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Relationship of Depression to Increased Risk of Mortality and Rehospitalization in Patients With Congestive Heart Failure
Wei Jiang, MD;
Jude Alexander, MD;
Eric Christopher, MD;
Maragatha Kuchibhatla, PhD;
Laura H. Gaulden, NP;
Michael S. Cuffe, MD;
Michael A. Blazing, MD;
Charles Davenport;
Robert M. Califf, MD;
Ranga R. Krishnan, MD;
Christopher M. O'Connor, MD
Arch Intern Med. 2001;161:1849-1856.
ABSTRACT
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Background Patients with congestive heart failure (CHF) may have a high prevalence
of depression, which may increase the risk of adverse outcomes.
Objective To determine the prevalence and relationship of depression to outcomes
of patients hospitalized with CHF.
Methods We screened patients aged 18 years or older having New York Heart Association
class II or greater CHF, an ejection fraction of 35% or less, or both, admitted
between March 1, 1997, and June 30, 1998, to the cardiology service of one
hospital. Patients with a Beck Depression Inventory score of 10 or higher
underwent a modified National Institute of Mental Health Diagnostic Interview
Schedule to identify major depressive disorder. Primary care providers coordinated
standard treatment for CHF and other medical and psychiatric disorders. We
assessed all-cause mortality and readmission (rehospitalization) rates 3 months
and 1 year after depression assessment. Logistic regression analyses were
used to evaluate the independent prognostic value of depression after adjustment
for clinical risk factors.
Results Of 374 patients screened, 35.3% had a Beck Depression Inventory score
of 10 or higher and 13.9% had major depressive disorder. Overall mortality
was 7.9% at 3 months and 16.2% at 1 year. Major depression was associated
with increased mortality at 3 months (odds ratio, 2.5 vs no depression; P = .08) and at 1 year (odds ratio, 2.23; P = .04) and readmission at 3 months (odds ratio, 1.90; P = .04) and at 1 year (odds ratio, 3.07; P
= .005). These increased risks were independent of age, New York Heart Association
class, baseline ejection fraction, and ischemic etiology of CHF.
Conclusions Major depression is common in patients hospitalized with CHF and is
independently associated with a poor prognosis.
INTRODUCTION
PATIENTS WITH cardiovascular diseases, such as ischemic heart disease,
acute myocardial infarction, and stroke, have a high prevalence of depressive
disorder1-4
and greater morbidity compared with such patients without depression.5-8 Patients
with depression after acute myocardial infarction, for example, have much
greater mortality than such patients without depression.6-7
Although many studies have examined the relationship between depression and
cardiovascular disease, few have focused on patients with congestive heart
failure (CHF) and the relationship of depression to prognosis.9-11
Congestive heart failure has become a major public health problem. According
to the National Heart, Lung, and Blood Institute, more than 2 million Americans
have this condition, and about 400 000 new cases are diagnosed each year.
The average mortality rate is about 10% at 1 year after diagnosis, increasing
to 50% after 5 years.12 Further, the readmission
rate is 25% to 50% within 3 to 6 months after discharge.13-15
Medical expenditures in this population are high; in fact, the largest Medicare
expenditure is for CHF, with more than $7 billion spent on about 1 million
admissions annually.12 These figures have changed
little over time despite significant improvements in the understanding and
treatment of this condition.
Depression may be particularly prevalent in patients with CHF.9, 16 Koenig9
found the prevalence of major depression to be 36.5% in 542 consecutive inpatients
aged 60 years or older admitted to a nonpsychiatry service at a tertiary care
hospital. Frasure-Smith et al,6 reporting on
222 patients within 1 to 3 weeks of myocardial infarction, noted a higher
incidence of major depression among those with an ejection fraction of 35%
or less (20.3% vs 14.1%) or a classification of Killip class II or greater
(21.3% vs 14.3%). Whether depression relates to increased mortality and readmissions
in such patients is unknown. We prospectively studied patients hospitalized
with CHF to investigate the prevalence of depression and its effect on all-cause
mortality and readmissions (rehospitalizations) during the first year after
screening for depression.
SUBJECTS AND METHODS
PATIENT SAMPLE
Adult patients aged 18 years or older admitted to the cardiology service
at Duke University Medical Center, Durham, NC, between March 1, 1997, and
June 30, 1998, were eligible for enrollment if they had clinically diagnosed
CHF, defined as New York Heart Association (NYHA) classification II or greater,
an ejection fraction of 35% or less (by radionuclide study, echocardiography,
or angiography), or both. The institutional review board approved the protocol;
all study procedures were in accord with ethical standards outlined in the
Helsinki Declaration of 1975, as revised in 1983. All participants provided
informed consent according to review board guidelines. Exclusion criteria
included pregnancy, active suicidal ideation, planned major surgery, and the
inability to provide consent.
ASSESSMENTS
All participants first completed a self-administered questionnaire,
the Beck Depression Inventory (BDI). The 21-item BDI was developed to assess
the severity of depression in psychiatric patients diagnosed as having affective
disorder. It also has been used to screen for depression in various other
populations.17-18 The documented
psychometric properties of the BDI support its use as a sensitive depression
screening tool and a clinically useful scale to measure its severity.7, 19 We chose a cutoff score of 10 to be
consistent with prior diagnostic1 and prognostic6, 20 studies.
Patients who scored 10 or higher on the BDI questionnaire then underwent
a structured interview using a modified version of the National Institute
of Mental Health Diagnostic Interview Schedule (DIS). This tool screens for
major depressive disorder according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition
(DSM-IV). The depression section of the DIS that
we used was the modified version by Carney and Freedland21
for use in studies of depression in cardiac patients. Frasure-Smith et al6 also have used a modified DIS in studies of patients
who have suffered myocardial infarction; DSM-II and Diagnostic and Statistical Manual of Mental Disorders, Revised
Third Edition (DSM-III-R) depressive disorders
were associated with significantly increased mortality in these studies. Patients
with a positive DIS interview were classified as having major depression.
Patients with a negative DIS interview and a score of 10 or higher on the
BDI were classified as having mild depression.
INITIAL DATA COLLECTION
Detailed demographic data were collected from medical records, including
age, race, sex, primary reason for admission, concomitant illnesses, vital
signs, physical examination results, NYHA class, ejection fraction (lowest
measurement obtained during the index admission), and discharge medications.
FOLLOW-UP
All participants were contacted by mail at 3 months and 1 year after
the initial assessment, to collect data on mortality and readmissions. We
telephoned patients if information was not received 4 to 6 weeks after the
initial mailing or for clarification of the information received. The Duke
Databank for Cardiovascular Disease was used to obtain missing data and contact
information. Follow-up data were 99.7% complete; only 1 patient was lost to
follow-up at 1 year.
All patients received routine inhospital and postdischarge care from
their primary care physicians and cardiologists during follow-up. If a patient
met the modified DSM-IV criteria for major depressive
disorder, we reported the DIS results to the primary care team for the index
admission. Further intervention for depression was deferred to their clinical
judgment. We specified no particular treatment plan for such patients because
no evidence exists about the safety or efficacy of treatment of depression
in this population.
STATISTICAL ANALYSIS
We examined the relationship of depression measures and all-cause mortality
and readmission at 3 months and 1 year, after grouping patients in 2 ways
according to BDI score and DIS result. The first approach placed patients
into 1 of 3 categories: (1) those having no depression (BDI score, <10;
hereafter referred to as the no depression group), (2) mild depression (BDI
score,  10 but a negative DIS interview; hereafter referred to as the mild
depression group), or (3) major depression (BDI score, 10 and a positive
DIS interview; hereafter referred to as the major depression group). This
was designed to assess how outcomes may differ by severity of depression.
We also compared the rates of mortality and readmission based on a BDI score
of less than 10 vs 10 or more, as in previous studies.7, 22
Logistic regression analyses were performed to assess the relationships of
depression with mortality and readmission. The independent ability of depression
to predict mortality and readmission was examined by logistic regression models
that adjusted for age, ejection fraction, and NYHA class. The cause of CHF
(ischemic vs nonischemic) was added as a covariate to these models because
of increased mortality and readmission noted in patients with an ischemic
cause of CHF.23 Cox proportional hazards models
were used to examine the association of depression with mortality over time.
All analyses were performed using SAS software (Version 6.12, SAS, Cary, NC).
Statistical significance was defined as P<.05.
RESULTS
PATIENTS
A total of 374 patients consented to participate in the survey (Figure 1). Of these, 357 patients completed
the BDI questionnaire. We excluded 17 patients who provided consent but did
not complete the questionnaire before discharge. A total of 126 (35.3%) of
the 357 patients scored 10 or higher on the BDI. Of these, 26 did not complete
the DIS interview because they refused further evaluation or were discharged
before the interviewer could arrive, leaving 331 patients for analyses involving
DIS measures (100 who completed the interview, plus the 231 patients with
a BDI score <10). Of patients who underwent the DIS interview, 13.9% (46
of 331 patients) had a positive result and were considered to have major depressive
disorder. Patients who did not meet the DSM-IV criteria
for major depression but who had a BDI score of 10 or higher were considered
to have mild depression. No patient who consented to participate
expressed active suicidal ideation.
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Figure 1. Disposition of patients.
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Age, race, previous infarction, cause of CHF, primary reason for admission,
ejection fraction, and discharge medications were similar among groups (Table 1). The major depression group did
include a greater proportion of women. Higher NYHA classes were observed in
both the mild and major depression groups compared with the no depression
group. The baseline characteristics for the 26 patients who had a BDI score
of 10 or higher but did not complete the DIS interview also are summarized
in Table 1.
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Table 1. Baseline Characteristics by Severity of Depression
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GRADED DEPRESSION MEASURES AND MORTALITY
Overall mortality was 7.9% at 3 months and 16.2% at 1 year. Patients
with major depression had the highest mortality rates at 3 months and 1 year
(13.0% and 26.1%, respectively) (Table 2). Patients with mild depression had mortality rates of 7.4% at
3 months and 11.1% at 1 year, similar to those of patients whose BDI score
was less than 10 (5.7% and 13.7%, respectively). Logistic regression revealed
that patients with major depression had roughly twice the mortality risk at
1 year of those without depression (odds ratio [OR], 2.23; P = .04). Although the 3-month mortality rate in the major depression
group also was high, more than twice the rate of the no depression group,
the difference was not statistically significant (OR, 2.50; P = .08) (Table 3). Compared
with the mild depression group, the major depression group had higher mortality
at both intervals, but the differences likewise were not statistically significant
(Table 4). Mortality did not differ
significantly between patients with mild vs no depression (Table 2 and Table 3).
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Table 2. Rate of All-Cause Mortality and Readmission by Severity of
Depression
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Table 3. Univariate and Multivariate Effects of Mild and Major Depression
on Outcomes
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Table 4. Univariate and Multivariate Effects of Major Depression on
Outcomes
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The association of depression with mortality over 1 year derived from
Cox modeling was similar to the results from logistic regression (Figure 2). With major depression vs no depression,
the relative risk was 1.44 (95% confidence interval [CI], 1.033-2.011; P = .03); with major depression vs mild depression, the
relative risk was 2.48 (95% CI, 0.929-6.596; P =
.06); and with mild depression vs no depression, the relative risk was 0.83
(95% CI, 0.346-1.989; P = .68).
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Figure 2. Mortality among patients with
congestive heart failure and major depression (light solid line), mild depression
(heavy solid line), or no depression (broken line), using Cox proportional
hazards modeling.
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GRADED DEPRESSION MEASURES AND READMISSION
Of the entire cohort, 40.2% had 1 or more readmissions within 3 months
and 60.5% by 1 year. Similar to the mortality results, the major depression
group had the highest readmission rates at 3 months and 1 year (52.2% and
80.4%, respectively), followed by the mild depression group (42.6% and 55.6%)
and the no depression group (36.5% and 52.3%) (Table 2). Compared with the no depression group, the major depression
group had an OR of 1.90 for readmission at 3 months (P
= .04) and 3.07 at 1 year (P = .005) (Table 3). Readmission in the major depression group was similar
to that in the mild depression group at 3 months (OR, 1.47; P = .34) but was significantly elevated at 1 year (OR, 3.29; P = .009) (Table 4).
The mild depression group had slightly higher rates of readmission at 3 months
and 1 year compared with the no depression group, but not significantly so
(P = .41 and .82, respectively) (Table 3).
BDI MEASURES AND MORTALITY AND READMISSION
A total of 357 patients completed the BDI questionnaire, of whom 126
(35.3%) scored 10 or higher. The 26 patients whose BDI score was 10 or higher
but who did not complete the DIS interview were included in this analysis.
Patients with a BDI score of 10 or higher had mortality rates of 11.9% at
3 months and 20.8% at 1 year vs 5.7% and 13.7%, respectively, for patients
whose BDI score was less than 10 (Table
5). These differences were statistically significant at 3 months
(P = .04), but not at 1 year (P = .08). Cox proportional hazards analysis yielded a relative mortality
risk at 1 year of 1.62 with major depression vs no depression (95% CI, 0.959-2.72; P = .07). Of the patients with a BDI score of 10 or higher,
46.8% were readmitted by 3 months and 66.4% by 1 year, compared with readmission
rates of 36.5% and 57.3%, respectively, for those with a BDI score less than
10 (P = .06 and P = .09,
respectively).
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Table 5. Mortality and Readmission by Beck Depression Inventory (BDI)
Score
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INDEPENDENT EFFECT OF DEPRESSION ON MORTALITY AND READMISSION
Advanced age was significantly associated with increased mortality at
3 months (OR, 1.05 for each 1-year increase; 95% CI, 1.011-1.091; P = .01) and at 1 year (OR, 1.035; 95% CI, 1.009-1.062; P = .01). Age also was associated with increased readmissions at 3
months, but not at 1 year (OR, 1.03; 95% CI, 1.012-1.05; P = .002 and OR, 1.008; 95% CI, 0.99-1.025; P
= .39, respectively). Although the NYHA class was not associated with either
outcome at 3 months, it was associated with increased risks for both at 1
year (for death: OR, 1.846 for each higher class; 95% CI, 1.208-2.821; P = .005; for readmission: OR, 1.773; 95% CI, 1.245-2.525; P = .002). Ejection fraction (as a continuous variable
and dichotomized as  20% vs >20%) was not associated with mortality or
readmission. The prevalence of depression was similar by the cause of CHF,
but patients with an ischemic origin had significantly increased mortality
and readmission rates at both intervals (Table 6).
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Table 6. Relationship of Heart Failure Cause and Prognosis
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The relationships between major depression and mortality and readmission
were attenuated when risk factors such as age, NYHA class, and ejection fraction
were included in multiple regression modeling (Table 3 and Table 4).
The effect of major depression was no longer statistically significant for
3-month and 1-year mortality and 3-month readmission, but it remained statistically
significant for readmissions at 1 year. Although an ischemic origin of heart
failure was statistically significantly associated with mortality and readmission
in this population, its effects on the prognostic ability of depression were
minimal.
COMMENT
Major depression may play a significant role in increased mortality
and readmissions in patients with CHF. Overall mortality in this population
was 7.9% at 3 months and 16.2% at 1 year, comparable with the finding of previous
studies in such populations.21-24
Patients with CHFwho have major depression were more than twice as likely
as nondepressed patients to die or be readmitted within 3 months to 1 year
after hospitalization. Consistent with the findings of previous studies,23-25 advanced age and
higher NYHA class were associated with higher mortality and readmissions during
the 12 months of the current study. These factors might have attenuated the
prognostic ability of major depression with regard to mortality at 3 months
and 1 year, and for readmission at 3 months, but a trend persisted after adjustment
for age, NYHA class, and baseline ejection fraction. The adjusted readmission
rate at 1 year was almost 3 times higher in patients with major depression
vs their nondepressed and mildly depressed counterparts, a statistically significant
difference. Thus, the prognostic ability of major depression for poor short-term
outcomes in these patients seems not to depend on the effects of traditional
risk factors such as age and deteriorated cardiac function. The prognostic
ability of major depression likewise showed no interaction with the adverse
effects of ischemic heart disease.
Most studies examining the prognostic value of depression in patients
with cardiovascular disease have used questionnaires for its assessment.2-3,8, 26-27
Frasure-Smith et al6-7 are the
exception, using psychiatry-oriented, individual interviews and self-administered
BDI questionnaires to establish a clinical diagnosis of major depression after
acute myocardial infarction. In 222 such patients, they noted a significant,
negative prognostic effect of major depression at 6 months, but not at 18
months. An elevated BDI score (10) in their study had significant prognostic
value at 18 months, independent of traditional risk factors after myocardial
infarction.7 The relationship between BDI measures
and survival at 6 months, however, was not reported. They also reported a
similarly poor prognosis at 1 year with BDI scores of 10 or higher in a larger
population that included the 222 original patients.22
In our study, a BDI score of 10 or higher had significant prognostic value
for 3-month outcomes and showed a trend toward poorer outcomes at 1 year.
When we divided the cohort into patients with no depression, mild depression,
or major depression, however, the mild depression group (patients with a BDI
score 10 but a negative DIS result) showed mortality and readmission rates
only slightly higher than those of patients with a BDI score less than 10.
Significantly increased mortality and readmission were found only in the major
depression group. The group with a BDI score of 10 or higher included patients
with a positive DIS result and patients who did not complete the DIS interview,
who were excluded in the graded depression analysis model. Our study distinguished
different prognoses of patients with a BDI score of 10 or higher and a positive
DIS for major depression from those with a BDI score of 10 or higher and a
negative DIS result. The use of standardized psychiatric diagnostic measures
may be necessary to identify patients with CHF at higher risk for death or
readmission.
The significant prognostic ability of a high BDI score (10) reported
by Frasure-Smith et al6 was not evident in
our population. These disparate results may reflect that our patients differed
from those studied by Frasure-Smith et al.6-7,22
First, most of our patients were admitted because of exacerbation of heart
failure, unstable angina, or arrhythmia. Second, symptoms of depression (using
BDI measures) may have differed between the populations. Patients with CHF
may score higher on the BDI because of chronic physical deconditioning, which
may lead to symptoms similar to the neurovegetative signs of depression—fatigue,
reduced energy, sleep disturbance, and weight changes—rather than a
truly depressed state. This may explain the decreased prognostic ability of
the BDI score of 10 or higher in our patients. Alternatively, a much larger
sample size might be needed to show the significantly increased mortality
and readmission with mild depression in patients with CHF. The association
of higher BDI scores with longer-term prognosis (>1 year) in this population
needs further study.
Two studies have reported no relationship of depression with prognosis
in patients with CHF. One study used self-reporting, the Center for Epidemiological
Study Depressive Symptomatology Questionnaire, to screen for depression. The
investigators found that depressive symptoms assessed before admission were
not independently associated with cardiovascular events in 292 hospitalized
patients who later were diagnosed as having CHF.11
The major concern with this study, however, is that depression assessment
occurred long before CHF was diagnosed. Koenig,9
in 1998, reported a high prevalence (36.5%) of major depression by DSM-IV criteria in 107 elderly patients (60 years old) with CHF
admitted to general medicine, cardiology, or neurology services.9
Mortality was not significantly higher during a median 46 weeks of follow-up
in these patients compared with such patients without depression or with only
minor depression (28.2%, 20.0%, and 30.4% mortality, respectively). In his
study, most patients (57.5%) met criteria for either major or minor depression,
and the population had a higher overall mortality rate (24.3%). We speculate
that the discrepancies between this and the current study result from differences
in populations and sample sizes.
The mechanism for the poorer outcomes in patients with depression who
have CHF may reflect several factors. First, patients with depression in our
study were in higher NYHA classes than nondepressed patients, which may represent
a greater deterioration in cardiopulmonary function, increased fluid retention,
or both. This finding could explain reports of greater somatic symptoms28-29 and diminished functional status27 in patients with depression. Patients with depression
have been reported to have poor social contacts and support networks10, 30-34
and to be noncompliant with treatment,35-36
which could adversely affect outcomes. Evidence suggests that platelet activity
is high in patients with depression, especially those with concomitant vascular
diseases.37 Finally, decreased heart rate variability,
considered a reflection of autonomic dysregulation, occurs in patients with
depression alone38-39 and has
been associated with poorer prognosis in the population with CHF.40-42 These important issues
were beyond the scope of the current study, but all of these possible mechanisms
for the poorer outcomes of patients with depression who have CHF deserve further
study.
A noteworthy limitation of this study is the high rate of dropout before
completion of the DIS interview (26 of 126 patients), which interfered with
the assessment of major depression prevalence and its prognostic value in
our population. It is reasonable to hypothesize that a higher rate of major
depression may occur in this group. A refusal or an inability to complete
the further psychiatric interview might be secondary to severe depressive
symptoms, such as anhedonia or fatigue. Strategies should be developed to
include such patients in future studies. About two thirds of the patients
did not undergo DIS interview because of a BDI score less than 10. Although
experience indicates that the likelihood of clinical depression is very low
in patients with a BDI score less than 10, the ideal design would have had
all participants undergo the DIS interview, to have a more precise review
of depressive disorder in this population. Of note, 12.1% of the patients
with a BDI score less than 10 were taking antidepressants at first discharge.
These patients had a poor prognosis, regardless of depression measures. Given
the lack of information about the continuation and regulation of antidepressants
during the follow-up phase, we cannot draw any conclusions from this finding.
Further studies are required to assess the efficacy and safety of antidepressants
in patients with CHF. Finally, the population we studied is limited to patients
with CHF and significant underlying cardiovascular disease, who were suffering
a significant cardiac event requiring hospitalization. Whether these findings
pertain to patients with CHF who are followed up as outpatients with stable
clinical manifestations should be investigated.
Important advances have been made in the treatment of CHF. Ample opportunity
remains to improve outcomes, however, given the mortality rates of more than
15% at 1 year and more than 30% at 2 years among treated patients.24, 43 The difference in outcomes by depression
status in our study emerged almost immediately after the index admission.
This could offer an opportunity for early intervention or secondary prevention,
if the treatment of depression in these patients is shown to reduce mortality
or readmission.
CONCLUSIONS
Depression is common in patients with CHF and may play a significant
role in their short-term prognosis. The adverse effect of depression on prognosis
seems to be independent of traditional risk factors. Recognition and clinical
management of depression in this population is important. Whether treatment
of depression can reduce mortality and readmissions is unknown, but this issue
must be explored.
AUTHOR INFORMATION
Accepted for publication January 18, 2001.
This study was supported in part by grant 5P60AG11268 from the National
Institute on Aging, National Institutes of Health, Bethesda, Md, Claude D.
Pepper Older Americans Independence Centers (Dr Jiang).
We thank Rebekka Arias, Christopher Simons, and Yan Zhang for their
technical contributions and Pat French for editorial assistance.
Reprints: Wei Jiang, MD, 3203 Winfield Dr, Durham, NC 27707
(jiang001{at}mc.duke.edu).
From the Departments of Psychiatry (Drs Jiang, Alexander, Christopher,
and Krishnan and Mr Davenport) and Medicine (Drs Cuffe, Blazing, Califf, and
O'Connor and Ms Gaulden) and the Division of Biometry (Dr Kuchibhatla), Department
of Community and Family Medicine, Duke University Medical Center, Durham,
NC.
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25. The SOLVD investigators. Effect of ena |
