Increased subsequent risk of acute coronary
syndrome for
patients with depressive disorder: A
nationwide
population-based retrospective cohort study
Yen-Nien Lin,
MD,
1Cheng-Li Lin,
MSc,
2,4Yen-Jung Chang,
PhD,
2,4Chiao-Ling Peng,
MSc,
2,4Fung-Chang Sung,
PhD,
2,4Kuan-Cheng Chang,
MD1and Chia-Hung Kao,
MD3,5
*
D
EPRESSIVE DISORDER IS a psychiatric illness that afflicts a significant portion of the population in all countries, and is more common among Taiwanese people than what has been previously suggested.1,2 Numerous epidemiological studieshave indicated that high comorbidity exists between depression and coronary heart disease (CHD).3 The
overall relative risk for CHD among patients with depression was 1.64 in a meta-analysis, including 11 cohort studies.4 Following myocardial infarction,
the emergence of clinical depression poses heightened risk of morbidity and mortality.5 Thus, some
previous studies have indicated that depression is
bidirectionally associated with a complicated pathophysiological mechanism connected with ischemic
CHD.5–7 Although depression may be associated with
CHD, previous findings of such association have been limited to small population studies, meta-analysis, and mechanism discussions. Acute coronary syndrome (ACS) is an acute life-threatening condition of
the incidence rates of ACS (per 100 000) is 208 in the USA8 and around 100 in
Taiwan in 2008.9,10 Lower
BMI, reduced protein/fat in the diet, and variation in comorbidities in Eastern countries may result in this
difference in incidence. Despite this difference, cardiovascular disease is the first leading cause of death in the
USA and the second leading cause of death in Taiwan. Few studies have specifically examined the risk of ACS frequency among people with a depression diagnosis in the general population. Therefore, the objective of this national population-based study was to examine the risk of subsequent ACS among patients with depression in Taiwan within the following years.
METHODS
Data sourcesThis study used the reimbursement data of the universal National Health Insurance Research Database
(NHIRD) in Taiwan, which has registered all medical claims and has provided affordable health care for all the island’s residents in Taiwan since 1996. This insurance program provides health care to 99% of over 23 million residents in Taiwan and is contracted with 97% of the hospitals and clinics.11 The claims
database includes comprehensive information by the National Health Research Institute (NHRI). These subset data include claims data randomly sampled for 1 million insured people from the nationwide population-based database released by the NHRI until 2009. The details of this database have been published previously.12,13 The diagnoses were coded
using the ICD-9-CM. These datasets were linked with scrambled identification to strengthen data security to protect people’s privacy. We confirm that all data were de-identified and analyzed anonymously.
Disease diagnoses were made by qualified cardiologists and psychiatrists in Taiwan. These diagnoses are
clearly listed at the medical reimbursement and claims and the medical reimbursement and discharge
notes are scrutinized by strict peer review. Several Taiwan studies have demonstrated the high accuracy and validity of the diagnoses in NHIRD.14–17 In
addition, this study was also approved by the Ethics Review Board at China Medical University (CMU-REC-101-012).
Study subjects and outcome measures
This study comprises of a study cohort and a comparison cohort. The study cohort contained all patients
with depressive disorder aged 18 years or older. Patients with newly diagnosed depressive disorder in the period of 2000–2002 from both ambulatory care and inpatient care were included as the exposure cohort (ICD-9-CM codes 296.2, 296.3, 300.4 and 311). The index date for the depressive disorder patients was the date of their first outpatient visit. Subjects with a history of acute coronary syndrome diagnosed (ICD-9-CM 410–411.1) before the index date or with missing information on age or sex were
excluded. For the comparison cohort, we used a systematic random sampling method and selected four
insured people without depressive disorder in the same period with frequency matched on age, sex and the year of index date. The follow-up person-years were estimated for each subject from the index date to the data of the subjects who were diagnosed with acute coronary syndrome, or who withdrew from the insurance system before the end of 2009.
Statistical analysis
The distributions of categorical sociodemographic characteristics and comorbidities comprising sex, age, hypertension, diabetes mellitus, hyperlipidemia, stroke, cancer, and peripheral arterial occlusive diseases (PAOD) were compared between the depressive
disorder cohort and the non-depressive disorder cohort, and the differences were examined using the χ2-test. Poisson regression was used to estimate incidence
analysis of events in person-year data structures. Cox’s proportional hazard regressions were used to estimate the risk of developing ACS associated with ACS, adjusting for variables that were significantly related to ACS as observed through the χ2-test.
Hazard ratio (HR) and 95% confidence interval (CI)
were assessed in the model. All analyses were performed by SAS (version 9.2 for Windows; SAS, Cary,
NC, USA). We used a two-tailed P-value lower than 0.05 with the statistically adopted significance level.
RESULTS
For the period 2000 to 2009, we identified 10 871 patients with depressive disorder as the exposure group and 43 484 subjects without depressive disorder as the control group. Among our subjects, 61.6% of them were women and 79.6% were younger than
65 years old (Table 1). Compared with the non-depressive disorder cohort, patients were significantly more prevalent
with hypertension, diabetes mellitus, hyperlipidemia, stroke and peripheral vascular diseases. The
overall incidence rate of ACS was 177% higher in the study cohort than in the comparison cohort (1.61 vs 4.45 per 1000 person-years incidence) with an adjusted HR of 1.88 (95%CI = 1.63–2.17) (Table 2).
Sex-specific analysis shows the study cohort to comparison cohort rate ratio was higher for men than
women, and there were 40% higher risks for men. Patients aged 45–64 years had the highest incidence (6.78 per 1000 person-years, 95%CI = 5.17–8.88) and risk of ACS increases with age. Additionally, Table 2 shows the incidence of ACS measured by
comorbidities status as consistently lower in the comparison cohort and higher risks of ACS were estimated
in the non-comorbidity group (Table 3).
A Kaplan–Meier graph of cumulative ACS incidence curve for depressive disorder patients and
the comparison cohort is shown in Figure 1. The log–rank test indicates that patients with depressive
disorder had significantly higher ACS survival rates (P < 0.001).
DISCUSSION
Based on our research, this is the first nationwide population-based study to investigate specifically the risk of ACS among patients with depression. During a 10-year follow-up, 379 (4.45%) and 562 (1.61%)
ACS episodes among depressed patients and nondepressed subjects, respectively, were documented.
For adults older than 18 years, a diagnosis of depression was associated independently with a nearly
2.77-fold increased risk of ACS during 10 years of follow-up, after adjusting for comorbid medical disorders
and sociodemographic characteristics. Women are at higher risk than men (HR 2.33 vs 3.21). The association persisted in further analyses stratified according to age, especially within the ages of 45–64
years (HR 6.78). Finally, as compared with the nondepressed cohort, a higher risk of ACS occurrence
was observed among depressed patients without comorbid medical diseases except for cancer (HR 4.02). Depression may cause ACS through independent mechanisms other than common cardiovascular
risk factors.
The results of our study are consistent with those of previous studies that have identified depression as a risk factor for CHD.4,18 In a meta-analysis, including
11 cohort studies, depression was used to predict the development of CHD in initially healthy people
with a relative risk of 1.64. There might be a dose– response relation between depression and CHD.4
More recently, another meta-analysis of 28 studies with a total of 80 000 depressed patients was conducted.
18 This previous study discovered that patients
with depression are associated with a wide range
of cardiovascular diseases, including myocardial infarction, coronary heart disease, and stroke (relative
no previous studies have focused on ACS per se but on the association between depression and a more general condition, (i.e., CHD), our study added depression to the list of psychological conditions that have been associated with increased risk of ACS. Previous studies have determined that frequency of depression in older adults was lower compared to younger adults.19 However, risks of ACS and
CHD were positively proportional to increasing age. Patients with depression were observed to develop ACS and CHD during the period of 43–78 years of age.4,18 This wide age distribution can be attributed to
the variability of study designs. Our study enrolled a population over the age of 18 and the results suggested that ACS risk is higher within the age range of
45–64; regarding the younger group, the age-range was within 18–44 years. This finding correlates with
relevant literature that identifies depression as a psychological condition that promotes atherosclerosis.20
Bidirectional associations between depression and
cardiovascular diseases have been extensively documented. The mechanisms by which cardiac risk is
intensified in people with depression remains to be elucidated; however, preliminary evidence suggests several potential mechanisms.6,21–25 First, neuroendocrine
and neurohumoral changes in depressed people may lead to dysfunction of the hypothalamic– pituitary–adrenal axis and activation of the renin– angiotensin–aldosterone system. Second, patients with mood disorders tend to have autonomic and cardiovascular dysregulation, including an increased sympathetic drive, withdrawal of parasympathetic tone, cardiac rate and rhythm disturbances, and an altered baroreceptor reflex function. Their heart rate increases while the heart rate variability decreases, suggesting a possible link to ACS.22 Third, mental
stress-induced ischemia is related to significantly
states can activate pro-inflammatory cytokines, heighten platelet activation, and alter hemodynamic reactivity that contributes to the genesis of coronary
atherosclerosis and triggers ACS.24 Fourth, patients with depression might engage
in behavioral changes,
including fatigue and physical inactivity, leading to further risk of CHD or ACS. Finally, antidepressants, especially tricyclics but not selective serotonin
reuptake inhibitors, might contribute to increased risk of myocardial infarction.6,25
This study has several limitations that merit attention. First, the data used in this study were retrieved
from the NHIRD database and lacked specific social and personal information and drug histories. Therefore, we could not evaluate all other possible impacts, including smoking, body mass index, dietary habits, physical exercise, medication interaction, patients’ drug compliance, and treatment response. Second, we also could not obtain information about individual severity of depression. People with depression who never sought medical attention were overlooked. In addition, approximately one-quarter of myocardial infarctions are ‘silent’ and might also be overlooked in the claims. Third, although the full regression models were specified after adjusting for certain concurrent illnesses, the patients with depression could have been less healthy and could have had higher rates of comorbid medical problems that could affect their risk for ACS. Finally, the evidence derived from a cohort study is generally of lower methodological quality than that obtained from randomized trials, because a cohort study design is subject to many biases related to adjusting for confounders. Despite our
meticulous study design involving adequate control of confounding factors, a key limitation was that bias could still remain because of possible unmeasured or unknown confounders. Nevertheless, apart from these potential problems, the data on depression and
ACS diagnosis were highly reliable.
In clinical practice, both psychiatrists and cardiologists should respect the link between depression and
ACS. For patients with depression, previous studies have suggested that β-blockers and antidepressants, other than tricyclics, should be added in prescriptions for primary and secondary ACS prevention.6,22
In addition, there should be universal screening and cardiovascular referral. Among patients with ACS-developed depression symptoms, initiation of depression therapy may improve the response to treatment for both depression and cardiovascular disease. However, depression screening, referrals, and treatment among patients with ACS are still
controversial because of a lack of supportive randomized control trials or systematic evidence-based
reviews.26 Conclusions
In conclusion, this national population-based retrospective cohort study proved a significant association
between depression and subsequent ACS risk in Taiwan, especially in middle-aged patients with comorbid medical diseases. This finding is compatible with previous meta-analyses. Further study is
required to extend this positive link to clinical purposes, thereby establishing treatment in prevention
and evaluating the benefits of post-ACS depression screening and treatment.
