Depression and cardiovascular morbidity and mortality: cause or consequence?

Ralph A.H. Stewarta,f,*, Fiona M. Northb, Teena M. Westa, Katrina J. Sharplesb, R.John Simesc, David M. Colquhound,e, Harvey D. Whitea,e and Andrew M. Tonking,h,i for the Long-Term Intervention With Pravastatin in Ischaemic Disease (LIPID) Study Investigators

a Green Lane Hospital, Auckland, New Zealand
b Department of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand
c National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia
d Wesley Medical Centre, Brisbane, Australia
e Department of Medicine, University of Queensland, Brisbane, Australia
f Department of Medicine, University of Auckland, Auckland, New Zealand
g Austin and Repatriation Medical Centre, Melbourne, Australia
h Monash University, Melbourne, Australia
i The National Heart Foundation of Australia, Melbourne, Australia

* Correspondence to: Dr Ralph Stewart, Cardiology Department, Green Lane Hospital, Private Bag 92-189, Auckland 1030, New Zealand. Tel: +64-9-630 9903; Fax: +64-9-630 9978
E-mail address: rstewart{at}adhb.govt.nz

Received 19 January 2003; revised 14 July 2003; accepted 21 August 2003

Abstract

Background Depression after myocardial infarction has been associated with increased cardiovascular mortality. This study assessed whether depressive symptoms were associated with adverse outcomes in people with a history of an acute coronary syndrome, and evaluated possible explanations for such an association.

Methods and results Depressive symptoms were assessed using the General Health Questionnaire at least 5 months after hospital admission for acute myocardial infarction or unstable angina in 1130 participants of the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study, a multicentre, placebo-controlled, clinical trial of cholesterol-lowering treatment. Cardiovascular symptoms, self-rated general health, cardiovascular risk factors, employment status, social support and life events were also assessed at the baseline visit. Cardiovascular death (n=114), non-fatal myocardial infarction (n=108), non-fatal stroke (n=53) and unstable angina (n=274) were documented during a median follow-up period of 8.1 years. Individuals with depressive symptoms (General Health Questionnaire score ≥5; 22% of participants) were more likely to report angina, dyspnoea, claudication, poorer general health, not being in paid employment, few social contacts and/or adverse life events (P<0.05 for all). There was a modest association between depressive symptoms and cardiovascular events (hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.13–1.77), but not cardiovascular death (HR 1.12. 95% CI 0.71–1.77). After adjustment for symptoms related to cardiovascular disease, the HR for cardiovascular events was 1.22 (95% CI 0.97–1.53). After further adjustment for employment status, social support and life events, the HR was 1.13 (95% confidence interval 0.87–1.47).

Conclusions There was no significant association between depressive symptoms and fatal or non-fatal cardiovascular events after adjustment for cardiovascular symptoms associated with poorer prognosis. Previously observed associations between depression and cardiovascular mortality may not be causal.

Key Words: Cardiovascular disease • Depression • General HealthQuestionnaire • Mortality • Myocardial infarction

1. Introduction

Many studies have described an association between depression or depressive symptoms and mortality from cardiovascular disease.1Particularly strong associations have been reported in patients experiencing depressive symptoms while in hospital for myocardial infarction,2–4unstable angina5or heart failure.6,7These studies raise an important question. Does depression increase cardiovascular risk, or is it a marker for increased risk determined by other factors? In the first instance, treatment of depression may improve prognosis as well as mood. In the second, alternative strategies may be needed to reduce mortality.

Because mood may be influenced by the health consequences of cardiovascular disease, it is possible that individuals with more severe disease are more likely to be depressed. Assessment of depression performed during hospitalization for myocardial infarction,2–4,8unstable angina,5cardiac investigation9or coronary artery bypass grafting8–11is likely to be influenced by the severity of cardiac disease, prognosis and treatment options. For many patients, depression that follows a coronary event resolves during follow-up.12For these reasons, it is important to know whether depressive symptoms in stable outpatients with coronary artery disease are associated with a poorer prognosis and, if so, whether any such association is explained by more severe cardiac disease.

This report describes the association between depressive symptoms assessed at least 5 months after an acute coronary event and recurrent cardiac events in 1130 outpatients who participated in the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study.13A number of possible mediators that could explain an association between depressive symptoms and cardiovascular mortality were evaluated, including biomedical risk factors, medical treatments, socioeconomic factors, measures of the severity of cardiovascular disease, and general health.

2. Methods

2.1. Study population
The LIPID Study was a randomized, placebo-controlled, clinical trial of cholesterol-lowering treatment with pravastatin involving 9014 patients in Australia and New Zealand.13Men and women aged 31–75 years who had had an acute myocardial infarction or had been hospitalized for unstable angina between 3 months and 3 years previously were eligible for enrolment. The exclusion criteria included cardiac failure (New York Heart Association functional class III or IV) and significant medical illness or surgery during the preceding 3 months. After a 2-month run-in phase, participants were randomly assigned to receive either 40mg/day of pravastatin or a matching placebo between June 1990 and December 1992. The patients’ care was otherwise under the direction of their usual doctors. The LIPID Study was completed in 1997,13but follow-up was continued in the form of the LIPID Cohort Study until December 1999.14The reasons for all hospital admissions and causes of death were documented. The two primary endpoints of the current study were mortality from cardiovascular disease and a composite endpoint including cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke (both reviewed by an Outcome Assessment Committee), and hospitalization for unstable angina. Percutaneous coronary intervention and coronary artery bypass grafting were not included as primary endpoints because of the possibility that the likelihood of these interventions could be influenced by mood.

The LIPID Psychological Well-Being Substudy was designed to assess whether cholesterol reduction had an adverse effect on psychological factors associated with suicide, accidental death or violent death.15From 36 LIPID Study centres, 734 New Zealand patients and 488 Australian patients were randomly selected by the central coordinating centre and invited to participate in the substudy. Of those approached, 1130 (93%) completed the baseline questionnaire at the randomization visit.

2.2. Measurement of depressive symptoms
The 30-question version of the General Health Questionnaire16was used to assess anxiety and depression. A patient was classified as having depressive symptoms if the total score obtained by summing the General Health Questionnaire scores (0, 0, 1, 1) for each question was ≥5. In addition, severity was assessed by summing the Likert scores (0, 1, 2, 3) for each question to obtain a total score (General Health Questionnaire Likert score). Subscales identifying anxiety, worry and tension; feelings of incompetence and low self-esteem; depression and hopelessness; difficulty coping; and social dysfunction were also examined.17In order to assess the possible influence of more severe mood changes, patients with the highest 10% of scores on General Health Questionnaire subscales were compared with the lower 90%.

2.3. Assessment of social and economic factors
Important life events occurring during the preceding year (including financial difficulty, divorce or separation, marital or family problems, and change of job or residence) were documented using the scale devised by Holmes and Rahe.18The employment status of patients was classified as: 1=employed, including keeping house and family; 2=retired; or 3=unemployed or out of work owing to sickness or disability. Information as to whether a person was living alone and the estimated number of visits with friends or family during the preceding month were used to assess social integration or isolation.19The socioeconomic status was estimated by linking the patient's residential address at study entry to 1991 general population census data. The median personal income for all persons aged >15 years living in the same census collection district (approximately 200 households) was used as the measure of socioeconomic status. Finally, the age on leaving full-time education was recorded.

2.4. Cardiovascular risk factors, cardiovascular disease severity and medical treatments
The following cardiovascular risk factors were assessed prior to randomization into the LIPID Study: serum lipid levels, body mass index, white blood cell count, self-reported diagnosis of hypertension or diabetes, and history of smoking (never, previous or current). The following clinical measures of disease severity were also assessed: myocardial infarction or unstable angina as the qualifying event, a history of myocardial infarction prior to the qualifying event, a history of stroke or claudication, the Canadian Cardiovascular Society anginal class, and the New York Heart Association functional class. In addition, patients rated their overall health during the previous 2 months as poor, average, good or very good.

Usage of aspirin, beta-blockers, angiotensin-converting-enzyme inhibitors and calcium-channel antagonists was documented at the baseline visit. Compliance with the study medication during the follow-up period was assessed by a pill count at each clinic visit. Patients were classified as fully compliant if they did not stop taking the study medication during the study. It was documented if patients underwent percutaneous coronary intervention or coronary artery bypass grafting after the qualifying event or during follow-up.

2.5. Statistical analysis
Associations between depressive symptoms and other baseline risk factors were examined using logistic regression (with presence/absence of depressive symptoms as the outcome measure) to allow adjustment for age, sex and country of residence. Cox proportional hazards regression analyses with time-constant covariates were used to examine associations between baseline variables and cardiovascular morbidity and mortality, and associations between depression scores and cardiovascular morbidity and mortality. The proportionality of hazards was assessed by plotting scaled Schoenfeld residuals20against each covariate, and no significant departures from the base model were discovered. The results are presented as hazard ratios and 95% confidence intervals.

To fully explore confounding, covariates were considered for the Cox regression models if, univariately, they were or were expected to be prognostic, or if there was an association between the covariate and depressive symptoms regardless of statistical significance. For each successive group of covariates (social circumstances, cardiovascular risk, self-reported health), model-building involved selecting the variables that were prognostic or that confounded the association between depressive symptoms and outcome. The nature of the association between depression scores and outcomes was examined using a linear term, quintiles and a binary measure in the models. For ease of interpretation, continuous risk factors in the final models were expressed using categorical classifications since it had been established that the results were not sensitive to continuous or categorical expression. Where a conventional cut-off was not available, the upper or lower quartile was used to categorize the covariate. In the final models, 10-year age groups were used to adjust for confounding by age.

3. Results

Of the 1222 patients approached to participate in this substudy, 1130 (93%) completed the baseline questionnaire at the randomization visit. The associations between baseline characteristics and depressive symptoms at baseline (General Health Questionnaire score ≥5), cardiovascular death, and the combined endpoint ofcardiovascular death, myocardial infarction, stroke or unstable angina during follow-up are presented in Table 1. Patients younger than 58 years (the lowest quartile) were more likely to have depressive symptoms than older patients. There was no significant sex difference after adjustment for age. Depressive symptoms were more common in Australian patients than in New Zealand patients. The reason for this difference between countries is unclear.


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Table 1 Odds of depressive symptoms at baseline, cardiovascular death, and cardiovascular events during follow-up, according to baseline characteristics

 
After adjustment for age, sex and country of residence, there was a strong association between depressive symptoms and shortness of breath, angina and claudication. There was also a trend for more depressive symptoms in patients with hypertension and diabetes. Each of these measures of cardiac disease was associated with adverse cardiovascular events during follow-up(Table 1). Patients with a previous myocardial infarction had a worse prognosis, but were not more likely tohave depressive symptoms. Average or poor self-rated health was associated with both depressive symptoms at baseline and increased cardiovascular morbidity and mortality during follow-up. The likelihood of depressive symptoms did not differ significantly according to serum lipid levels, obesity, an elevated white cell count, current smoking, or treatment with aspirin, beta-blockers or angiotensin-converting-enzyme inhibitors (data not presented).

Although patients with depressive symptoms were more likely to discontinue the study medication during follow-up, this characteristic was not significantly associated with an increase in cardiovascular events (Table 1). However, depressive symptoms were more common in patients who were unemployed, those with fewer social contacts, and those who reported adverse life events during the preceding year, including divorce, financial difficulties, and marital or family problems. Cardiovascular events were more common in the unemployed and in those reporting major financial difficulties (Table 1). There was no association between depressive symptoms and a residential area-based measure of socioeconomic status.

After adjustment for age, sex and country of residence, there was no association between depressive symptoms and cardiovascular mortality (Fig. 1), but there was a modest association between depressive symptoms and cardiovascular events (Fig. 2, Table 2). This association appeared to be stronger for unstable angina than for myocardial infarction or stroke, and was also present for percutaneous coronary intervention and coronary artery bypass grafting (Table 2). The association between depressive symptoms and cardiovascular events remained significant after adjustment for socioeconomic variables and adverse life events, but was substantially reduced after adjustment for previous myocardial infarction, shortness of breath, angina, claudication, diabetes, hypertension, and percutaneous coronary intervention or coronary artery bypass grafting after the qualifying event (Table 3). The association was not statistically significant after further adjustment for self-rated health at baseline.



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Fig. 1 Cumulative freedom from cardiovascular death in patients without and with depressive symptoms (General Health Questionnaire score ≥5) at baseline, estimated from a Cox proportional hazards model adjusted for: (a) age, sex and country of residence; and (b) age, sex, country of residence, previous myocardial infarction, hypertension, claudication, diabetes, coronary artery bypass grafting, Canadian Cardiovascular Society anginal class, New York Heart Association functional class, and self-rated health.

 


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Fig. 2 Cumulative survival free from cardiovascular death, myocardial infarction, stroke or unstable angina in patients without and with depressive symptoms (General Health Questionnaire score ≥5) at baseline, estimated from a Cox proportional hazards model adjusted for: (a) age, sex and country of residence; and (b) age, sex, country of residence, previous myocardial infarction, hypertension, claudication, diabetes, coronary artery bypass grafting, Canadian Cardiovascular Society anginal class, New York Heart Association functional class, and self-rated health.

 

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Table 2 Associations between depressive symptoms and different cardiovascular outcomes

 

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Table 3 Associations between depressive symptoms (General Health Questionnaire score ≥5) and primary outcome measures after adjustment for potential confounders

 
The associations between depressive symptoms and any adverse cardiovascular event were similar among patients with the highest 10% of scores on the subscales ‘depression’, ‘anxiety’, ‘social dysfunction’, ‘coping’ and ‘incompetence’ (Table 4). For each subscale there was no association with cardiovascular death. The associations between each subscale and cardiovascular events decreased substantially after adjustment for angina, the New York Heart Association functional class, diabetes, claudication, hypertension, percutaneous coronary intervention or coronary artery bypass grafting after the qualifying event, and self-rated general health at baseline. There was also no association between depressive symptoms assessed as a continuous measure (General Health Questionnaire Likert score) and cardiovascular events after adjustment for these covariates.


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Table 4 Associations between General Health Questionnaire Likert subscales and cardiovascular outcomes

 
4. Discussion

In this study there was no significant association between depressive symptoms at baseline and subsequent cardiovascular mortality, but there was a modest association with the composite endpoint of cardiovascular mortality, myocardial infarction, stroke or unstable angina. Patients with cardiovascular symptoms and poor general health were more likely to havedepressive symptoms at baseline. After adjustment for these and other predictors of increased cardiac risk, there was no significant association between depressive symptoms and cardiac events during long-term follow-up. However, a modest increase in cardiac events related to depressive symptoms cannot beexcluded.

Selected studies of the possible association between depression and mortality after myocardial infarction are summarized in Table 5.3,21–28To reduce the impact of publication bias, the table includes cohort studies published before March 2003 that reported at least 30 fatal events, and excludes multiple publications from the same cohort. In eight of the 10 studies listed, there was no statistically significant association between depression and mortality after adjustment for potential confounders. Hemingway and Marmot have undertaken a larger systematic review,29which included additional studies with fewer fatal and non-fatal endpoints and studies of patients referred for cardiac investigation30or admitted to hospital with unstable angina5or heart failure.6,7Many of these studies reported associations between depressive symptoms and coronary events, but there were several potential sources of bias.29These include the possibility of publication bias due to selected reporting from comparisons between numerous psychosocial variables and outcomes in one study, and failure to publish smaller studies in which there was no significant association between depression and cardiovascular events.


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Table 5 Studies evaluating the association between depressive symptoms and mortality after MI

 
In most previous studies, depressive symptoms were assessed during or shortly after hospitalization for myocardial infarction,2–4,8unstable angina,5heart failure,6,7cardiac investigations9or cardiac surgery.10This is an appropriate time to assess cardiovascular risk and institute treatment. However, when patients are in hospital, the severity of cardiac disease, available treatment options and prognosis are discussed, and these factors are likely to have a significant impact on mood. In the current study, depression was assessed more than 5 months after hospitalization in clinically stable persons at a time when prognostic information was not provided, thus their mood would have been less likely to be influenced by the severity and prognosis of their cardiac disease. Subjects were selected for the study by their willingness to participate in a randomized clinical trial. A potential limitation, which is shared by other studies (Table 5), is that the study cohort may not have included subjects with more severe depression or poorer general health.

Failure to recognize or adequately adjust for confounding is a potential limitation of all observational studies. In the current study, information on the left ventricular ejection fraction and angiographic severity of coronary artery disease was not available. Failure to adjust for these risk predictors is likely to lead to overestimation of any association between depressive symptoms and outcome. However, in studies examining the association between depressive symptoms and cardiac risk, it may be most important to adjust for prognostic predictors that directly influence quality of life, and hence mood. In contrast to some previous studies, the current study adjusted for measures of disease severity likely to influence perceived health, such as the presence and severity of angina, shortness of breath and claudication. Poor health is likely to cause depressive symptoms, but in some patients depression may contribute to poor health. To account for the possibility of over-adjustment in the models, hazard ratios for the associations between depressive symptoms andoutcomes are presented including and excluding self-reported health as a covariate.

The current study used the 30-question version of the General Health Questionnaire to assess depressive symptoms. This scale was developed as a screening tool for psychiatric illness in general populations, is well validated, and has been widely used in many countries.31Although the General Health Questionnaire is not specific for depression, its scores correlate closely with and have similar sensitivity and specificity to those of other depression scales such as the Centre for Epidemiological Studies Depression Scale and the Beck Depression Inventory.31,32The General Health Questionnaire identified associations between depressive symptoms and general health, social isolation, unemployment and adverse life events. For the purpose of analysis, responses to the General Health Questionnaire were definedcategorically, as a continuous measure and by various subscales reflecting different aspects of mood. It is therefore unlikely that the use of the General Health Questionnaire to assess depressive symptoms explains the failure to predict adverse outcomes.

Other possible explanations for an association between depressive symptoms and cardiovascular morbidity were evaluated. Lower socioeconomic status,33social isolation and poor social support22have been associated with increased cardiovascular morbidity and mortality in previous studies. In the current study, there was no evidence of a socioeconomic gradient in depressive symptoms, but persons who were unemployed and those with few social contacts were more likely to be depressed. Individuals who reported adverse life events during the preceding year were also more likely to have depressive symptoms. A modest association betweenthese life events and adverse cardiovascular outcomes is possible. Patients with depressive symptoms were more likely to discontinue the study medication during follow-up, raising the possibility that poorer compliance with certain medical treatments may contribute to adverse outcomes. However, adjustment for compliance with the study medication did not significantly influence the risk of cardiovascular events. Patients with depressive symptoms were also more likely to undergo percutaneous coronary intervention or coronary artery bypass grafting during follow-up. Although this could be explained by greater disease progression, depressed patients had more angina and dyspnoea at baseline, indicating a greater need for coronary revascularization at the time when mood was assessed.

Associations between depressive symptoms and mortality have been reported in patients without known coronary artery disease,11,34–37but these reported associations were in general weaker than those observed in studies of patients with cardiac disease. In several large community studies, there was no association between depression at baseline and subsequent cardiovascular mortality.38–40In two of these studies,39,40there was a modest increase in mortality with increases in depressive symptoms over time. In a study of middle-aged military personnel, there was no association between depression or anxiety and the extent of coronary artery disease estimated by CT calcium scoring.41To establish a causal association between depression and adverse cardiac events, large randomized clinical trials are needed to demonstrate whether or not treatment of depression reduces cardiac morbidity andmortality.12,42

In conclusion, in this study of patients with stable coronary artery disease, depressive symptoms were more common in those with average or poor self-rated health, angina, exertional dyspnoea and claudication—all markers for poorer prognosis. After adjustment for cardiovascular risk factors, socioeconomic variables and symptoms of cardiovascular disease, there was no evidence of an association between depressive symptoms and fatal or non-fatal cardiovascular cardiac eventsduring long-term follow-up.

Acknowledgments

The LIPID Study was supported by a grant from Bristol-Myers Squibb (Princeton, New Jersey, USA) and conducted under the auspices of the National Heart Foundation of Australia (Melbourne, Australia). The design, management, analysis and interpretation of this LIPID substudy were conducted independently of the sponsor. Honorary Professor White received partial salary funding from the Green Lane Hospital Research and Educational Fund (Auckland, NewZealand). The authors are indebted to Deborah Scott (Dunedin, New Zealand), Sarah Mulray and Wendy Hague (National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia) for managing the study, Charlene Nell for secretarial assistance and Anna Breckon for editorial assistance with the manuscript, the LIPID Study Management Committee for their support, and the Psychological Well-Being Substudy Investigators and participants for their contribution to the study. See Reference 14 for the full list of investigators.

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