A Population-Based Cohort Study on
Peripheral Arterial Disease in Patients
with
Schizophrenia
Wen-Yu Hsu1,2,3, Cheng-Li Lin4,5, Chia-Hung Kao6,7*
Introduction
Peripheral arterial disease (PAD) is the narrowing of arteries, mostly in the lower limbs, leading
to claudication. The prevalence of PAD in both men and women has increased from 3%
among those aged 25–29 years to 24% among those 95–99 years in high-income countries [1].
PAD is considered the leading cause of atherosclerotic cardiovascular morbidity, followed by
coronary artery disease and stroke [2, 3]. The distal superficial femoral artery is the most common
site of PAD occurrence, leading to claudication in the calf muscle region. However, patients do not always exhibit typical PAD symptoms. The incidence of
asymptomatic PAD is
higher than that of symptomatic PAD in the general population [4]. In a previous study,
asymptomatic PAD was a crucial predictor of cardiovascular morbidity and mortality [5].
However, PAD is typically underrecognized and undertreated in clinical practice [6,
7]. The
ankle—brachial index (ABI) is a simple noninvasive test that can identify adults at a high risk
of PAD. Prevention and early management of PAD may lower the risk of myocardial infarction,
stroke, or death. Several risk factors, such as old age, diabetes, smoking, dyslipidemia, obesity,
may be
helpful in the management of PAD [8], and some of these risk factors are easily identified in
patients with schizophrenia.
Schizophrenia is a chronic, severe brain disorder causing disability. The global lifetime prevalence
of schizophrenia is approximately 1%. Several studies have reported an increase in the
risk of myocardial infarction, stroke, or death in the schizophrenia population [9–
11]. Schizophrenia
is associated with excess deaths from coronary heart disease and stroke in persons
younger than 75 years. Cardiovascular disease occurs more frequently in people with schizophrenia
and is the commonest cause of death [12]. Several PAD associated risk factors, such as
smoking, low physical activity, diabetes, and hyperlipidemia, were higher prevalent in schizophrenia
population. Several articles reported schizophrenia population has higher tobacco smoking rate than general population [13–15]. Smoking is the key risk factor related with PAD
in our schizophrenia patients. Patients with schizophrenia have fewer physical activity [16].
Low physical activity might related with negative symptoms of schizophrenia. Patients with
schizophrenia have higher prevalence of diabetes, and schizophrenia patients are at least double
the risk of developing type 2 diabetes mellitus [15, 17]. And, history of diabetes can deeply
influence PAD evolution and cardiovascular diseases [18]. Patients with schizophrenia also
had a much higher prevalence of hyperlipidemia in young adulthood than that in the general
population [19], and increased risk of initiation of anti-hyperlipidemia medications was noted
among patients with schizophrenia [20]. Owing to sharing these risk factors, higher PAD in
studied the
relationship between PAD and schizophrenia.
The cause for higher PAD incidence in the schizophrenia population than in the general
population remains unknown. It is crucial to understand this cause for the prevention and
treatment of related diseases in the schizophrenia population. Early awareness of cardiovascular
risk in this population can facilitate early intervention.
We hypothesize that the incidence of PAD is higher in the schizophrenia population than in
the general population. Accordingly, we conducted this population-based cohort study in Taiwan
to investigate the prevalence of PAD are between the schizophrenia and general populations.
Methods
Data Source
The Taiwan National Health Insurance (NHI) program was implemented in 1995 and offers
comprehensive medical coverage to all residents of Taiwan
(http://www.nhi.gov.tw/english/index. aspx). The Taiwanese National Health
Research Institutes (NHRI) maintain the National Health
Insurance Research Database (NHIRD), which contains the claims data of the enrollees. Before
the electronic files are released for research purposes by the NHRI, the personal identification
information is encrypted to protect patient privacy. The data used in this retrospective cohort
study were obtained from the NHIRD. International Classification of Diseases, Ninth Revision,
ClinicalModification (ICD-9-CM) codes were used for coding the diseases relevant to this study.
Sampled Patients
All patients diagnosed with schizophrenia (ICD-9-CM code 295) from 2000 to 2011 were identified
from the Registry of Catastrophic Illness Database (RCIPD) of the NHIRD, and the first
diagnosed and characterized
schizophrenia in a patient as a catastrophic illness, then the patient can submit the
related information and apply for a catastrophic illness certificate. Under the guidelines of the
Ministry of Health and Welfare of Taiwan, the patient can submit this certificate to have copayments
related to the illness waived for both outpatient and inpatient care. We excluded patients
with a history of PAD (ICD-9-CM codes 440.0, 440.2, 440.3, 440.8, 440.9, 443, 444.0, 444.22,
444.8, 447.8, and 447.9) before the index date, and those with incomplete age or sex information.
Patients in the nonschizophrenia cohort were randomly selected from the insured patients
without any history of schizophrenia and PAD at baseline. The exclusion criteria for the
patients in the nonschizophrenia cohort were identical to those for patients in the schizophrenia
cohort. The nonschizophrenia cohort was frequency matched with the schizophrenia
cohort on the basis of age (in 5-y bands), sex, the year of index date and comorbidities of diabetes,
hypertension, hyperlipidemia, COPD, heart failure, CAD, stroke, obesity and asthma, and
medication of statin and aspirin.
Outcomes, Comorbidities, and Mediations
Both cohorts were followed until PAD diagnosis, censoring because of death, loss to follow-up,
withdrawal from the insurance system, or the end of 2011. Preexisting comorbidities for each
patient included diabetes (ICD-9-CM code 250), hypertension (ICD-9-CMcodes 401–405),
hyperlipidemia (ICD-9-CM code 272), chronic obstructive pulmonary disease (COPD)
[ICD-9-CMcodes 491, 492, 496]), heart failure (ICD-9-CM code 428), coronary artery disease (CAD
code 278)
and asthma (ICD-9-CMcode 493). Statin and aspirin were also analyzed between the schizophrenia
patients and the nonschizophrenia cohort. In addition, we hypothesized that typical
and atypical antipsychotics exert different effects on PAD in patients with schizophrenia.
Ethics Statement
The NHIRD encrypts patient personal information to protect privacy and provides researchers
with anonymous identification numbers associated with relevant claims information, including
sex, date of birth,medical services received, and prescriptions. We excluded all individually identifying
or patient demographic information. Therefore, the patient consent is not required to access
the NHIRD. This study was approved by the Institutional Review Board (IRB) of ChinaMedical
University (CMUH104-REC2-115). The IRB specifically waived the consent requirement.
Statistical Analysis
We compared the distributions of age, sex, comorbidities and medications between the schizophrenia
and nonschizophrenia cohorts using the chi-square test. Student t test was used to compare the differences in the mean age and mean follow-up years between the 2 cohorts. The
incidence density rate of PAD (per 10 000 person-y) was calculated on the basis of sex, age and,
comorbidities for each cohort. Univariate and multivariate Cox proportional hazard regression
models were employed to examine and compare the risk of PAD associated with schizophrenia
between the 2 cohorts, and the risk was evaluated as a hazard ratio (HR) with a 95% confidence
interval (CI). Multivariate models were employed after adjustment for age, sex, and comorbidities
(diabetes, hypertension, hyperlipidemia, COPD, heart failure, CAD, stroke, obesity and
asthma) and medication of statin and aspirin. Further analysis was performed to assess the role
of antipsychotics in influencing the PAD outcomes. The Kaplan—Meier method was employed
for estimating the cumulative incidence of PAD between the schizophrenia and nonschizophrenia
cohorts, and the differences were assessed using a log-rank test. Statistical analysis was
performed using the SAS 9.3 statistical package (SAS Institute Inc., NC, USA), and P<0.05 in
2-tailed tests was considered significant.
Results
We identified 59 234 patients with newly diagnosed schizophrenia from 2000 to 2011 as the
schizophrenia cohort and 59 234patients without any schizophrenia diagnosis as the nonschizophrenia
cohort (Table 1). The mean (± standard deviation [SD]) age of patients in the schizophrenia and nonschizophrenia cohorts was 38.6(±13.2) and 38.5(±13.6) years, respectively,
and approximately 45% of these patients were in the age group of 20–34 years. The number of men (52.3%) was higher than that of women (47.3%). The prevalence of preexisting
comorbidities (diabetes, COPD, heart failure, stroke, obesity and asthma)and statin use and
aspirin use were similar in the schizophrenia cohort than in the nonschizophrenia cohort. The
mean follow-up duration was 6.40 (SD = 3.37) and 6.46 (SD = 3.32) years for the schizophrenia
and nonschizophrenia cohorts, respectively. Fig 1 shows that the cumulative incidence of PAD
was higher in the schizophrenia cohort than in the nonschizophrenia cohort (log-rank test,
P = 0.001). The overall incidence of PAD was 1.26-fold higher in the schizophrenia cohort
than that in the nonschizophrenia cohort (16.8 and 13.9 per 10 000 person-years, respectively),
with a crude HR of 1.21 (95% CI = 1.08–1.36, Table 2). After adjustment for age, sex, comorbidities
(diabetes, hypertension, hyperlipidemia, COPD, heart failure, CAD, stroke, obesity and
asthma) and medication of statin and aspirin, patients in the schizophrenia cohort had a
1.26-fold higher risk of PAD than those in the nonschizophrenia cohort (HR = 1.26, 95%
CI = 1.13–1.42). Sex-specific analysis showed that the risks of PAD were higher in women than
in men, and these risks were higher in the schizophrenia cohort than in the nonschizophrenia
cohort (HR = 1.08, 95% CI = 1.03–1.14 for men; HR = 1.50, 95% CI = 1.26–1.77, P for interaction
= 0.01). The incidence densities of PAD increased with age in both cohorts. The age-specific
schizophrenia-to-nonschizophrenia relative risk of PAD was higher for younger patients
(age = 20–34 y, HR = 1.72, 95% CI = 1.25–2.37) than for older patients (age >50 y, HR = 1.06,
95% CI = 0.89–1.26, P for interaction = 0.02). The comorbidity-specific schizophrenia-to-nonschizophrenia
risk of PAD was significantly higher for patients without comorbidities
(HR = 1.39, 95% CI = 1.18–1.65). The incidence densities of PAD increased for patients with
statin use or aspirin use in both cohorts. The risk of PAD in schizophrenia patients had nearly
1.25-fold higher than the risk in nonschizophrenia cohort by follow-up _31 year (HR = 1.25,
95% CI = 1.20–1.30). The PAD risk in schizophrenia patient were 1.22, and 1.40-fold by 4–6
years (HR = 1.22, 95% CI = 1.17–1.28), and 7–9 years (HR = 1.40, 95% CI = 1.31– 1.49),
respectively. Table 3 shows the association of the risk of PAD with treatments between the schizophrenia
and nonschizophrenia cohorts. The patients in the schizophrenia cohort were at a significantly
higher risk of PAD than those in the nonschizophrenia cohort. Among the patients in the
antipsychotic treatment
exhibited a significantly higher risk of PAD (HR = 1.86, 95% CI = 1.34–2.59) than those in the comparison cohort, followed by those who received only atypical antipsychotic treatment
(HR = 1.28, 95% CI = 1.14–1.44) than those in the nonschizophrenia cohort. Compared
with the nonschizophrenia cohort, schizophrenia who received atypical antipsychotics treatment
for less than 1 year were associated with higher risk of PAD (HR = 1.55, 95% CI = 1.30–
1.86), followed by those who received atypical antipsychotic treatment more than 1 year
(HR = 1.19, 95% CI = 1.05–1.36).
Discussion
Our results show that the patients in the schizophrenia cohort have a 1.26-fold higher risk of
PAD than those in the nonschizophrenia cohort after controlling for age, gender, and comorbidities
of diabetes, hypertension, hyperlipidemia, COPD, heart failure, CAD, stroke, obesity
and asthma, and medication of statin and aspirin. Peripheral vasculature has not been explored
exclusively in patients with schizophrenia. This is the first study to report that patients with
schizophrenia have a higher risk of PAD than their comparable controls. Patients with PAD
are at a high risk of adverse cardiovascular events [21]. PAD, a manifestation of systemic atherosclerosis,
leads to segmental narrowing and occlusion of arteries. Our results are in agreement
with those of Israel et al, in which peripheral endothelial dysfunction was reported in
unmedicated patients with acute schizophrenia [22]. Besides, schizophrenia patients have
higher prevalence of tobacco smoking, low physical activity, diabetes, and hyperlipidemia.
These would worst their vascular health.
men in the
nonschizophrenia cohort, which is similar to those of previous reports [23, 24]. In addition, we
found that the risk of PAD increased in both men and women in the schizophrenia cohort.
Men in the schizophrenia cohort had a 1.50-fold higher adjusted HR for PAD than those in the
nonschizophrenia cohort. Women in the schizophrenia cohort had a 1.08-fold higher adjusted
HR for PAD than those in the nonschizophrenia cohort. In a previous study, the rate of smoking
was higher in men than in women in patients with schizophrenia [25]. Early onset of schizophrenia in males might result in early process of peripheral endothelial dysfunction. A
high rate of smoking and early onset age of schizophrenia in men in the schizophrenia cohort
may explain our results and the rate of smoking was accounted for by adjusting for smokingassociated
diseases (such as asthma).
Age plays a crucial role in PAD. The prevalence of PAD increased in older patients in a previous
study [1]. In our study, we observed that the incidence of PAD was higher in older patients in both the cohorts. However, patients aged between 20 and 34 years in the schizophrenia
cohort have a 1.72-fold higher adjusted HR for PAD than those in the nonschizophrenia
cohort. Age between 35 and 49 schizophrenia cohort have a 1.31-fold higher adjusted HR
for PAD development than the age between 35 and 49 years in the nonschizophrenia cohort.
No significant difference in both the age more than 50 year old cohorts. These results indicate
that younger patients with schizophrenia have a high PAD risk. The results of our study
showed that schizophrenia may facilitate the progress of atherosclerosis and is consistent with
the report of Israel et al [22], in which peripheral endothelial dysfunction was reported in
unmedicated patients with schizophrenia. The anti-inflammatory mediator nitric oxide exerts
a protective effect on endothelial functioning. Burghardt et al suggested that patients with
schizophrenia may lose the genetic protection provided by nitric oxide once their condition
progresses to the pro-inflammatory state of metabolic syndrome [26].
In our study, we investigated the effect of different antipsychotics.We found that patients in
the schizophrenia cohort who received atypical antipsychotic treatment had a higher HR for
PAD (1.28) than those in the nonschizophrenia cohort after adjustment for age, sex, and
comorbidities of diabetes, hypertension, hyperlipidemia, COPD, heart failure, CAD, stroke,
obesity and asthma, and medication of statin and aspirin. No significant difference was
observed for typical antipsychotic treatment after adjustment for confounding factors between
the schizophrenia and nonschizophrenia cohorts for PAD. Compared with patients in the nonschizophrenia
cohort, patients in the schizophrenia cohort who received combined typical and atypical antipsychotic treatment had a higher HR (1.86) for PAD after adjustment. Antipsychotics,
particularly atypical antipsychotics, may play a role in the development of PAD. The
Clinical Antipsychotic Trials of Intervention Effectiveness study revealed an association
between the use of atypical antipsychotics in schizophrenia and metabolic syndrome [27]. The
American Diabetes Association, the American Psychiatric Association, the American Association
of Clinical Endocrinologists, and the North American Association for the Study of Obesity
suggest that baseline screening and follow-up monitoring is essential for mitigating the likelihood
of developing CVD, diabetes, or other diabetes-related complications while prescribing
atypical antipsychotics [28]. Atypical antipsychotics may counteract some vascular health benefits
of a diet high in omega 3 fatty acids, as reported in the study by Ellingrod [29]. Our study
results were in agreement with those of the aforementioned reports.
However, some limitations were encountered while conducting this study. First, the accuracy
of the incidence of PAD was not validated by reviewing the medical charts, and PAD cases
were identified only on the basis of the ICD-9-CM codes(440.0, 440.2, 440.3, 440.8, 440.9, 443,
444.0, 444.22, 444.8, 447.8, and 447.9). Second, the use of ICD system should be considered as
a limitation of this study. The use of ICD could be considered as a further limitation of this
study. However, the NHIRD covers a highly representative sample of Taiwan’s general population
because the reimbursement policy is universal and operated by a single-buyer, the government
in Taiwan. All insurance claims should be scrutinized by medical reimbursement specialists and peer review according to the standard diagnosed criteria in the study. If these
doctors or hospitals make wrong coding for the diagnoses, they will be punished with a lot of
penalties. Therefore, the diagnoses based on ICD-9 codes in this study should be highly reliable.
Third, the incidence of asymptomatic PAD is higher than that of symptomatic PAD in the general population. In our study, asymptomatic PAD was not considered as part of the
study design. Fourth, lack of data (e.g, smoking status, obesity, and family history) may have
influenced the results of our study. Therefore, we applied proxy measures, such as hyperlipidemia
and diabetes as indicators of obesity and COPD as an indicator of smoking, for controlling
the potential confounding effects. However, the effects of some unmeasured confounders
aspirin) in
schizophrenia cohort might be poorer than in nonschizophrenia cohort. Sixth, the experimental
design is another limitation. Our study is a retrospective cohort study. The evidence derived
from a retrospective cohort study is generally of lower methodological quality than that from
randomized trials by the experimental design because a retrospective cohort study is subject to
many biases related to the necessary adjustments for confounding factors. Despite the meticulous
design of this study and its adequate control of confounding factors, biases could remain
because of possibly unmeasured or unknown confounding factors.
In conclusion, this nationwide population-based cohort study shows that patients in the
schizophrenia cohort have a 1.26-fold higher adjusted HR for PAD than that in the nonschizophrenia
cohort after adjustment. This is the first study to report the association between schizophrenia
and the risk of PAD. Patients with schizophrenia who were treated using atypical antipsychotics have a high risk of PAD. However, most patients with the new onset schizophrenia
patients received atypical antipsychotics. It is crucial to adequately assess the risk of PAD
among patients with schizophrenia, particularly those who are unable to exercise adequate personal
care or gain access to health care by themselves because of their illness. In-depth ABI
analyses may facilitate PAD diagnosis. Early diagnosis and management of PAD may further
facilitate the prevention of myocardial infarction, stroke, and other cardiovascular diseases.
