepsy ( p<0.001 for all end points other than MI;p=0.11 for MI); and therefore, the final analysis wasstratified for previous stroke. Furthermore, in themodel, we subgrouped patients with epilepsy intothose treated and not treated with AEDs.Antiepileptic drug persistence was assessed by

identifying the proportion of the patients alive andclaiming a prescription for their respective baselineAED at 5 and 10years of follow-up, that is, in 2001and 2006, a method described in detail previously.18

The risk of MI, stroke, CV death, and all-cause deathassociated with baseline use of the different AEDswas estimated by multivariable Cox proportional haz-ard models in the cohort of patients with epilepsy.Monotherapy with carbamazepine was chosen as thereference because carbamazepine is a traditionalAED with wide indications, and it was the most fre-quently used AED in the cohort.The Cox regression models were adjusted for gender,

age, previousMI, previous stroke (only the nonstratifiedmodels), psychiatric disease, concomitant medication,income, and comorbidity. Model assumptions (i.e., pro-portional hazards, linearity of continuous variables, andlack of interactions) were found to be valid unless other-wise indicated. For all analyses, a two-sided P < 0.05was considered statistically significant. All statistical

analyses were performed with SAS, version 9.1 (SASInstitute Inc., Cary, NC, USA).

Ethics

No ethical approval is required for retrospective registerstudies in Denmark. The study was approved by TheDanish Data Protection Agency (No. 2003-54-1269).

RESULTS

The main cohort comprised 4 614 807 individuals.From 1978 to 1996, epilepsy was diagnosed in 54693 (1.2%) individuals, of whom 25 488 (46.6%) usedan AED in the period 1995–1996. A total of 76 893(1.7%) individuals had a previous MI, and 85 073(1.8%) individuals had a previous stroke. All baselinecharacteristics are displayed in Table 1.

Risk of MI, stroke, CV death, and all-cause deathassociated with epilepsy

Results from crude and multivariable Cox proportional-hazard analyses are displayed in Table 2. In patientswithout previous stroke, epilepsy was associated withan increased risk of MI, stroke, CV death, and all-cause death (Table 2). In patients with epilepsy andno previous stroke, the risk of MI was not significantlydifferent between patients treated with and withoutAEDs ( p=0.39); however, the risk of stroke, CVdeath, and all-cause death was increased in patientstreated with AEDs (all p-values<0.0001).In patients with previous stroke compared with

patients without epilepsy, AED-treated epilepsy wasassociated with an increased risk of stroke, CV death,and all-cause death (all p-values<0.0001); but AED-treated epilepsy did not increase the risk of MI ( p=0.17). Furthermore, in patients with previous stroke,non–AED-treated epilepsy was associated with in-creased risks of stroke ( p=0.0006) and CV death( p=0.02), while the risks of MI ( p=0.41) and all-cause death ( p=0.56) were not increased comparedwith those in patients without epilepsy.

Risk associated with individual AEDs

Baseline characteristics of the 25 488 patients withepilepsy and baseline use of AEDs are displayed inTable 1. In this study population, 18 039 (70.8%) onlyreceived one AED. The mean 5-year and 10-year AEDtreatment persistence rates were 62.7% and 53.2%, re-spectively. The frequency of patients claiming a pre-scription for their baseline AED within 6 monthsbefore they experienced a study end point was 62.1%

j. b. olesen ET AL.966


for MI, 64.5% for stroke, 62.7% for CV death, and62.0% for all-cause death.The multivariable Cox proportional hazard models

demonstrated a decreased risk of MI (HR 0.72, 95%CI 0.59–0.87) and stroke (HR 0.86, 95%CI 0.76–0.96) associated with valproate compared with carba-mazepine monotherapy (Table 3). There was no differ-ence in the risk of all-cause death between the two drugs( p=0.99). Oxcarbazepine was associated with signifi-cantly increased risk of stroke, CV death, and all-causedeath compared with carbamazepine (Table 3). Pheno-barbital was associated with increased risk of CVdeath and all-cause death (Table 3). Lamotrigineshowed a trend towards lowered risk of stroke (HR,0.88; 95%CI, 0.76–1.03; p=0.12) and CV death(HR, 0.85; 95%CI, 0.74–0.97; p=0.02) compared withcarbamazepine (Table 3).

Sensitivity and corroborative analyses

We analysed the risk associated with monotherapywith individual AEDs and with AED combinations(AED polytherapy) in the cohort of AED-treatedpatients with epilepsy. For the individual AEDs, wefound results that were concordant with those of the

main analyses (not shown), whereas polytherapy in-creased the risk of all-cause death (HR, 1.14; 95%CI,1.07–1.21).Furthermore, in the population of AED-treated

patients with epilepsy, we performed a set of multivar-iable Cox proportional-hazard analyses with the indi-vidual AED treatments analysed as time-dependentexposure-covariates; that is, enabling patients to shift,initiate, and terminate AED treatment, as described indetail previously.15,16 Compared with carbamazepine,the risk of MI was decreased with valproate; the riskof stroke was increased with oxcarbazepine, phenobar-bital, and clobazam; the risk of CV death was increasedwith oxcarbazepine, valproate, and phenobarbital; therisk of all-cause death was increased with oxcarbaze-pine, valproate, phenobarbital, and clonazepam; andthe risk of stroke and CV death was decreased withphenytoin.Finally, we performed a Cox regression analysis on

the total Danish population. Compared with a refer-ence population that did not use an AED at baselineand did not have epilepsy, we evaluated the risk asso-ciated with epilepsy and specific baseline AED treat-ment. Epilepsy and treatment with carbamazepinewas associated with increased risk of MI (HR, 1.17;

Table 1. Baseline characteristics of the study populations

Population without epilepsy* AED-treated patients with epilepsy Non–AED-treated patients with epilepsy

n (mean age�SD) 4 560 114 (44.3�19.9) 25 488 (46.6�19.8) 29 205 (36.6�19.8)Men (mean age�SD) 2 237 689 (43.0�19.1) 13 125 (46.2�19.4) 15 221 (35.8�19.1)Women (mean age�SD) 2 322 425 (45.5�20.6) 12 363 (47.1�20.2) 13 984 (37.5�20.5)Previous MI* (%) 75 498 (1.7) 795 (3.1) 600 (2.1)Previous stroke* (%) 78 982 (1.7) 4 173 (16.4) 1 918 (6.6)Living alone (%) 1 543 034 (33.8) 13 220 (51.9) 12 471 (42.7)Charlson’s Comorbidity IndexScore 0 4 420 976 (97.0) 22 894 (89.8) 27 752 (95.0)Score 1–2 118 971 (2.6) 2 233 (8.8) 1 226 (4.2)Score 3–4 14 172 (0.3) 287 (1.1) 176 (0.6)Score>4 5 995 (0.1) 74 (0.3) 51 (0.2)

Use of CV medications† (%) 598 614 (13.1) 6 171 (24.2) 3 966 (13.6)Use of antidepressants† (%) 216 249 (4.7) 2 889 (11.3) 2 161 (7.4)Use of antipsychotics† (%) 134 219 (2.9) 2 783 (10.9) 1 730 (5.9)Use of glucose-lowering drugs† (%) 81 657 (1.8) 682 (2.7) 619 (2.1)AEDs†

Carbamazepine (%) 16 254 (0.4) 9 934 (39.0)Oxcarbazepine (%) 5 349 (0.1) 6 511 (25.6)Valproate (%) 7 272 (0.2) 6 760 (26.5)Phenytoin (%) 2 043 (0.0) 2 064 (8.1)Phenobarbital (%) 7 945 (0.2) 3 996 (15.7)Lamotrigine (%) 1 366 (0.0) 3 448 (13.5)Clonazepam (%) 6 354 (0.1) 1 630 (6.4)Clobazam (%) 3 781 (0.1) 1 010 (4.0)Monotherapy with an AED (%) 40 142 (0.9) 18 039 (70.8)

*Diagnosed in the period 1978–1996.†Prescriptions claimed in the period 1995–1996.AED, antiepileptic drug; CV, cardiovascular; MI, myocardial infarction.



95%CI, 1.05–1.30), whereas epilepsy and treatmentwith valproate was associated with decreased risk ofMI (HR, 0.80; 95%CI, 0.66–0.95), as compared withindividuals without epilepsy not treated with AED atbaseline. All combinations of epilepsy and AED treat-ment were significantly associated with increased riskof stroke, CV death, and all-cause death except for ep-ilepsy and lamotrigine, where there was no differencein the risk of stroke and CV death.

DISCUSSION

We found that epilepsy was associated with increasedrisk of MI in patients without a history of stroke, but thatepilepsy had no independent effect on the risk of MI inpatients with a history of stroke. Furthermore, epilepsywas associated with increased risk of stroke, CV death,and all-cause death both in patients with and without ahistory of stroke. Our analyses also demonstrated thatvalproate was associated with a lower risk of MI andstroke compared with carbamazepine monotherapy,whereas oxcarbazepine was associated with increasedrisk of stroke, and oxcarbazepine and phenobarbitalwere associated with increased risk of CV death andall-cause death. The risk of CV death associated withlamotrigine was decreased, whereas risks of all exam-ined end points with phenytoin, clonazepam, and

clobazam were not significantly different from therisk associated with carbamazepine monotherapy.Our findings of increased risk of MI and stroke in

patients with epilepsy are in concordance with previ-ous results.1,2,19 A common pathophysiological sub-strate (e.g., atherothrombosis) is likely to contributeto this finding, and a relationship between CV risk fac-tors (e.g., cholesterol levels and left ventricular hyper-trophy) and risk of late-onset epilepsy has also beensuggested.20 Furthermore, CV risk factors and ele-vated levels of circulating markers of oxidative stressare more prevalent in patients with epilepsy than inthe general population.3,21 Indeed, we found that therisk of adverse CV outcomes and all-cause death wasincreased in patients with epilepsy without previousstroke. The high risk of stroke, CV death, and all-cause death associated with epilepsy in patients withprevious stroke suggests that the presence of epilepsyin patients with previous stroke can be viewed as amarker of increased atherothrombotic risk.

Pathophysiological mechanisms linking AEDs withcardiovascular disease

Several studies have reported that liver cytochromeP-450 enzyme induction by carbamazepine can

Table 2. Risks associated with epilepsy* and previous stroke*

MI Stroke CV death All-cause death

Subjects without previous strokeNo epilepsyCrude HR (95%CI){ 1.00 1.00 1.00 1.00Multivariable HR (95%CI)} 1.00 1.00 1.00 1.00

AED†�treated epilepsyCrude HR (95%CI){ 1.23 (1.13–1.34) 2.59 (2.44–2.75) 2.05 (1.95–2.14) 2.72 (2.64–2.79)Multivariable HR (95%CI)} 1.09 (1.00–1.19) 2.22 (2.09–2.36) 1.64 (1.57–1.72) 1.92 (1.86–1.97)

Non–AED†-treated epilepsyCrude HR (95%CI){ 1.36 (1.24–1.48) 1.89 (1.76–2.04) 1.80 (1.70–1.90) 2.14 (2.06–2.21)Multivariable HR (95%CI)} 1.15 (1.06–1.26) 1.58 (1.47–1.70) 1.42 (1.35–1.50) 1.50 (1.45–1.55)

Subjects with previous strokeNo epilepsyCrude HR (95%CI){ 2.23 (2.20–2.25) 3.47 (3.42–3.53) 2.33 (2.31–2.36) 1.93 (1.91–1.95)Multivariable HR (95%CI)} 1.28 (1.25–1.31) 2.66 (2.62–2.71) 1.69 (1.67–1.71) 1.37 (1.36–1.39)

AED†�treated epilepsyCrude HR (95%CI){ 1.95 (1.76–2.16) 6.29 (5.93–6.67) 3.88 (3.71–4.06) 2.94 (2.83–3.05)Multivariable HR (95%CI)} 1.38 (1.25–1.53) 4.62 (4.36–4.90) 2.66 (2.54–2.78) 1.79 (1.72–1.86)

Non–AED†-treated epilepsyCrude HR (95%CI){ 1.73 (1.49–2.02) 4.23 (3.84–4.66) 2.72 (2.52–2.93) 2.25 (2.11–2.39)Multivariable HR (95%CI)} 1.20 (1.03–1.40) 3.16 (2.86–3.48) 1.85 (1.72–2.00) 1.40 (1.31–1.49)

*Diagnosed in the period 1978–1996.†Prescriptions claimed in the period 1995–1996.{Adjusted for gender and age.}Adjusted for gender, age, previous MI, psychiatric disease, concomitant medication, income, and comorbidity.Results from Cox proportional hazard models. AED, antiepileptic drug; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction.



contribute to elevated levels of homocysteine and ath-erogenic lipoproteins including lipoprotein(a),3,7,8,22–25

in conjunction with a decrease of folate and thyroidhormone levels,5,6,8 all of which may contribute toCV risk. Oxcarbazepine bears close pharmacologicalresemblance to carbamazepine, and phenobarbitaland phenytoin are also liver enzyme inducers thatmay have proatherogenic effects by increasing homo-cysteine levels.7,8 At present, however, the reasonsunderlying our current findings that phenobarbitaland oxcarbazepine were associated with increased risk

of stroke, CV death, and all-cause death comparedwith carbamazepine, while no significant differencesin adverse CV outcomes were observed between phe-nytoin and carbamazepine, are not clear.Lamotrigine is devoid of liver enzyme-inducing

activity and recent evidence has indicated that switch-ing from carbamazepine or phenytoin to lamotrigine(or levetiracetam) can lead to rapid and clinicallysignificant decrease in serological markers of in-creased atherothrombotic risk (i.e., total cholesterollevels, triglycerides, C-reactive protein, lipoprotein(a),and homocysteine).24 Whether these effects contrib-uted to the observed reduced risk of CV death withlamotrigine compared with carbamazepine requiresfurther study.Valproate is a liver enzyme inhibitor, and it was re-

cently suggested that this agent can diminish experimen-tal atherosclerosis by inhibition of glycogen synthasekinase-3, a mitogen and growth factor-regulated serine/threonine kinase implicated in promotion of apoptosisand activation of nuclear factor-kB.26 Moreover, valpro-ate can attenuate left ventricular remodelling in animalmodels of MI by mechanisms involving inhibition ofhistone deacetylase, an enzyme involved in controlof gene expression.27 On the other hand, limited clini-cal evidence has indicated that valproate may ad-versely influence the CV risk profile (e.g., bynegative microcapillary effects and induction of insulinresistance).8,9,23 Irrespective of mechanisms involved,our findings are suggestive of a net protective effectof valproate on the CV risk profile, as comparedwith patients treated with carbamazepine. Indeed,the finding that patients with epilepsy and baselinevalproate treatment also had a decreased risk ofMI compared with individuals without epilepsyand no baseline AED treatment is in alignment withprevious findings.16

We observed no differences in risk of adverse CVevents with the benzodiazepines clonazepam and clo-bazam as compared with carbamazepine monotherapy(Table 3). In therapeutic antiepileptic doses, theseagents have more sedative and hypnotic propertiesthan other AEDs; and it is possible that patients withpsychiatric comorbidities were more likely to receivethese agents. Smoking rates are known to be excep-tionally high among individuals with psychiatric dis-eases, and this unmeasured confounder may haveaffected the results.28

Study strengths and limitations

The main strength of the study was that it was basedon nationwide and complete data. Our study had no

Table 3. Risks associated with individual AEDs in patients with epilepsy*

MI Stroke CV deathAll-causedeath

Carbamazepine†

Crude HR 1.00 1.00 1.00 1.00Multivariable HR 1.00 1.00 1.00 1.00

Oxcarbazepine†

Crude HR(95%CI){

1.09(0.93–1.28)

1.42(1.29–1.57)

1.24(1.14–1.34)

1.18(1.12–1.25)

Multivariable HR(95%CI)}

1.00(0.85–1.17)

1.21(1.10–1.34)

1.10(1.02–1.19)

1.11(1.05–1.18)

Valproate†

Crude HR(95%CI){

0.72(0.59–0.87)

0.88(0.78–0.99)

0.97(0.89–1.07)

1.02(0.96–1.09)


0.72(0.59–0.87)

0.86(0.76–0.96)

0.95(0.87–1.04)

1.00(0.94–1.07)

Phenytoin†

Crude HR(95%CI){

0.98(0.81–1.19)

0.87(0.76–0.99)

0.93(0.84–1.02)

1.01(0.94–1.09)


1.03(0.85–1.25)

0.96(0.84–1.10)

1.01(0.91–1.11)

1.00(0.93–1.07)

Phenobarbital†

Crude HR(95%CI){

0.93(0.79–1.10)

1.10(1.00–1.22)

1.13(1.04–1.21)

1.32(1.25–1.39)


0.95(0.80–1.12)

1.07(0.97–1.19)

1.08(1.00–1.17)

1.18(1.12–1.25)

Lamotrigine†

Crude HR(95%CI){

0.97(0.76–1.24)

0.89(0.76–1.04)

0.83(0.73–0.96)

0.93(0.86–1.02)


0.99(0.77–1.26)

0.88(0.76–1.03)

0.85(0.74–0.97)

0.95(0.88–1.04)

Clonazepam†

Crude HR(95%CI){

1.11(0.82–1.50)

1.14(0.95–1.37)

1.13(0.97–1.32)

1.28(1.16–1.41)


1.06(0.78–1.44)

1.11(0.92–1.34)

1.07(0.92–1.25)

1.08(0.98–1.20)

Clobazam†

Crude HR(95%CI){

0.93(0.58–1.49)

1.03(0.78–1.35)

1.00(0.78–1.27)

1.10(0.95–1.28)


0.99(0.62–1.59)

1.10(0.84–1.45)

1.08(0.85–1.38)

1.07(0.93–1.24)

*Diagnosed in the period 1978–1996.†Prescriptions claimed in the period 1995–1996.{Adjusted for gender and age.}Adjusted for gender, age, previous MI, psychiatric disease, concomitant med-ication, income, and comorbidity.Results from Cox proportional hazard models.Monotherapy with carbamazepine was the reference.AED, antiepileptic drug; CV, cardiovascular; HR, hazard ratio; MI,myocardial infarction.



selection bias related to age, gender, race, socioeco-nomic status, job situation, or participation in specifichealthcare programs. A discharge diagnosis of epilepsyhas previous been validated in the Danish National Pa-tient Register, with a positive predictive value of81%.29 The specificity of the diagnosis is likely to beeven higher in patients with concomitant use of AEDs.Moreover, MI and stroke diagnoses have been vali-dated in the register, with a positive predictive valueof 92% and a sensitivity of 91% for MI,30 and a posi-tive predictive value of 97% for ischemic stroke (ICD-10: I63).31 Hemorrhagic strokes only comprised 5.8%of the unspecified strokes (ICD-10: I64).31

The main study limitation was its observational na-ture. For example, we had no information on the pre-cise indication for initiation of AED treatment, con-traindications for specific AEDs, reasons forchoosing a specific AED, and the type or severity ofepilepsy in individual patients. We analysed the riskassociated with epilepsy diagnosed at baseline andAED exposure at baseline; that is, patients who devel-oped epilepsy and patients who stopped their initialtreatment during the study period were analysedaccording to their baseline status throughout the pe-riod. This method was applied because of the rela-tively few individuals in the control population thatdeveloped epilepsy during the study period (0.08%per year) and the high AED treatment persistencerates. Furthermore, sensitivity analyses with AEDtreatment analysed as a time-dependent exposure cov-ariates yielded similar results. We were not able to ad-just the analyses for treatment duration at baseline be-cause we only had information on prescription claimsfrom 1995 and forth. There is also a risk of unmea-sured confounders; for example, we were not able toaccount for effects of smoking, a family history ofCV diseases, physical activity, alcohol intake, diethabits, or body mass index. For example, bodyweightgain is a frequent side effect of anticonvulsive drugs(e.g., valproate and carbamazepine), and baseline dif-ferences in bodyweight may have influenced the AEDdrug selection.32 If, for example, valproate-treatedpatients were selected according to a lower body massindex at baseline (e.g., in anticipation of an ensuingweight gain), this could contribute to the lower CVrisk found with the agent. Furthermore, no analysesof effects of specific AED combinations (AED poly-therapies) were performed because of insufficient sta-tistical power. However, we found no significantinteractions between different AEDs, and the concor-dant results of our monotherapy sensitivity analysesindicated that the results did not significantly reflecteffects of AED polytherapy.

CONCLUSIONS

In this nationwide register study, we found thatpatients with epilepsy had increased risk of MI, stroke,CV death, and all-cause death. The risk of stroke, CVdeath, and all-cause death was further increased by ep-ilepsy in patients with previous stroke, but epilepsywas not an independent risk factor for MI in thesepatients. In patients with epilepsy, treatment withvalproate was associated with a decreased risk of MIand stroke, whereas oxcarbazepine and phenobarbitalwere associated with an increased risk of the examinedadverse CV events, compared with carbamazepinemonotherapy. The results also suggested that inpatients with epilepsy, valproate may decrease the riskof MI, compared with individuals without epilepsy.The mechanisms underlying these findings require fur-ther investigation.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

KEY POINTS

• Epilepsy is a moderate cardiovascular risk factorboth in patients with and without previous stroke.

• The choice of antiepileptic treatment alters therisk of cardiovascular events.

• Valproate decreases the risk of myocardial in-farction compared with other antiepileptic drugs.

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Effects of epilepsy and selected antiepileptic drugs on risk of myocardial infarction, stroke, and death in patients with or without previous stroke: a nationwide cohort study