Abstract
Background
There have been few studies of the effect of depression on rehospitalization in patients with heart failure (HF), and even fewer on its role in multiple rehospitalizations.
Hypothesis
Depression is an independent risk factor for multiple readmissions in patients with HF.
Methods
A cohort of 662 patients with HF who were discharged alive after hospitalization were interviewed to evaluate symptoms of depression and were followed for 1 year. All‐cause readmissions were documented by chart review. A marginal proportional rates model was used to model the effect of depression on the rate of rehospitalization with adjustment for known predictors of HF outcomes.
Results
Depression symptoms predicted multiple readmissions (adjusted hazard ratio [HR]: 1.08, 95% confidence interval [CI]: 1.03‐1.13, P = 0.0008). Compared with patients without depression, those who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM‐IV) criteria for major depression at index were at the highest risk for multiple rehospitalizations (HR: 1.51, 95% CI: 1.15‐1.97, P = 0.003).
Conclusions
Depression is an independent risk factor for multiple all‐cause readmissions in patients with HF.
Introduction
Heart failure (HF) is a leading cause of hospitalization in elderly patients,1 and multiple readmissions are common in HF. A study of 1077 incident HF cases with a mean follow‐up of 4.7 years found that 67%, 54%, and 43% of the patients were rehospitalized at least 2, 3, or 4 times, respectively.2 Multiple readmissions are especially common shortly after HF diagnosis and again during the terminal phase of heart failure.3, 4 Excess HF readmissions account for the largest proportion of the variance among hospitals in penalties under the Center for Medicare & Medicaid Services Hospital Readmissions Reduction Program.5
Current risk‐prediction models for HF rehospitalization have only moderate predictive value.6, 7, 8, 9 Consequently, identification of novel, modifiable risk factors remains a priority in this area of research.9 There is evidence that depression predicts rehospitalization and death in HF,10, 11, 12, 13 but less is known about the role of depression in multiple readmissions. The purpose of this study was to determine whether depression predicts multiple readmissions in hospitalized patients with HF.
Methods
Study Cohort
The prevalence of HF is very low among individuals age <40 years,14 and major adverse cardiac events are relatively rare among HF patients age <40 years.15 Consequently, patients age <40 years were excluded at the preliminary screening stage, to enable the recruiters to focus their efforts on patients who were more likely to meet the study's criteria for HF. Patients age ≥40 years who were hospitalized between January 1, 1994, and July 14, 1999, at Barnes‐Jewish Hospital at Washington University Medical Center, St. Louis, with an admitting diagnosis of HF, dyspnea, or acute myocardial infarction, were screened for study eligibility.
Inclusion required the permission of the patient's attending physician, a radiological report indicating HF, and clinical documentation of ≥2 of the following: (1) dyspnea, (2) third heart sound, (3) jugular venous distention, (4) hepatojugular reflux, (5) pulmonary rales, (6) peripheral edema, or (7) symptomatic or clinical improvement in response to diuretics. Patients were excluded if they (1) were too medically unstable to participate, based on the clinical judgment of the patient's attending physician; (2) had a clinical diagnosis of isolated right HF due to a pulmonary disorder or congenital defect; (3) had HF associated with valve disease for which surgical correction was pending; (4) had a terminal illness other than HF; or (5) had a neuropsychiatric condition or language barrier that would preclude informed consent or valid assessments. Participants signed an informed‐consent form approved by the Human Research Protection Office at Washington University School of Medicine. Patients who died during the index hospitalization (n = 20; 2.9% of 682 enrollees) were excluded from the analysis.
Data Collection at Index
An experienced cardiac‐research nurse reviewed each patient's hospital records and used a standardized medical data‐collection form to document (1) whether there had been any previous hospital admissions for HF, (2) comorbid medical conditions, (3) routine laboratory test values, and (4) medications. The patient's New York Heart Association (NYHA) classification during the past 2 weeks was determined from an interview and the medical chart review. Oversight of the medical data collection was provided by a co‐investigator with expertise in HF and geriatric cardiology (MWR).
Transthoracic 2D, Doppler, and color‐flow echocardiography were performed within 48 hours of hospital admission, if logistically feasible. The images were stored and digitized for offline analysis. All studies were performed by experienced cardiac sonographers. The left ventricular ejection fraction (LVEF) was calculated by the method of summation of disks (modified Simpson rule) from the apical 4‐chamber view at end‐diastole and end‐systole at end‐expiration. All measurements were obtained and averaged from 5 consecutive cardiac cycles by a co‐investigator with expertise in echocardiography.
To assess depression, experienced research interviewers administered a version of the National Institute of Mental Health Diagnostic Interview Schedule that had been used in previous studies of depression in patients with heart disease.16 The interview assessed the presence and duration of 9 symptoms of unipolar depression.17 In addition to a depression symptom count (range, 0–9), the interview was used to determine whether the patient met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM‐IV) criteria for a major or minor depressive episode during the index hospitalization. The diagnosis was derived from a computerized algorithm.
Follow‐up Interviews
The participants were contacted by telephone every 3 months for 1 year. The interview was re‐administered during these calls to assess changes in the number of depression symptoms. The participants were also asked to report any hospital admissions for any reason that had occurred during the past 3 months and to sign a release‐of‐information form for the records of each hospitalization. If the participant was deceased, too ill to be interviewed, or unavailable for other reasons, a collateral informant was asked about recent hospital admissions.
Ascertainment of Readmissions and Deaths
All readmissions to Barnes‐Jewish Hospital, regardless of admitting diagnosis, were identified through daily queries of the electronic medical record system. Each readmission record was examined to identify admissions to any other hospital since study enrollment. Medical records were requested for all admissions to other hospitals that were identified either from Barnes‐Jewish Hospital records or from follow‐up interviews with participants or collateral informants. Records were obtained for 100% of the identified readmissions. Dates of death were determined from hospital records or collateral informants.
Statistical Analysis
Data that were plausibly missing at random were imputed with the multiple imputation procedure in the SAS statistical software package, version 9.3 (SAS Institute, Inc., Cary, NC). Fifty imputed datasets were generated from an imputation model that consisted of auxiliary and measured variables likely to be related to the missing data mechanism. To minimize bias, all variables that were used in the analysis models were also included in the imputation model.
The Liu et al marginal proportional rates model18 was used to determine the relationship between depression and the rate of all‐cause readmissions over 1 year. The readmissions were partitioned into intervals corresponding to the periods between scheduled quarterly assessments (ie, the baseline evaluation and the follow‐up assessments at 3, 6, 9, and 12 months). The numbers of depressive symptoms at index and at each follow‐up interview were modeled as a time‐dependent predictor. The model was adjusted for factors that were documented during the index hospitalization and that had been previously shown to predict HF hospitalization, including age, sex, race, HF etiology (ischemic or nonischemic), LVEF, history of HF hospitalization, chronic obstructive pulmonary disease, blood urea nitrogen, creatinine, hemoglobin, sodium, and use of antidepressant medications.19, 20, 21, 22, 23, 24, 25, 26
Liu model parameters are estimated via Cox regression, so the standard assumptions of Cox regression (linearity, proportional odds, model fit, influential observations) are applicable. Martingale and Schoenfeld residuals were used to test the assumptions of linearity and proportional hazards, respectively; likelihood ratio tests were used to test overall goodness of fit.
Fatal events during the follow‐up period may affect the results of recurrent event (multiple rehospitalization) models, because patients are only at risk for rehospitalization while they are still alive. The marginal rates model accounts for death as an event that terminates the rehospitalization process. Also, during a fixed follow‐up period, patients with a high cumulative length of stay (LOS) spend fewer days out of the hospital and thus have fewer opportunities (ie, less exposure time) to be rehospitalized than do patients with a low cumulative LOS. Consequently, the marginal rates model included an offset term for cumulative LOS.
All statistical tests were 2‐sided with a type I error rate of 0.05 per test.
Results
Baseline Characteristics
As shown in Table 1, the study cohort included approximately equal numbers of men and women, and approximately 40% of the participants were African American. The mean age at enrollment was 66 years. Most were in NYHA class II/III HF prior to the index admission, and approximately 70% had an LVEF <45%. At index, 20% of the patients had major depression and 16% had minor depression.
Table 1.
Baseline Patient Characteristics
| DSM‐IV Depression Diagnosis | ||||
|---|---|---|---|---|
| Characteristics | Overall, N = 662 | No Depression, n = 425 | Minor Depression, n = 106 | Major Depression, n = 131 |
| Sociodemographic | ||||
| Age, y | 66.2 ± 11.9 | 67.8 ± 11.8 | 64.5 ± 11.3 | 62.6 ± 11.7 |
| Female sex | 342 (51.7) | 198 (46.6) | 59 (55.7) | 85 (64.9) |
| African American race | 276 (41.7) | 179 (42.1) | 42 (39.6) | 55 (42.0) |
| Marital status | ||||
| Single | 73 (11.0) | 48 (11.3) | 15 (14.1) | 10 (7.6) |
| Divorced or widowed | 251 (37.9) | 158 (37.2) | 38 (35.9) | 55 (42.0) |
| Married or partnered | 338 (51.1) | 219 (51.5) | 53 (50.0) | 66 (50.4) |
| Education (<12 y) | 236 (35.7) | 143 (33.7) | 40 (37.7) | 53 (40.5) |
| Employment status | ||||
| Working | 136 (20.5) | 91 (21.4) | 21 (19.8) | 24 (18.3) |
| Retired | 504 (76.1) | 322 (75.8) | 81 (76.4) | 101 (77.1) |
| Disabled | 21 (3.2) | 11 (2.6) | 4 (3.8) | 6 (4.6) |
| Prior history of major depression | 191 (28.9) | 93 (21.9) | 42 (39.6) | 56 (42.8) |
| Medical | ||||
| NYHA class prior to index admission | ||||
| I | 60 (9.1) | 55 (12.9) | 0 (0.0) | 5 (3.8) |
| II | 325 (49.1) | 229 (53.9) | 56 (52.8) | 40 (30.5) |
| III | 235 (35.5) | 127 (29.9) | 40 (37.7) | 68 (51.9) |
| IV | 42 (6.3) | 14 (3.3) | 10 (9.4) | 18 (13.7) |
| LVEF | ||||
| Interval‐scaled | 34.9 ± 16.9 | 34.5 ± 17.3 | 36.1 ± 17.1 | 34.9 ± 15.6 |
| <45% | 410 (70.2) | 262 (70.1) | 64 (68.1) | 84 (72.4) |
| Ischemic HF | 361 (54.5) | 241 (56.7) | 51 (48.1) | 69 (52.7) |
| Prior hospitalization for HF | 446 (67.4) | 286 (67.3) | 67 (63.2) | 93 (71.0) |
| COPD | 155 (23.7) | 87 (20.6) | 24 (23.3) | 44 (33.9) |
| DM | 286 (43.2) | 172 (40.5) | 51 (48.1) | 63 (48.1) |
| Laboratory | ||||
| Cr | 1.7 ± 1.4 | 1.7 ± 1.3 | 1.9 ± 1.6 | 1.6 ± 1.3 |
| BUN | 27.3 ± 18.2 | 27.6 ± 18.6 | 27.7 ± 16.7 | 25.8 ± 18.0 |
| Na | 138.9 ± 3.6 | 139.1 ± 3.6 | 138.8 ± 3.9 | 138.7 ± 3.6 |
| Hg | 11.9 ± 2.0 | 12.0 ± 2.0 | 11.8 ± 1.9 | 11.5 ± 2.1 |
| Medications | ||||
| Antidepressant | 84 (12.7) | 27 (6.4) | 17 (16.0) | 40 (30.5) |
| ASA | 382 (57.7) | 253 (59.5) | 62 (58.5) | 67 (51.2) |
| β‐Blocker | 120 (18.1) | 85 (20.0) | 19 (17.9) | 16 (12.2) |
| ACEI | 483 (73.0) | 310 (72.9) | 79 (74.5) | 94 (71.8) |
Abbreviations: ACEI, angiotensin‐converting enzyme inhibitor; ASA, aspirin; BUN, blood urea nitrogen; COPD, chronic obstructive pulmonary disease; Cr, creatinine; DM, diabetes mellitus; DSM‐IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; HF, heart failure; Hg, hemoglobin; LVEF, left ventricular ejection fraction; Na, sodium; NYHA, New York Heart Association; SD, standard deviation.
Data are presented as n (%) or mean ± SD.
Follow‐up
The mean number of depression symptoms in the cohort as a whole varied from a high of 3.3 at index to a low of 0.9 at 12 months. On average, patients who met the criteria for major depression at index had more depression symptoms at every follow‐up point than those who had minor depression or no depressive disorder at index (results not shown).
Readmissions and Deaths
One hundred twenty‐two (18.4%) of the patients died within 12 months of the index discharge. One‐hundred and twenty‐seven (19.2%) patients were rehospitalized at least once within 30 days of the index discharge. Whereas 211 (31.9%) of the patients were never rehospitalized during the study, 259 (39.1%), 357 (53.9%), 415 (62.7%), and 451 (68.1%) were rehospitalized at least once during the first, second, third, or fourth quarter of the follow‐up year, respectively. One hundred eighty‐two (27.5%) of the patients were rehospitalized only once during the year, 100 (15.1%) were rehospitalized twice, and 169 (25.5%) were rehospitalized ≥3 times. The average number of all‐cause rehospitalizations per patient was 1.7 (SD, 2.1) over 1 year. Out of a total of 1161 readmissions, 980 (84.4%) occurred at Barnes‐Jewish Hospital in St. Louis and 181 (15.6%) were at other hospitals. The mean numbers of readmissions and the number of deaths within each follow‐up interval are shown in Table 2.
Table 2.
Deaths and Readmissions During the 1‐Year Follow‐up Period
| No. of Readmissions | |||
|---|---|---|---|
| Follow‐up Interval | No. of Deaths (%) | Mean | SD |
| Between index discharge and 3 mo | 28 (4.2) | 0.59 | 0.88 |
| Between 3 and 6 mo | 38 (5.7) | 0.47 | 0.82 |
| Between 6 and 9 mo | 29 (4.4) | 0.43 | 0.82 |
| Between 9 and 12 mo | 27 (4.1) | 0.37 | 0.72 |
Abbreviations: SD, standard deviation.
The marginal proportional rates model is displayed in Table 3. There were no serious violations of the Liu model. Depression symptoms predicted the rate of readmissions in both unadjusted (hazard ratio [HR]: 1.10, P < 0.0001) and adjusted (HR: 1.09, P = 0.0006) models. Other significant predictors of rehospitalizations included race (with black patients at higher risk of multiple rehospitalizations than whites), comorbid chronic obstructive pulmonary disease, blood urea nitrogen, and hemoglobin. Ischemic etiology was nearly significant (P = 0.06) as well. Left ventricular ejection fraction did not predict multiple readmissions, despite recent evidence of differences in readmission rates between HF patients with preserved and reduced LVEF.27
Table 3.
Marginal Rates Model of Multiple Readmissions Over 1 Year
| Parameter | Adjusted HR (95% CI) | P Value |
|---|---|---|
| Depression (per symptom) | 1.09 (1.03‐1.13) | 0.0006 |
| Age (per 10 years) | 1.01 (0.92‐1.12) | 0.78 |
| Male sex | 1.08 (0.86‐1.35) | 0.51 |
| African American race | 1.40 (1.12‐1.76 | 0.003 |
| LVEF, % | 0.99 (0.99‐1.00) | 0.24 |
| Ischemic HF | 1.26 (0.99‐1.60) | 0.06 |
| COPD | 1.50 (1.16‐1.94) | 0.002 |
| Prior hospitalization(s) for HF | 1.09 (0.86‐1.39) | 0.47 |
| Antidepressant medication | 1.19 (0.89‐1.59) | 0.23 |
| BUN | 1.01 (1.00‐1.02) | 0.009 |
| Cr | 1.03 (0.93‐1.14) | 0.58 |
| Hg | 0.91 (0.86‐0.97) | 0.004 |
| Na | 0.98 (0.95‐1.01) | 0.27 |
Abbreviations: BUN, blood urea nitrogen; CI, confidence interval; COPD, chronic obstructive pulmonary disease; Cr, creatinine; HF, heart failure; Hg, hemoglobin; HR, hazard ratio; LVEF, left ventricular ejection fraction; Na, sodium.
The Figure 1 displays the mean cumulative function plot of the number of rehospitalizations over time by DSM‐IV depression diagnosis at index. The data points along each line represent rehospitalization events, and the slope of the line represents the rate of readmissions within each subgroup. The rate of rehospitalization was significantly higher in patients with major depression than in nondepressed patients (HR: 1.51, 95% confidence interval [CI]: 1.15‐1.97, P = 0.003). The difference between patients with minor depression and no depressive disorder fell short of statistical significance (HR: 1.36, 95% CI: 0.98‐1.88, P = 0.06).
Figure 1.
Rate of readmissions, by depression diagnosis at index. Abbreviations: D, depression; DSM‐IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; MCF, mean cumulative function; ND, no depression.
Discussion
In this study, a DSM‐IV symptom count was used to assess the severity of depression at index and on quarterly interviews during a 1‐year follow‐up after hospitalization for HF. The results show that a high depression symptom count predicts multiple all‐cause rehospitalizations in patients with HF, even after adjusting for known predictors of HF outcomes. Patients with HF who met the DSM‐IV criteria for a major depressive episode during the index hospitalization were at particularly high risk for multiple rehospitalizations.
There have been several other studies of depression and hospitalization or rehospitalization in HF, but most of them have focused on single events. In one of the earliest studies, Jiang et al11 found that major depression predicted readmission within 3 months (adjusted odds ratio: 1.90, P = 0.04) and 1 year (adjusted odds ratio: 3.07, P = 0.005) in 374 adult patients hospitalized in NYHA class II to IV HF. In a cross‐sectional study of noncardiac comorbidities in 122 630 Medicare beneficiaries with HF, Braunstein et al10 found that a chart diagnosis of depression was associated with an increased risk of HF hospitalization (adjusted risk ratio: 1.11, 95% CI: 1.05‐1.16). Lesman‐Leegte et al12 administered the Centers for Epidemiologic Studies Depression scale (CES‐D) to 958 patients enrolled after hospitalization for HF and found that it predicted HF rehospitalization (adjusted HR: 1.16, P = 0.02). Finally, in a recent community‐based study of 402 individuals with HF, Moraska et al13 found that scores in the moderate‐to‐severe range on the Patient Health Questionnaire (PHQ‐9) depression scale were associated with an increased risk of hospitalization (adjusted HR: 1.79, 95% CI: 1.30‐2.47). Although these studies employed different designs and diverse measures of depression, they consistently show that depression is a risk factor for hospitalization and rehospitalization in HF.
To our knowledge, only 1 previous study has examined depression in relation to multiple readmissions in patients with HF. Johnson et al28 found that scores in the depressed range on the Geriatric Depression Scale predicted repeated HF hospitalizations in a subset of 784 (87%) of the 902 participants in the Heart Failure Adherence and Retention Trial (HART; adjusted incidence rate ratio: 1.45, P = 0.006). Our study differs from theirs in a number of ways, including the measures of depression that were used, the inclusion or exclusion of non‐HF rehospitalizations, and the underlying study designs. Nevertheless, these 2 studies found associations of similar magnitude between depression and the rate of multiple rehospitalizations.
Less than one‐third of the participants who had major depression were taking an antidepressant at enrollment. It is possible that the outcomes might have differed if a higher proportion of the depressed patients were treated for depression. However, research to date has not established that treatment of depression decreases hospitalizations in patients with HF. Nevertheless, the present findings suggest that it may be possible to reduce the rate of rehospitalization by improving the management of depression in patients with HF. The Figure shows that although the rehospitalization rates of the depressed and nondepressed subgroups diverge over 1 year, they are fairly similar during the first 30 days after the index discharge. Thus, although early treatment of major depression can help to prevent worsening depression and improve quality of life, it may have little impact on rehospitalizations in the context of short‐term case management after hospital discharge. Depression is a chronic or recurrent problem in many cases, and it may have to be monitored and managed over longer periods to reduce HF rehospitalization rates. Further research is needed to determine whether treatment of depression can decrease rehospitalizations and improve other medical outcomes in patients with HF.
Most efforts to predict rehospitalization in patients with HF have focused on 30‐day readmissions.29 This study suggests that longer follow‐up intervals and ascertainment of multiple rehospitalizations may reveal patterns that are not necessarily apparent during the first 30 days after hospitalization for HF.
Study Limitations
The participants were enrolled in this study in the mid to late 1990s. Because of recent advances in HF care and changes in health care policies and practices, depression may have weaker or stronger effects on rehospitalization rates and other HF outcomes in contemporary cohorts than in this study population. In addition, data on prognostic biomarkers30 such as B‐type natriuretic peptide31, 32 were not available. Prospective replications in contemporary patient cohorts are needed.
Although the biobehavioral mechanisms that underlie the relationship between depression and adverse outcomes in HF have not been firmly established,33 there is considerable interest in the role of inflammation.34, 35 Unfortunately, data on inflammatory biomarkers were not available for the present study.
Only about one‐third of the patients were enrolled during their first‐ever hospitalization for HF. However, prior history of hospitalization for HF was not a significant predictor of outcomes in any of the models. Time‐dependent data were available only on depression; other risk factors for rehospitalization were ascertained only during the index hospitalization. It might be possible to strengthen the predictive value of these models by incorporating time‐dependent data on other risk factors for rehospitalization.
Finally, the cohort was restricted to patients who were age ≥40 years at the time of the index hospitalization. Consequently, the results of this study cannot be generalized to patients who are age <40 years. Because of the low prevalence of HF in this age group, it would be necessary to conduct a much larger study to evaluate risk factors for multiple rehospitalizations in younger patients with HF.
Conclusion
Depression is an independent risk factor for multiple all‐cause rehospitalizations of patients with HF. It appears to have a greater impact on the rate of multiple rehospitalizations over 1 year than it does on the risk of rehospitalization within 30 days, and major depression has a stronger effect than minor depression on the rate of rehospitalization. Prospective replications of these findings are needed. Further research is also needed to identify the biobehavioral mechanisms that account for the effect of depression on HF rehospitalizations.
This study was funded by grant R01MH051419 from the National Institute of Mental Health.
The authors have no other funding, financial relationships, or conflicts of interest to disclose.
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