Research

JAMA Psychiatry | Original Investigation

Association of Secondary Preventive Cardiovascular

Treatment After Myocardial Infarction With Mortality
Among Patients With Schizophrenia
Pirathiv Kugathasan, MSc; Henriette Thisted Horsdal, MSc, PhD; Jørgen Aagaard, MD, DMSc;
Svend Eggert Jensen, MD, PhD; Thomas Munk Laursen, MSc, PhD; René Ernst Nielsen, MD, PhD

Editorial page 1215

IMPORTANCE Cardioprotective medication use is an important secondary preventive
treatment after cardiovascular events. Patients with schizophrenia have excess
cardiovascular morbidity and mortality, but no studies have investigated whether taking
recommended cardioprotective medication can reduce this excess mortality.

OBJECTIVE To assess the association of exposure to secondary cardiovascular treatment with

all-cause mortality after myocardial infarction among patients with schizophrenia compared
with the general population.

DESIGN, SETTING, AND PARTICIPANTS This nationwide cohort study included individuals
admitted with first-time myocardial infarction in Denmark from January 1, 1995, to December
31, 2015. The cohort was dichotomously divided by a diagnosis of schizophrenia. Data on the
prescription of guideline-recommended cardioprotective medication, including
antithrombotics, β-blockers, vitamin K antagonist, angiotensin-converting enzyme inhibitors,
and statins, were obtained from the nationwide registries.

EXPOSURES Time exposed to cardioprotective medication.

MAIN OUTCOMES AND MEASURE Cox proportional hazards regression was used to calculate
hazard ratios (HRs) with 95% CIs for the association between treatment exposure and all-cause
mortality after myocardial infarction between patients with and without schizophrenia.

RESULTS The cohort included 105 018 patients with myocardial infarction, including 684
patients with schizophrenia (0.7%; 483 male [70.6%]; mean [SD] age at diagnosis, 57.3 [10.6]
years) and 104 334 general population patients (99.3%; 73 454 male [70.4%]; mean [SD] age
at diagnosis, 61.0 [10.6] years), with a total follow-up of 796 435 person-years and 28 059
deaths. Patients diagnosed with schizophrenia who did not receive cardioprotective
treatment had the highest mortality rate (HR, 8.78; 95% CI, 4.37-17.64) compared with the
general population treated, with treated patients diagnosed with schizophrenia having an
increased HR of 1.97 (95% CI, 1.25-3.10). The analyses of the associations of different cardiac
therapy strategies with mortality rates revealed that patients with schizophrenia who were
treated with any combination of triple therapy had mortality rates similar to those observed Author Affiliations: Department of
in the general population (HR, 1.05; 95% CI, 0.43-2.52) in the multivariable analysis. Psychiatry, Aalborg University
Hospital, Aalborg, Denmark
(Kugathasan, Aagaard, Nielsen);
CONCLUSIONS AND RELEVANCE Cardioprotective medication after myocardial infarction Department of Clinical Medicine,
should be carefully managed to improve prognosis. The study results suggest that some of Aalborg University, Aalborg, Denmark
(Kugathasan, Aagaard, Jensen,
the increased cardiac mortality among patients with schizophrenia can be reduced if these
Nielsen); National Centre for
patients are efficiently administered combinations of secondary preventive treatments after Register-Based Research, University
cardiac events. of Aarhus, Aarhus, Denmark (Horsdal,
Laursen); Department of Cardiology,
Aalborg University Hospital, Aalborg,
Denmark (Jensen).
Corresponding Author: Pirathiv
Kugathasan, MSc, Department of
Psychiatry, Aalborg University
Hospital, Mølleparkvej 10,
JAMA Psychiatry. 2018;75(12):1234-1240. doi:10.1001/jamapsychiatry.2018.2742 9000 Aalborg, Denmark
Published online October 24, 2018. Corrected on May 1, 2019. (p.kugathasan@rn.dk).

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 Cardiovascular Treatment and Mortality in Post–Myocardial Infarction Patients With Schizophrenia
C
ardiovascular disease, including ischemic heart dis-
ease and stroke, is the leading cause of death worldwide.1
Deaths from cardiovascular disease have decreased dur-
ing the past decades, especially in Western Europe, North
America, and Japan.2 This decrease in cardiovascular death is be-
lieved to be a result of multiple factors, including improvement
in lifestyle behavior (eg, smoking cessation, physical activity, and
balanced diet), implementation of interventional cardiologic pro-
cedures (eg, coronary artery bypass grafting and percutaneous
coronary intervention [PCI]), and increases in prophylactic car-
diovascular treatment (antithrombotics, β-blockers, angiotensin-
converting enzyme inhibitors [ACEIs], and statins).3
Patients with schizophrenia have an excess cardiac mortal-
ity, which contributes to a shortened life expectancy of 15 to 20
years compared with the general population.4,5 Studies6,7 on sur-
vival after ischemic heart disease have reported worse outcomes
in patients with schizophrenia compared with people without
mental illness. The causes of the differences in outcome are un-
clear, although earlier findings suggest deficits in quality of medi-
cal care and fewer cardiac interventions performed in patients
with schizophrenia compared with the general population.8-10 Re-
cent studies6,11 indicate that patients with schizophrenia who re-
ceive cardiac revascularization procedures have poorer outcome
afterischemicheartdisease,andarecentDanishpopulation-based
study11 found that patients with severe mental illness (SMI) are
less likely to receive recommended, long-term, secondary pre-
ventive medications after PCI; this finding is further supported
by a study12 that found no differences in short-term mortality
but an increased long-term mortality rate after ischemic heart dis-
ease in patients with schizophrenia compared with the general
population.
Takingrecommendedcardioprotectivemedicationaftermyo-
cardial infarction (MI) reduces hospital admissions,13 health care
costs, and all-cause mortality in patients without psychiatric
conditions.14 Studies11,15 on the prescription rate of cardioprotec-
tive medication in patients with SMI have been limited, and no
studies have examined the association of prophylactic cardiac
treatment exposure with mortality rates after MI in patients with
schizophrenia compared with the rates in the general population.
In the current study, we investigated the association of second-
ary preventive cardiovascular treatment with all-cause mortal-
ity after MI in patients with schizophrenia compared with those
without schizophrenia using the Danish nationwide health care
registries.
Methods
Study Population
This nationwide, retrospective cohort study included all indi-
viduals admitted with first-time MI (International Statistical
Classification of Diseases and Related Health Problems, Tenth
Revision [ICD-10] code I21) in Denmark from January 1, 1995, to
December 31, 2015, identified from the Danish National Patient
Registry (NPR). The NPR covers all somatic hospitalizations from
January 1, 1977, to December 31, 1994, and from January 1, 1995,
onward, covering all somatic and psychiatric inpatient and out-
patient contacts with all public hospitals in Denmark.16 Persons
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Original Investigation Research
Key Points
Question Is use of cardioprotective medication after myocardial
infarction associated with reduced mortality rates among patients
with schizophrenia?
Findings In this Danish nationwide cohort study of 105 018
patients with myocardial infarction, patients with schizophrenia
who were not exposed to cardioprotective medication had an
excess mortality rate; however, exposure to medication was
associated with a reduced mortality.
Meaning The increased cardiovascular mortality among patients with
schizophreniawasreducedinthecurrentstudyifpatientswereefficiently
administered cardioprotective treatment after cardiac events.
in the NPR with a diagnosis of MI (International Classification of
Diseases, Eighth Revision [ICD-8] code 410 or ICD-10 code I21) be-
fore 1995 were excluded from the study population to include only
patients with incident MI in this study. The Danish Data Protec-
tion Agency and the National Board of Health approved the use
of the data. Retrospective studies do not require ethical approval
in Denmark. All data were deidentified.
From the initial sample, we established a cohort of patients
with a previous diagnosis of schizophrenia, defined as an ICD-8
or ICD-10 code of 295 or a Danish Psychiatric Central Research Reg-
ister (DPCRR) or NPR code of F20. The DPCRR was established
in 1969 and contains information on every psychiatric inpatient
hospitalization from January 1, 1969, to December 31, 1994, and
from January 1, 1995, onward, covering all inpatient and outpa-
tient contacts with all psychiatric hospitals in Denmark.17 The re-
maining patients with MI from the cohort served as controls rep-
resenting patients with MI in the general population. Incident
cases of schizophrenia after MI diagnosis in the control cohort
were excluded from the analyses. We excluded patients younger
than 30 years who had an MI to minimize inclusion of patients
with potential congenital heart defects.
Drug Exposure
From the NPR, we identified all dispensed prescriptions for
guideline-recommended secondary preventive treatments after
MI using the Anatomical Therapeutic Chemical (ATC) code in
agreement with the World Health Organization.18 Data on every
dispensed prescription, including dispensing date, defined daily
dose, and the total amount of pills dispensed, are available from
January 1, 1995, in the NPR for the entire Danish population.19
We defined 5 therapeutic drug groups: antiplatelets (ATC code
B01AC), vitamin K antagonists (ATC codes B01AA, B01AE, and
B01AF), β-blockers (ATC code C07), ACEIs (ATC code C09), and
statins (ATC codes C10). Because of the natural progress of change
in treatment regimens during follow-up, we allowed patients to
switch among therapeutic groups at any time.
The treatment exposure groups were created as time-varying
covariates. We assumed the use of 1 defined daily dose per day
with a grace period of 14 days. The grace period was introduced
to allow for some degree of nonadherence and for irregular dis-
pensing attributable to stockpiling. Periods of concomitant treat-
ment were collapsed to coherent periods during the follow-up.
For each individual, we defined exposed and unexposed periods
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 Research Original Investigation Cardiovascular Treatment and Mortality in Post–Myocardial Infarction Patients With Schizophrenia
during the entire follow-up period, and these periods where used
in the calculation of hazard ratios (HRs) for mortality estimates.
Monotherapy was defined as treatment periods with use of
one of the previously described treatment groups. Dual therapy
was defined as 2 overlapping periods of concurrent treatments,
whereas triple therapy was defined as 3 or more overlapping treat-
ment periods. Patients were allowed to switch groups at any time
during the follow-up, according to the use of time-varying covar-
iates in the Cox proportional hazards regression model.
Outcome Measures
The primary study outcome was time to all-cause mortality using
time of medication exposure as a time-dependent covariate. Mor-
tality data were retrieved from the Danish Causes of Death Reg-
ister, which contains data on age of death and underlying cause
of death.20 The discharge date of the MI hospitalization was used
as the index date. All individuals were followed up from the time
of index until the time of death or until December 31, 2015, which-
ever came first. Patients were allowed to initiate and discontinue
use of medications throughout follow-up and thus change expo-
sure status during the study period. The secondary outcome was
time to all-cause mortality, comparing exposure to monotherapy,
dual therapy, and triple therapy in patients diagnosed or not di-
agnosed with schizophrenia.
Covariates
This study included the demographic covariates sex, age, and cal-
endar year of the index date. The number of MI readmissions af-
ter index were divided into 0, 1, or 2 or more. Furthermore, we
defined patients who had received PCI according to the Danish
health care classification system codes KFNG02 and KFNG05.
Cardiovascular Risk Factors
Patients were defined as having diabetes if they had a registered
ICD-8 diagnosis code of 249 or 250 or an ICD-10 diagnosis code
of E10 to E14 (diabetes). In addition, patients who claimed pre-
scriptions for glucose-lowering drugs (ATC code A10B or A10XA)
or insulins (ATC code A10A) without a registered diagnosis in the
NPR were also considered as having diabetes because patients
treated by the general practitioner are not registered in the NPR.
Patients who had a registered ICD-8 diagnosis code of 491 or 492,
an ICD-10 diagnosis code of J41 to J44, or any prescription of drugs
for chronic obstructive pulmonary disease (COPD) (ATC code R03)
were considered to have COPD. We defined hypertension as an
ICD-8 diagnosis code of 400 to 404, ICD-10 diagnosis code of I10
to I15, or prescriptions for antihypertensives (ATC code C02),
diuretics (ATC code C03) (except loop diuretics [code C03C]), or
calcium antagonists (ATC code C08) (except verapamil hydro-
chloride [code C08DA01] and diltiazem hydrochloride [code
C08DB01]). We also included substance abuse (ie, alcohol-related
[ICD-10 code F10.x] or drug-related substance abuse [ICD-10 codes
F11.x-F19.x]), excluding tobacco abuse (ICD-10 code F17.x), as ex-
planatory variables.
Statistical Analysis
Descriptive analysis of the study population’s demographics and
illness history was initially conducted. The frequency and distri-
bution of patient characteristics were described by calculating
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means (SDs) for continuous variables and numbers (percentages)
for categorical variables.
The primary analysis was a Cox proportional hazards regres-
sion model that evaluated all-cause mortality using drug expo-
sure as defined previously as a time-varying covariate. We ad-
justed for sex, year of birth, age at MI, calendar year, and PCI in
the first adjusted model and then further adjusted for substance
abuse, diabetes, COPD, and hypertension in the second adjusted
model. We calculated unadjusted and adjusted HRs and their 95%
CIs by using treated patients from the general population as ref-
erence and compared these data with those of patients diagnosed
with schizophrenia.
The secondary outcome was the association of each thera-
peutic class from the guideline-recommended secondary preven-
tive treatments using a Cox proportional hazards regression model
with specific therapy exposure as a time-varying covariate. We
used triple therapy in patients from the general population as a
reference because this protocol is currently recommended in
the Danish guidelines of treatment after MI (depending on risk
profile).
The assumption for linearity in the Cox proportional hazards
regression was met in the primary and secondary analyses. The
significance level was defined as 2-sided P < .05. Statistical analy-
ses were performed with Stata statistical software, version 14
(StataCorp) at the Statistics Denmark server with remote access.
Sensitivity Analysis
We evaluated the role of prior exposure to any of those medica-
tions investigated because many patients might already have ini-
tiated the treatment before incident MI. Thus, we applied the pri-
mary analysis considering only patients who were naive to these
medications at the time of MI and started the follow-up from 1996
(because we did not have data on prior medication use for patients
included in 1995). In addition, we compared patients with
schizophrenia with all others experiencing an MI excluding all
with any previous psychiatric diagnosis (comparing patients di-
agnosed with schizophrenia with a group of psychiatrically
healthy persons).
Results
Population Characteristics
The cohort included 105 018 patients with MI, including 684 pa-
tients with schizophrenia (0.7%; 483 male [70.6%]; mean [SD] age
at diagnosis, 57.3 [10.6] years) and 104 334 general population pa-
tients (99.3%; 73 454 male [70.4%]; mean [SD] age at diagnosis,
61.0 [10.6] years), yielding 3827.09 and 792 608.14 person-years
of follow-up, respectively. The proportion of individuals readmit-
ted with MI was higher in the general population compared with
patients with schizophrenia (1 readmission: 173 patients with
schizophrenia [25.3%] vs 28 340 general population patients
[27.2%]; ≥2 readmissions: 215 patients with schizophrenia [31.4%]
vs 40 598 general population patients [38.9%]; P < .001). Fewer
patients with schizophrenia had PCI compared with patients in
the general population (134 [19.6%] vs 24 334 [23.3%]; P = .02).
Furthermore,patientswithschizophreniahadahigherprevalence
of diabetes (222 [32.5%] vs 24 871 [23.8%]; P < .001), COPD (314
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 Cardiovascular Treatment and Mortality in Post–Myocardial Infarction Patients With Schizophrenia Original Investigation Research

Table 1. Patient Characteristicsa

Patients With General
Schizophrenia Population
Characteristic (n = 684) (n = 104 334) P Value
Age at diagnosis, mean (SD), y 57.34 (10.64) 61.00 (10.65) <.001
Male sex 483 (70.6) 73 454 (70.4) .90
No. of person-years 3827.09 792 608.14 NA
No. of deaths 307 (44.9) 27 752 (26.6) <.001
Causes of death
Cardiovascular 209 (68.1) 18 595 (67.0)
.69
Noncardiovascular 98 (31.9) 9157 (33.0)
MI diagnosis in calendar period
1995-1999 95 (14.8) 17 518 (17.3)
2000-2004 150 (22.0) 23 805 (22.9)
.29
2005-2009 170 (24.8) 26 498 (25.3)
2010-2015 269 (38.4) 36 513 (34.5)
No. of MI readmissions after index
0 296 (43.3) 35 396 (33.9)
1 173 (25.3) 28 340 (27.2) <.001
≥2 215 (31.4) 40 598 (38.9)
PCI 134 (19.6) 24 334 (23.3) .02
Physical comorbidity
Diabetes 222 (32.5) 24 871 (23.8) <.001
COPD 314 (45.9) 39 094 (37.5) <.001
Hypertension 489 (71.5) 77 991 (74.8) .05
Substance abuse 171 (25.0) 4809 (4.6) <.001 Abbreviations:
ACEI, angiotensin-converting enzyme
Prescriptions
inhibitors; COPD, chronic obstructive
Antiplatelets 581 (84.9) 95 814 (91.8) <.001 pulmonary disease; MI, myocardial
Vitamin K antagonists 109 (15.9) 25 216 (24.2) <.001 infarction; NA, not applicable;
β-Blockers 507 (74.1) 88 617 (84.9) <.001 PCI, percutaneous coronary
ACEIs 485 (70.9) 90 351 (86.6) <.001 intervention.
a
Statins 494 (72.2) 91 045 (87.3) <.001 Data are presented as number
(percentage) of patients unless
None 53 (7.8) 3455 (3.3) <.001
otherwise indicated.

[45.9%] vs 39 094 [37.5%]; P < .001), and substance abuse
(171 [25.0%] vs 4809 [4.6%]; P < .001) compared with the gen-
eral population. The prevalence of hypertension (489 [71.5%] vs
77 991 [74.8%]; P = .051) was similar in both populations. In pa-
tients diagnosed with schizophrenia, a lower proportion of pre-
scriptions of antiplatelets (581 [84.9%]), vitamin K antagonists
(109 [15.9%]), β-blockers (507 [74.1%]), ACEIs (485 [70.9%]), and
statins (494 [72.2%]) and the highest proportion of patients with
absence of any prescriptions after MI (53 [7.8%]) were observed
compared with the general population (P < .001 for all) (Table 1).
Drug Exposure and Mortality Rates After MI
A total of 307 patients with schizophrenia (44.9%) and 27 752
patients from the general population (26.6%) died after index
(P < .001). Causes of death were equally distributed between
groups, with 66.2% of all deaths being defined as cardiovascu-
lar deaths. Patients diagnosed with schizophrenia who did not
receive cardioprotective treatment had the highest mortality rate
(HR, 8.78; 95% CI, 4.37-17.64) compared with the general popu-
lation treated, with treated patients diagnosed with schizophre-
nia having an increased HR of 1.97 (95% CI, 1.25-3.10). No differ-
ence was found in mortality rates between nonexposed patients
from the general population (HR, 2.95; 95% CI, 2.62-3.32) and pa-
tients with schizophrenia exposed to treatment (HR, 1.97; 95%
CI, 1.25-3.10) when adjusting for baseline characteristics (Table 2).
The subanalysis of mortality rates for each cardioprotective
treatment showed a generally increased mortality rate among pa-
tients diagnosed with schizophrenia who were treated compared
with treated patients in the general population with the excep-
tion of antiplatelets and statins (Table 2). Similarly, patients di-
agnosed with schizophrenia who were not exposed to cardiopro-
tective treatment had increased rates of mortality compared with
patients from the background population who were not exposed
to cardioprotective treatment (Table 2) for both the unadjusted
and adjusted models. Patients diagnosed with schizophrenia who
were exposed to cardioprotective treatment did not have a lower
mortality rate than nonexposed patients from the background
population (Table 2). In the sensitivity analysis that included
only patients who initiated treatment without any prior use
(n = 87 355), we observed patterns similar to the findings in the
main analysis.
Medication Therapy and Mortality Rates
In the adjusted model, we found that patients diagnosed
with schizophrenia did not have an increased HR for all-cause
mortality compared with patients from the general population
who received triple therapy as cardioprotective treatment
(adjusted HRs: 1.86 [95% CI, 1.71-2.02] vs 6.65 [95% CI, 3.56-12.40]
for dual therapy and 4.38 [95% CI, 3.87-4.95] vs 13.10 [95% CI,
6.51-26.35] for no treatment). With lowered treatment intensity

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 Research Original Investigation Cardiovascular Treatment and Mortality in Post–Myocardial Infarction Patients With Schizophrenia

Table 2. Cox Proportional Hazards Regression Model Investigating Mortality Rates Using Treatment Exposure as a Time-Varying Covariate
in Patients From the General Population and Patients With Schizophrenia

Crude HR (95% CI) Adjusted HR (95% CI)a Adjusted HR (95% CI)b

General Patients With General Patients With General Patients With
Treatment Population Schizophrenia Population Schizophrenia Population Schizophrenia
Any Treatment
Treated 1 [Reference] 2.27 (2.00-2.58) 1 [Reference] 2.34 (1.49-3.67) 1 [Reference] 1.97 (1.25-3.10)
Untreated 1.22 (1.19-1.26) 2.45 (1.93-3.11) 2.78 (2.47-3.13) 9.80 (4.89-19.66) 2.95 (2.62-3.32) 8.78 (4.37-17.64)
Antiplatelets
Treated 1 [Reference] 2.44 (2.12-2.82) 1 [Reference] 2.00 (1.16-3.46) 1 [Reference] 1.71 (0.99-2.95)
Untreated 1.55 (1.51-1.59) 2.86 (2.38-3.43) 2.57 (2.38-2.77) 9.80 (5.78-16.60) 2.54 (2.35-2.74) 7.97 (4.69-13.55)
Vitamin K Antagonists
Treated 1 [Reference] 1.63 (0.92-2.87) 1 [Reference] 2.53 (1.43-4.46) 1 [Reference] 2.21 (1.25-3.90)
Untreated 0.71 (0.68-0.74) 1.62 (1.44-1.83) 0.94 (0.90-0.98) 2.85 (2.52-3.22) 0.97 (0.93-1.02) 2.53 (2.24-2.86)
β-Blockers
Treated 1 [Reference] 2.20 (1.80-2.68) 1 [Reference] 2.23 (1.16-4.30) 1 [Reference] 1.96 (1.02-3.79)
Untreated 1.45 (1.41-1.49) 3.23 (2.82-3.71) 1.67 (1.56-1.80) 5.53 (3.47-8.82) 1.71 (1.59-1.84) 4.40 (2.75-7.04)
ACEIs
Treated 1 [Reference] 2.35 (1.95-2.82) 1 [Reference] 2.45 (1.27-4.73) 1 [Reference] 2.06 (1.07-3.99)
Untreated 1.13 (1.10-1.15) 2.45 (2.11-2.80) 1.62 (1.51-1.74) 4.56 (2.86-7.27) 1.78 (1.66-1.91) 4.08 (2.56-6.52)
Statins
Treated 1 [Reference] 2.16 (1.80-2.58) 1 [Reference] 1.87 (1.03-3.38) 1 [Reference] 1.56 (0.86-2.83)
Untreated 1.81 (1.77-1.85) 3.69 (3.20-4.27) 2.46 (2.29-2.65) 8.34 (5.10-13.65) 2.45 (2.28-2.64) 7.04 (4.30-11.55)
b
Abbreviations: ACEI, angiotensin-converting enzyme inhibitors; Adjusted for sex, birth year, age at myocardial infarction, calendar year,
HR, hazard ratio. percutaneous coronary intervention, diabetes, chronic obstructive pulmonary
a
Adjusted for sex, birth year, age at myocardial infarction, calendar year, and disease, hypertension, and substance abuse.
percutaneous coronary intervention.

Table 3. Cox Proportional Hazards Regression Model Investigating the Association of Different Cardiac Therapy Strategies and Mortality Rates

Crude HR (95% CI) Adjusted HR (95% CI)a Adjusted HR (95% CI)b

General Patients With General Patients With General Patients With
Therapy Strategy Population Schizophrenia Population Schizophrenia Population Schizophrenia
Triple therapy 1 [Reference] 2.07 (1.68-2.56) 1 [Reference] 1.19 (0.50-2.87) 1 [Reference] 1.05 (0.43-2.52)
Dual therapy 1.48 (1.43-1.52) 3.82 (3.09-4.72) 1.76 (1.62-1.92) 7.66 (4.11-14.28) 1.86 (1.71-2.02) 6.65 (3.56-12.40)
Monotherapy 2.25 (2.18-2.32) 4.37 (3.43-5.58) 3.72 (3.38-4.10) 8.39 (3.14-22.39) 3.90 (3.53-4.30) 6.89 (2.57-18.42)
No treatment 1.63 (1.57-1.69) 3.25 (2.56-4.13) 3.99 (3.53-4.50) 13.95 (6.95-28.01) 4.38 (3.87-4.95) 13.10 (6.51-26.35)
b
Abbreviation: HR, hazard ratio. Adjusted for sex, birth year, age at myocardial infarction, calendar period,
a
Adjusted for sex, birth year, age at myocardial infarction, calendar year, and percutaneous coronary intervention, diabetes, chronic obstructive pulmonary
percutaneous coronary intervention. disease, hypertension, and substance abuse.

differences being observed for dual therapy and no treatment,
the difference in monotherapy did not reach statistical signifi-
cance (adjusted HRs: 3.90 [95% CI, 3.53-4.30] vs 6.89 [95% CI,
2.57-18.42] for monotherapy) (Table 3). We furthermore con-
ducted a post hoc sensitivity analysis to investigate a potential
associationofSMIinthecomparisongroup.Whencomparingonly
patients diagnosed with schizophrenia with a comparison group
in which all with a previous psychiatric diagnosis were excluded,
we found similar results as in our main analysis.
Discussion
In this large, nationwide, retrospective cohort study of 105 018
patients with MI with a total follow-up of 796 435 person-years,
we found that when patients with schizophrenia were not ex-
posed to cardioprotective treatment, the mortality rate was high
compared with patients exposed, using treatment-exposed pa-
tients from the general population as reference. By comparing the
associationsbetweendifferentcardiactherapystrategiesandmor-
tality rates, we found that patients with schizophrenia who
received any combination of triple therapy had the lowest
mortality rates.
Previous studies have found that patients with schizophre-
nia have increased cardiovascular mortality5,21 and a lower
prescriptionrateforcardioprotectivetreatment11,15 comparedwith
the general population. The current study was the first, to our
knowledge, to investigate the association between exposure to
cardioprotective medication after MI and mortality rates among
patients with schizophrenia compared with the general popula-
tion. Mitchell et al15 found lower odds of prescribing ACEIs (odds
ratio [OR], 0.89; 95% CI, 0.81-0.98), β-blockers (OR, 0.90; 95%
CI, 0.84–0.96), and statins (OR, 0.61; 95% CI 0.39–0.94) among
patients with SMI compared with patients without psychiatric
conditions. A recent study by Jakobsen et al11 found similar results
of lower prescription rates for β-blockers, statins, and ACEIs 1 year

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 Cardiovascular Treatment and Mortality in Post–Myocardial Infarction Patients With Schizophrenia
after MI among patients with SMI compared with the general
population. These findings are similar to our finding of a lower
use of antiplatelets, vitamin K antagonists, β-blockers, ACEIs, and
statins in patients with schizophrenia compared with the general
population. Nevertheless, studies from the United States have
found that patients with schizophrenia were more adherent to
statins than patients without psychiatric conditions,22,23 although
these studies were limited by the inclusion of patients who had
at least 2 refills during a 12-month period in payer-provided care,
which might have biased results toward an overrepresentation
of well-functioning patients diagnosed with schizophrenia. A
number of factors contribute to reduced medication adherence,
including poor insight into physical illness, negative attitudes
toward medication, or lack of understanding the purpose of the
medications.24 These contributing factors may be even worse in
patients with schizophrenia, who have cognitive impairment,
which has been linked to reduced medication adherence in
general.25 One study26 found that adherence to hypoglycemic and
antihypertensive medications was worse than adherence to an-
tipsychotics in patients with schizophrenia. This explanation is
further supported by earlier findings that suggest that patients
with schizophrenia are less likely to consult their cardiologist af-
ter cardiac events.27,28 Together, we believe that these results
could point toward a deficit in establishing an appropriate cardiac
treatment plan in patients with schizophrenia that causes failure
in initiation and maintenance of cardioprotective treatment. This
hypothesis could explain the results of a generally increased mor-
tality rate among patients with schizophrenia, especially when
the results suggest that these patients die of cardiovascular causes
that might be treatable. The current data do not show causality
as a result of the study design, and as such, more studies are
needed to confirm the results.
Prior observational studies3,29 have suggested that concomi-
tant exposure to multiple cardioprotective medications results
in lowered mortality rates compared with monotherapy or no
treatment in people experiencing cardiovascular events. The re-
sults of the current study indicate a similar cardioprotective as-
sociation with mortality rates in patients diagnosed with schizo-
phrenia and the general population when exposed to multiple
secondary preventive treatments. These findings are similar to
those of the study by Korhonen et al,3 who compared the asso-
ciation of multiple preventive therapies with mortality rates af-
ter MI in populations without psychiatric conditions and found
a generally favorable association between triple therapy and mor-
tality rates. According to European and US guidelines for the treat-
ment of patients with MI, cardioprotective triple therapy should
be considered in patients with high ischemic and bleeding risk.30,31
We do not have information on the specific risk variables in each
patient or on any changes in treatment strategy provided by the
cardiologists during follow-up. Therefore, the reason for persons
not taking their medication may be their own initiative or their
practitioner’s recommendation. In our study, treatment with car-
diac triple therapy was associated with reduced excess mortal-
ity rates among patients with schizophrenia, which could suggest
a necessity of implementing and monitoring multiple secondary
preventive cardiac treatments in patients with schizophrenia.
The current findings might be explained by confounding by
indication because patients with increased severity of MI might
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Original Investigation Research
be more intensively treated with triple therapy, but the finding
that all-cause mortality diminishes as treatment intensity in-
creases may suggest that increased treatment intensity, despite
increased cardiac risks, affects long-term outcome. The bias of
increased cardiac risk associated with increased treatment inten-
sity would be conservative and bias the results toward an in-
creased mortality rate associated with an increased treatment in-
tensity. On the other hand, more severely ill patients may have
difficulties complying with planned treatment because of the
complexity of taking multiple drugs, which could bias the results
in the opposite direction. Given the increased cardiovascular risk
among patients with schizophrenia, we believe that the current
findings support the use of intensive cardioprotective treatments
in patients with schizophrenia. In addition, these patients should
be provided with accurate treatment that is closely monitored dur-
ing follow-up, and treatment intensity should be increased after
cardiac events in patients with schizophrenia in general because
a diagnosis of schizophrenia may be associated with an increased
cardiac risk, which potentially can be countered by secondary pre-
ventive cardiac treatment.
Limitations
There are several limitations that need to be addressed. First, treat-
ment exposure was based on whether patients redeemed pre-
scriptions; thus, we cannot be certain that the patients were ac-
tually taking the prescribed medication for the full amount of days
that we calculated. However, we assume that when patients re-
deem prescriptions, they have the intention to take their medi-
cations. Second, we did not have information on the severity of
MI (eg, left ventricular function and symptom status) or informa-
tion on lifestyle factors, such as diet habits, physical activity, and
smoking status; therefore, we were unable to adjust for these con-
founders in the regression models. Future research should at-
tempt to assess the degree to which these factors contribute to
the increased mortality in patients with schizophrenia. Despite
adjusting for multiple confounders in the regression models, it
is possible that some residual confounding may have occurred.
We also did not have information on in-hospital medication, but
because we included patients with MI from the general popula-
tion in the main analyses, we expect that any bias would affect
both populations equally. Third, we included patients across a
broad period, and we are aware that treatment patterns and guide-
line recommendations for preventive cardiovascular assessment
have changed significantly. However, we indirectly accounted for
this difference by including patients without schizophrenia
and adjusting to calendar year in the Cox proportional hazards
regression model.
Conclusions
Our study suggests that patients with schizophrenia who are
treated with cardioprotective treatment after MI have a lower mor-
tality risk compared with patients who are not treated, similar to
those treated in the general population. This finding suggests that
some of the increased cardiac mortality among patients with
schizophrenia can be reduced if these patients are efficiently ad-
ministered secondary preventive treatment after cardiac events.
(Reprinted) JAMA Psychiatry December 2018 Volume 75, Number 12 1239
 Research Original Investigation
ARTICLE INFORMATION
Accepted for Publication: July 14, 2018.
Published Online: October 24, 2018.
doi:10.1001/jamapsychiatry.2018.2742
Correction: This article was corrected on May 1, 2019,
to fix a typographial error in the Discussion section.
Author Contributions: Mr Kugathasan and Dr
Horsdal had full access to all the data in the study
and take responsibility for the integrity of the data
and the accuracy of the data analysis.
Concept and design: Kugathasan, Aagaard, Jensen,
Laursen, Nielsen.
Acquisition, analysis, or interpretation of data:
Kugathasan, Horsdal, Laursen, Nielsen.
Drafting of the manuscript: Kugathasan, Nielsen.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Kugathasan, Horsdal,
Laursen, Nielsen.
Obtained funding: Nielsen.
Administrative, technical, or material support:
Kugathasan, Nielsen.
Supervision: Horsdal, Aagaard, Jensen,
Laursen, Nielsen.
Conflict of Interest Disclosures: Dr Nielsen
reported receiving research grants from
H. Lundbeck and Otsuka Pharmaceuticals for
clinical trials; receiving speaking fees from
Bristol-Myers Squibb, AstraZeneca, Janssen & Cilag,
Lundbeck, Servier, Otsuka Pharmaceuticals, and
Eli Lilly and Company; and acting as adviser to
AstraZeneca, Eli Lilly and Company, Lundbeck,
Otsuka Pharmaceuticals, Takeda, and Medivir.
No other disclosures were reported.
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