THE IMPACT OF DEPRESSION ON OUTCOMES FOLLOWING

ACUTE MYOCARDIAL INFARCTION.

A thesis submitted in conformity with the requirements for the degree of

Doctor of Philosophy in Clinical Epidemiology

Graduate Department of Health Policy, Management, and Evaluation in the

University of Toronto

ABSTRACT

Paul Andrew Kurdyak

The Impact of Depression on Outcomes Following Acute Myocardial Infarction
Doctor of Philosophy, 2009
Department of Health Policy, Management, and Evaluation (HPME)
University of Toronto

This thesis uses observational study design methods to explore the relationship

between depression and various outcomes following acute myocardial infarction (AMI).

There are three main studies. First, the relationship between depression and mortality

following AMI was measured. The main finding was that the factor determining the

increased mortality rate in depressed patients is reduced cardiac functional status. The

main implication was that efforts to address increased mortality in depressed patients

with cardiovascular illnesses should focus on processes that impact cardiac functional

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status. Second, the impact of depression on service consumption following AMI was

examined. Depressive symptoms were associated with a 24% (Adjusted RR:1.24; 95%

CI:1.19-1.30, P<0.001), 9% (Adjusted RR:1.09; 95% CI:1.02-1.16, P=0.007) and 43%

(Adjusted RR: 1.43; 95% CI:1.34-1.52, P<0.001) increase in total, cardiac, and

noncardiac hospitalization days post-AMI respectively, after adjusting for baseline patient

and hospital characteristics. Depressive-associated increases in cardiac health service

consumption were significantly more pronounced among patients of lower than higher

cardiac risk severity. The disproportionately higher cardiac health service consumption

among lower-risk AMI depressive patients may suggest that health seeking behaviors

are mediated by psychosocial factors more so than by objective measures of

cardiovascular risk or necessity. Third, methodological issues related to missing data

were explored. A systematic review of three psychiatric journals revealed that a small

minority of studies (5.8%) addressed the impact of missing data in a meaningful way. An

example using real data demonstrated the potential bias introduced by missing data and

different ways to address this bias. The paper concludes with recommendations for both

reporting and analyzing studies with substantial amounts of missing data.

Overall, the studies add to the literature exploring the relationship between

depression and outcomes following acute myocardial infarction. Future studies

measuring the relationship between depression and mortality will need to factor the

mediating relationship between depression and cardiac functional status. The increased

health service utilization associated with depression will need to be replicated in other

illness models. Together, the studies add to the existing conceptual framework for

measuring relationships between depression and outcomes in patients with

cardiovascular illnesses.

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 Chapter 1: Introduction to Depression and AMI

The
purpose of this chapter is to:

1) Highlight the importance of depression after acute myocardial infarction (AMI)

2) Describe the role depression might play in health service consumption following

AMI

3) Describe issues related to missing depression data

4) Introduce the primary thesis questions

Depression and Medical Comorbidity

Comorbidity exists when any two medical or psychiatric conditions co-occur. The

prevalence of depression is substantially higher in populations with medical illnesses

than in populations without medical illnesses 1, 2. The high rate of depression in persons

with medical illnesses is understandable given the burden imposed by chronic medical

illnesses. However, the burden of depression is increasingly being considered

substantial in its own right, with disability related to depression projected to be second

only to ischemic heart disease in developed countries by the year 2020 3.

The ways that depression interacts with medical illnesses are complex. In the

Medical Outcomes Study 4, Wells et al. demonstrated that depressed patients perceived

their general health and social and vocational functioning as more impaired than patients

with one of seven other chronic medical conditions. Furthermore, the disability was

additive when depression was comorbid with other chronic medical conditions 4. These

findings have been replicated in a prospective cohort study of primary care patients 5.

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Thus, depression is a chronic, disabling illness that is quite common and, when

comorbid with chronic medical conditions, cumulatively disabling.

Measurement of depression with comorbid medical illness

A diagnosis of depression is made after certain criteria are met for a specific

period of time and if a level of distress or functional impairment has occurred6.

Measuring depression when it co-occurs with a comorbid medical condition is a

challenge. Given the symptomatic burden of chronic medical conditions, certain criteria

(e.g., reduced appetite, sleep disturbance, reduced energy) could be ascribed to either

depression or a medical condition. If a somatic symptom that is a diagnostic criterion for

major depressive disorder is due to a medical condition, there is the potential for a bias

towards increased depression prevalence because the depression threshold is reached

due to somatic symptoms potentially unrelated to depression.

Adding to this potential bias is the finding that persons with both depression and

chronic medical conditions tend to amplify physical symptoms related to a medical

condition. A recent systematic review suggests that patients with both depression and

medical conditions compared with patients with medical conditions alone reported

significantly higher numbers of medical symptoms even after adjusting for severity of

illness 7. This phenomenon would likely create problems both for generating a

prevalence rate for depression (given the reliance on reporting of physical symptoms to

make a depression diagnosis) as well as an accurate ascertainment of medical illness

severity where objective measures of severity do not exist.

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Depression and health care consumption

Several studies have shown significantly higher health care costs for depressed

patients in primary care settings compared to non-depressed patients 8-10. The increased

service utilization persists after adjustment for chronic medical conditions 8, 9. The

increased costs also occur in any health utilization category measured, including primary

care visits, medical specialty visits, lab tests, pharmacy costs, inpatient medical costs,

and mental health visits 11. Other studies have shown that approximately 35% of “high

utilizers” of health care services in primary care settings have recurrent major depression

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. Hospitalizations are the most costly services provided in a health care system.

Depression, after controlling for medical illness severity, increases both length of stay

and likelihood for readmission 13, 14.

Depression Following Acute Myocardial Infarction

Depression is highly prevalent following AMI, occurring in approximately 20%

of AMI survivors 15, 16 compared with the approximately 3% prevalence in a

communitybased sample 17. Furthermore, depression after AMI tends to persist when

assessed up to

four months following AMI 16, 18.

Numerous studies have suggested that depression independently increases the risk

of mortality following AMI 16, 19-24. However, the relationship between depression and

mortality following AMI has not been consistent, with numerous other studies suggesting

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no increased risk of mortality related to depression 15, 18, 25-29. The studies differ widely in

terms of the way depression is measured, patient population, timing of depression

measurement, and risk adjustment. Authors have cited the timing of depression

measurement following AMI25 and confounding by non-cardiac comorbidity, somatic

symptoms or cardiac illness severity23, 27 as potential reasons for discrepant results.

Depression measurement with comorbid medical illness has already been described.

Following AMI, patients are likely to experience some of the somatic symptoms of

depression whether depressed or not. Additionally, these symptoms are more likely to

occur immediately following an acute event like AMI than in the weeks following. Many

of the studies that have found a large positive association between depression and

mortality following AMI have measured depression within 7 days of incident AMI22, 30-34.

One study found that depression measured during hospitalization for AMI predicted

mortality at 4 months but was not a predictor of mortality after 8 years of follow-up 29.

There is a high likelihood that somatic symptoms could be erroneously attributed to

depression rather than natural phenomena immediately following AMI, especially since

depression rating scales are unable to make a distinction between the potential causes

of somatic symptoms. Additionally, a diagnosis of depression requires a two week

duration of symptoms6. Patients following AMI may experience immediate distress

following AMI that does not persist to become a depressive episode.

The variation in the relationship between depression and mortality following AMI

suggests that the relationship may be quite complex. Biological mechanisms that

increase risk of cardiac events may be more prevalent in depressed patients following

AMI such as increased platelet aggregation35-37 and decreased heart rate variability38-40.

Depression is twice as common in women compared to men and women have a higher
likelihood of mortality following AMI41. In addition, individuals with depression are more

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likely to have cardiac risk factors such as smoking and diabetes and less likely to adhere
to recommendations and medications that can alter risk of mortality following AMI 42-44.
Furthermore, cardiac functional status, a measure of peak oxygen capacity,

has been shown to be a robust predictor of mortality following AMI 45, 46 and to be lower in

patients with depression 47. Thus, the relationship between depression and mortality

following AMI could be related to depression per se or to factors that are known to both

correlate with depression and to be associated with an increased risk of mortality

following AMI.

It is not possible to use rigorous methodologies such as randomized controlled

trials to study the relationship between depression and mortality following AMI because

depression does not occur randomly and is associated with a number of factors

described above that are also related to mortality following AMI. In other words,

depressed and non-depressed individuals differ in systematic ways, and many of these

differences are related to the likelihood to experience an AMI and to have differential

survival following

AMI21. Ascertainment of any relationship between depression and mortality following

AMI requires careful observational study design, elucidation of potential mediating

factors, and risk adjustment for potential confounding factors.

Depression and Health Service Consumption Following AMI

Individuals with depression use 50% more health care services than individuals

without depression 48, 49. Such increases in depression-related health service

consumption are associated with high health care costs 50 and have prompted targeted

interventions to try to address the needs of depressed people while simultaneously

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reducing health service consumption51. Similar high rates of health service consumption

have been observed in

patients with cardiovascular illnesses generally 52, 53 and following AMI specifically54.

The reason for elevated rates of health service consumption in patients with depression

following AMI is unclear. On the one hand, the elevated health service consumption

might reflect greater clinical severity 21 as studies showing a significantly

positive association between depression and mortality following AMI would suggest 16, 18,
22-24
. However, others have argued that the relationship between depression and health

service consumption may reflect depression-related physical symptom amplification and

health seeking behaviours 48. If the increased health service consumption reflects

factors other than increased illness severity, then the increased health service

consumption is a potential source of unnecessary health care costs. The novel

contribution of this thesis is to assess the relationship between depression,

cardiovascular illness severity and health service consumption following AMI.

Depression and AMI – a conceptual framework

The conceptual framework for this thesis is adapted from earlier investigators

who conducted a review of the literature on the relationship between depression and

AMI 55 and is illustrated in Figure 1.1. This framework outlines a causal pathway for

factors that are involved in the relationship between depression and AMI. Cardiac risk

factors and patient demographics are important determinants of both AMI and the

subsequent development of depression. Once depression has occurred, cardiac illness

severity and functional status are important predictors of mortality following AMI. In

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addition, receiving revascularization procedures and the presence of medical

comorbidities influence mortality following AMI. These three factors (cardiac risk factors,

cardiac functional status, and revascularization procedures) also influence health service

consumption following AMI. Perceived general health and, possibly, provider effects

may also influence the likelihood of depression-related health service variation following

AMI.

The relationship between depression and outcomes such as mortality or health

service consumption following AMI is complex. Investigating these relationships requires

data that describe and measure the various factors outlined in the conceptual model

(Figure 1.1).

Data Sources

The primary data source for this study is the Socioeconomic Status and Acute

Myocardial Infarction (SESAMI) cohort, a prospective cohort of AMI survivors. The

SESAMI study group is led by Dr. David Alter. The study involved survivors of AMI in 53

hospitals across Ontario from December 1, 1999 to February 28, 2004. Data were

collected during the index AMI hospitalization, from chart abstraction of index AMI

hospitalization, and from a follow-up phone survey administered one month

postdischarge from the index hospitalization. In addition, administrative health data

were linked to the data collected from the baseline and follow-up survey and chart

abstraction to permit prospective and retrospective follow-up for mortality and health

service consumption measures. The sample and data collection processes have been

described in detail elsewhere56.

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 The SESAMI study is an ideal source of data because 1) it included measures for

all the factors outlined in Figure 1.1; 2) when compared to previous studies assessing

the relationship between depression and AMI, the sample size of the SESAMI study is

quite large and adequately powered; and 3) unlike prior studies, the measures for

medical comorbidity, cardiac illness severity, and cardiac functional status have been

validated, allowing for robust assessment of the influence of these factors on the

relationship between depression and the two outcomes.

The depression measures were included in the one-month follow-up survey. Of

the 2829 patients with successfully abstracted index AMI admissions and administrative

data linkage, 888 subjects did not complete the one-month follow-up survey, for a survey

response rate of 69%. This response rate is typical for population-based survey data

collection.

While the response rate is typical, it is unlikely that the 31% of AMI patients who

did not respond to the follow-up survey can be ignored. Sicker patients may be less

likely to participate in surveys than less acutely ill patients. If non-response is biased

towards sicker patients, then mortality rates would be falsely lowered by non-response.

The impact of missing data

Research studies with large sample sizes involving psychiatric diagnoses are

prone to missing data because psychiatric diagnoses are generated by completion of

psychiatric rating scales administered in a survey format. Invariably, there is less than

100% participation rate in surveys. The missing data are unlikely to be missing

randomly; that is, there are likely systematic differences between respondents and

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nonrespondents. If respondents differ systematically compared to non-respondents and

the variables determining such systematic differences are correlated with the outcome

measures, then the missing data can confer bias to estimates generated from analyses

in which missing data are ignored.

Typically, data collected from surveys are analyzed by removing any subject with

missing values for any variable included in a multivariate model. This method of

analyzing data is called a “complete case analysis” 57. In the SESAMI study, 31% of

patients did not respond to the phone survey that had depression measures. Thus, the

depression status is unknown for 31% of the sample. Any complete case analysis

including depression status as a variable would automatically remove those 31% of

subjects with no depression status value. This is problematic for two reasons: 1)

removing these subjects may result in biased estimates from analyses; and 2) by

removing the subjects, there is no way to estimate the effect of bias on the results from

the analysis.

Studies assessing the relationship between depression and mortality following

AMI are similar to other psychiatric studies in that the depression status (or any mental

illness diagnoses) is generated from survey instruments that generate missing data.

These studies have routinely ignored the impact of missing data by conducting complete

case analyses when there is reason to believe ignoring such data may confer bias on

estimates generated by complete case analyses in this instance. The SESAMI study

data are useful for estimating the impact of bias due to missing data because of the

richness of data that were collected at baseline, through chart abstraction and from

linked administrative sources. In other words, there are a large number of variables with

complete values for individuals with missing depression values; these complete variables

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in subjects with missing depression values can be used to analyze the impact of missing

data.

Thesis Questions

1) What is the relationship between depression and mortality following AMI and what is

the relative contribution of the physical health status of depressed patients in the

relationship? SESAMI data, a registry of AMI patients followed prospectively via followup

phone survey and linked administrative health, will be analyzed. (Chapter 2). 2) What is

the impact of depression on health service consumption following AMI? This part of the

thesis also uses SESAMI data to determine the magnitude by which depression

increases health service consumption following AMI, as well as the degree to which any

increased depression-related health service consumption reflects underlying cardiac

illness severity (Chapter 3).

3) What impact do missing data have on the analysis of depression-related outcomes

following AMI? In this chapter, missing data mechanisms are reviewed, as well as

different ways to analyze data with missing values. The three psychiatric journals with

the highest impact factors are reviewed over a two year period to determine how missing

data are handled currently. Finally, SESAMI data are re-analyzed using modern missing

data techniques to illustrate the impact of missing data on estimates generated from

different types of analyses (Chapter 4).

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Figure 1.1: Conceptual framework for thesis.

Cardiac Risk Factors

•Hypertension • Cardiac Functional
•Diabetes Status
•Smoking • Cardiac illness Mortality
•Elevated Serum Lipids severity
• Medical comorbidity

AMI Depression Processes

of Care

Demographics Health
•Age Service
•Sex Consumption
•SES
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