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The primary aim was to study the association between preoperative depression and long-term survival after coronary artery bypass grafting (CABG). Our secondary objective was to analyze the association between depression and cardiovascular events or all-cause mortality. In a nationwide, population-based, cohort study, all patients who underwent CABG in Sweden from 1997 to 2008 were included from the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies registry. Individual-level data were cross-linked from other national Swedish registers. Depression status and outcomes were obtained from the National Patient Register. The study population was 56,064 patients who underwent primary, isolated, nonemergent CABG. We identified 324 patients (0.6%) with depression before CABG. During a mean follow-up of 7.5 years, 114 patients (35%) with depression died, compared with 13,767 patients (25%) in the control group. Depression was significantly associated with increased mortality and the combined end point of death or rehospitalization for myocardial infarction, heart failure, or stroke (multivariate-adjusted hazard ratios [95% confidence intervals] 1.65 [1.37 to 1.99] and 1.61 [1.38 to 1.89], respectively). In conclusion, we found a strong and significant association between depression and long-term survival in patients with established ischemic heart disease who underwent CABG. Depression was also associated with an increased risk for a combination of death or rehospitalization for heart failure, myocardial infarction, or stroke.
Clinically significant depressive symptoms are common in patients with ischemic heart disease. Thirty-one percent to 45% of patients with coronary artery disease (CAD) suffer from depressive symptoms.
Studies have shown that depression is associated with longer hospital stay, more perioperative complications, more frequent rehospitalizations, and increased mortality in patients who underwent coronary artery bypass grafting (CABG).
We performed a nationwide, population-based, cohort study to determine whether preoperative depression was associated with long-term outcomes in patients with CAD who underwent CABG. The primary aim was to study the association between preoperative depression and long-term survival after primary isolated CABG. Our secondary objective was to analyze the association between depression and a combined end point of rehospitalization for myocardial infarction, heart failure, or stroke or all-cause mortality.
We conducted a nationwide, population-based, cohort study. The study was approved by the regional Human Research Ethics Committee, Stockholm, Sweden.
We identified all patients who underwent CABG in Sweden from 1997 to 2008 from the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART) registry.
was used by the National Board of Health and Welfare to retrieve information from the national registries and assemble the study database. Baseline patient characteristics were obtained from the SWEDEHEART and Swedish National Patient Register (Swedish National Board of Health and Welfare).
The National Patient Register covers all diagnoses for all patients hospitalized in Sweden from 1987. We used the National Patient Register (Swedish National Board of Health and Welfare) to identify patients with a diagnosis of depression (International Classification of Disease, version 10 [ICD-10], code: F3 and ICD-9 codes: 296, 311, 300.4, 309.0, and 309.1). Patients were divided into an exposed group consisting of patients with a diagnosis of depression preceding the date of CABG surgery and an unexposed group without a preoperative diagnosis of depression.
The primary outcome measure was all-cause mortality. Secondary outcome measures included a combined end point of all-cause mortality or rehospitalization for myocardial infarction, heart failure, or stroke. Survival status was ascertained in February 2011 using the Swedish personal identity number
and the continuously updated Total Population Register at Statistics Sweden. All patients with a postoperative diagnosis of myocardial infarction (ICD-10 code I21), heart failure (ICD-10 code I50), or stroke (ICD-10 codes I60 to I69) were identified. The validity of these diagnoses in the Swedish National Patient Register has been evaluated and was found to be 95% for a primary diagnosis of heart failure, and the positive predictive value for stroke was 98.6% and for myocardial infarction was 98% to 100%.
Using the personal identity number and linkage to the National Patient Register, the number of days between CABG and first rehospitalization for myocardial infarction, heart failure, or stroke could be calculated. Follow-up regarding myocardial infarction, heart failure, and stroke ended on December 31, 2008. Information regarding the cause of death was obtained from the Swedish Cause of Death Register (Swedish National Board of Health and Welfare).
Time to event was calculated as the time in days from the date of CABG to the corresponding clinical end point (death from any cause or the composite end point). We used the Kaplan-Meier method to calculate cumulative survival and construct survival curves for the exposed and unexposed group and used the log-rank test to compare differences between the curves. We used Cox proportional hazards regression to model survival. We created several multivariate models considering all baseline characteristics and reached a final parsimonious model that included the following variables: age, gender, diabetes mellitus, chronic obstructive pulmonary disease, peripheral vascular disease, preoperative left ventricular function, estimated glomerular filtration rate, history of myocardial infarction, history of heart failure, history of stroke, and acute perioperative kidney injury. We checked the assumption of proportional hazards, first by graphical examination of the survival function and then by including time-dependent covariates in the final model. Model fit was evaluated by analysis of Cox-Snell residuals. Some data were missing: left ventricular ejection fraction (32%), diabetes (36%), peripheral vascular disease (32%), estimated glomerular filtration rate (17%), and acute kidney injury (36%), so multiple imputation by chained equations was used to impute missing values. The event indicator and Nelson-Aalen estimator of the cumulative baseline hazard were included in the imputation model.
All analyses were performed on the imputed data set. We assumed that the missing values were missing at random. One hundred data sets were imputed, and estimates from these data sets were combined using standard methods. The objective of imputation was to retain statistical power and reduce selection bias that may occur when deleting observations with missing covariates. In addition, we performed a complete-case analysis, in which only observations without missing values for model covariates were included. Stata, version 12.1 (StataCorp LP, College Station, Texas), was used for all analyses.
We identified 69,243 patients who underwent CABG from 1997 to 2008 from the SWEDEHEART register (Figure 1). We excluded 1,234 patients who had previous cardiac surgery and 9,509 patients who had another cardiac procedure in addition to CABG. Finally, we excluded 2,436 patients who underwent emergency surgery defined as surgery within 24 hours of decision to operate. The final study population consisted of 56,064 patients who underwent primary, isolated, nonemergent CABG. We identified 324 patients with a preoperative diagnosis of depression from the National Patient Register. The remaining 55,740 patients were categorized as the control group. Baseline characteristics of the study population are listed in Table 1. Patients with depression and the control group were not balanced regarding several potentially confounding factors, most importantly, female gender, diabetes mellitus, peripheral vascular disease, chronic obstructive pulmonary disease, and a history of stroke.
Table 1Baseline characteristics
n = 56064
n = 55740
n = 324
Percent of study population
Age, mean (SD), (years)
Estimated GFR, mean (SD), (mL/min/1.73 m2)
Peripheral vascular disease
Chronic obstructive pulmonary disease
Prior myocardial infarction
Prior heart failure
Left ventricular ejection fraction
Acute perioperative kidney injury
Internal thoracic artery use
Coronary bypass without cardiopulmonary bypass
Acute perioperative kidney injury was defined as >0.3 mg/dl (26 μmol/L) increase in postoperative creatinine values.
The total follow-up time was 422,162 person-years (mean follow-up time 7.5 years), and there was no loss to follow-up. During follow-up, 114 patients (35.1%) with depression died, compared with 13,767 patients (24.6%) in the control group. The early mortality (death within 30 days of surgery) in patients with depression was 3.1%, and it was 1.5% in the control group. The age- and gender-adjusted relative risk for early mortality associated with depression was 2.06 (95% confidence interval [CI] 1.09 to 3.89). After multivariate adjustment, early mortality was not significantly greater in patients with depression (odds ratio 1.33, 95% CI 0.68 to 2.61).
The crude and multivariate-adjusted associations between depression and all-cause mortality are listed in Table 2.
Table 2Crude and multivariate-adjusted association between depression and all-cause mortality
In the unadjusted Cox regression analysis, depression was associated with increased mortality (hazard ratio [HR] 1.94, 95% CI 1.61 to 2.33). The Kaplan-Meier estimates of survival are shown in Figure 2. The unadjusted 1-, 5-, and 12-year survival was 93%, 80%, and 41% in depressed patients and 97%, 89%, and 63% in the control group (p <0.001), respectively. In the final multivariate Cox regression model, depression was significantly associated with increased mortality (HR 1.65, 95% CI 1.37 to 1.99). Depression was more common among women compared with men (1.1% vs 0.43%). The crude and multivariate-adjusted associations between depression and all-cause mortality stratified by gender are listed in Table 3. There was a significant association between depression and mortality in men (HR 1.96, 95% CI 1.55 to 2.47) but not in women (HR 1.24, 95% CI 0.90 to 1.71).
Table 3Crude and multivariate-adjusted association between depression and all-cause mortality stratified by gender
The crude and multivariate-adjusted associations between depression and combined end point of death or rehospitalization for myocardial infarction, heart failure, or stroke are listed in Table 4. In the unadjusted Cox regression analysis, depression was significantly associated with the combined end point (HR 2.01, 95% CI 1.73 to 2.35). The Kaplan-Meier estimated cumulative incidence is shown in Figure 3. Depression was significantly associated with the combined end point in the multivariate-adjusted model (HR 1.61, 95% CI 1.38 to 1.89).
Table 4Crude and multivariate-adjusted association between depression and the composite end point of all-cause mortality or rehospitalization for heart failure, myocardial infarction, or stroke. Hazards ratios and 95% confidence intervals
In 10 patients with depression, death occurred within 30 days from surgery. The cause of death in these patients was considered as cardiac-related death. In patients with late mortality, cause of death was cardiac in 45 patients and noncardiac in 24 patients. There was no confirmed suicide; however, cause of death was unknown in 35 patients.
We found that among all patients who underwent primary isolated CABG on a nonemergency basis in Sweden from 1997 to 2008, there was a strong and statistically significant association between depression and long-term survival. Depression was also associated with an increased risk of the combined end point of death or rehospitalization for heart failure, myocardial infarction, or stroke. The observed association between depression and mortality differed between men and women. Although depression was more common in women, the association between depression and long-term mortality was statistically significant only in men and not in women. This may in part be explained by the fewer number of female patients or other mechanisms that we were unable to identify.
The strengths of our study involve its population-based, longitudinal, cohort design; the large study population; and the complete and accurate follow-up and survival ascertainment due to the high-quality national Swedish registers.
Previous studies agree with our findings. Wang et al
investigated the impact of depression on the clinical outcomes in patients with CAD who underwent percutaneous coronary intervention (PCI). Four hundred patients who underwent PCI were assessed 1 day before and 2 weeks after PCI. The primary end point was major adverse cardiovascular events, which included mortality, nonfatal myocardial infarction, or repeat revascularization. Before PCI, 25.5% of patients were classified as depressed, and 2 weeks after the procedure, 38.5% of patients were depressed. The results showed that patients with depression after PCI had a significantly greater risk of major adverse cardiovascular events during the 3 years of follow-up, compared with nondepressed patients.
investigated the association between different mental disorders in 1,107,524 Swedish young men at conscription and the risk of incident CAD. The age-adjusted HR regarding depression at conscription and incident CAD was 1.30 (95% CI 1.05 to 1.60).
Considering the youth of the participants, it is most unlikely that the association between depression and incident CAD was due to reverse causation, that is, living with cardiovascular disease causes depression.
The Symptom Checklist-90 Revised was used. Twenty-three percent of the patients had a high level of depression before surgery, and this was significantly associated with longer hospital stay and late perioperative complications.
and it was also shown that the severity of depression affected length of hospital stay. Interestingly, a low socioeconomic status in addition to depression further prolonged postoperative hospital stay. We had no information regarding the socioeconomic status, which is a limitation to our study.
Previous research has reported that 31% to 45% of patients with CAD have depressive symptoms.
We found that 11% of all patients had a prescription for antidepressants before surgery. In the present study, we aimed to assess the association between severe depression and mortality in patients with established CAD who underwent CABG. Depressive status was established from ICD codes in the National Patient Register, with an almost complete coverage since 1973. Only 0.6% of all patients who underwent primary, isolated, nonemergent CABG in Sweden from 1997 to 2008 had a diagnosis of depression before surgery in the National Patient Register. There are several explanations. Mental health services have been reformed during the last decades, and patients with depression are more often treated in outpatient care.
Furthermore, many patients with depression do not seek help, and some will be depressed without knowing. With our registry-based study design, we were able to capture the most severely ill patients because these patients were treated in a hospital or by a psychiatrist in the specialized outpatient clinic because of their depression.
In our study, most depressed patients were men, but still depression was more than twice as common among women. Depression can take different shapes in men and women.
Men are more likely to report symptoms of anger, irritability, risk-taking behaviors, and substance abuse over more traditional symptoms such as sleep problems and withdrawal from social occasions. If clinicians only take traditional symptoms into account, depression could be underdiagnosed in men.
In a prospective cohort study in 1,024 patients with CAD, it was found that patients with depressive symptoms had an almost 50% greater risk for adverse cardiovascular events than patients without depressive symptoms. The increase in risk was still significant after adjustment for co-morbid conditions and left ventricular ejection fraction. However, after further adjustment for smoking, medication adherence, and physical activity, the difference in outcomes was no longer significant.
are more common among depressed patients. Another possible explanation could be that failure in communication and patient cooperation is more common among depressed patients, resulting in the possibility that depressed patients do not receive optimal coronary care.
Limitations include the observational study design, which prevents conclusions regarding causation. Although this was a large, nationwide, population-based study, the number of patients with depression was low. Still, we found a strong and statistically independent association between depression and mortality after multivariate adjustment. Other limitations were lack of information regarding socioeconomic status, medication, alcohol consumption, and substance abuse.
The authors have no conflicts of interest to disclose.
This work was supported by research grants (grant number: SLS-330221) from The Swedish Society of Medicine , the Capio Research Foundation , Karolinska Institutet Foundations and Funds , and the Mats Kleberg Foundation (Stockholm, Sweden).