Heart Care Info - Heart Disease Prevention & Treatment

Worsening depressive symptoms are associated with adverse clinical outcomes in patients with heart failure

A Sherwood, JA Blumenthal, AL Hinderliter... - Journal of the American ..., 2011 - Elsevier OBJECTIVES: The purpose of this study was to assess the impact of changes in symptoms of depression over a 1-year period on subsequent clinical outcomes in heart failure (HF) patients. BACKGROUND: Emerging evidence shows that clinical depression, which is ...

With more than 5 million Americans living with heart failure (HF), and another 670,000 new cases being diagnosed each year, HF is the most costly diagnosis in the Medicare population and is the most common cause for hospitalization in patients older than 65 years (1). Clinical depression also is common in HF, with prevalence estimates ranging from 24% to 42% (2). Studies from multiple investigative teams, including our own, have found that, independent of HF disease severity, depressive symptoms are associated with adverse clinical outcomes for HF patients ( [3], [4], [5], [6], [7] and [8]). Moreover, depressive symptoms that increase over time also have been associated with worse outcomes in patients with myocardial infarction (MI) ( [9], [10] and [11]). Although changes in depressive symptoms have been assessed previously in HF patients ( [12] and [13]), their relationship to HF clinical outcomes has not been evaluated. The present study extends our prior report (3) by evaluating the unique contribution of changes in depressive symptoms at 1 year of follow-up in the context of established risk factors, including baseline depressive symptoms and established HF disease severity biomarkers, on subsequent clinical outcomes defined by hospitalization or death across an overall median follow-up period of 5 years.

This was a prospective, observational study of a nonhospitalized cohort of HF patients, recruited from outpatient HF clinics in central North Carolina. We performed medical and psychosocial assessments at baseline and at the 1-year follow-up to evaluate their association with events, including mortality and hospitalizations over a median follow-up period of 5 years from baseline assessments (median of 4 years from the 1-year follow-up assessments with range of 3 to 6 years and no losses to follow-up).

The study sample comprised 147 patients recruited from the Heart Failure Programs at Duke University Medical Center and the University of North Carolina Health Care at Chapel Hill from January 2000 through December 2002. This sample represents a subset of the 204 participants whom we initially recruited (3); 27 patients died within the first year and 30 were alive but were unavailable to complete the depression assessment at the 1-year follow-up. Inclusion criteria were: left ventricular ejection fraction (LVEF) of 40% or less, documented within the last year by angiography, radionuclide ventriculography, or echocardiography; and New York Heart Association functional classes I to IV for at least 3 months in duration. Exclusion criteria were: pacemaker dependence; uncontrolled hypertension; MI, percutaneous coronary intervention, or coronary artery bypass graft within the last 3 months; and a patient's first visit to the heart failure clinic. Pacemaker dependence, fewer than 3 months after MI, percutaneous coronary intervention, and coronary artery bypass graft were excluded because the study also was designed to evaluate autonomic nervous system regulation. The study was approved by the Institutional Review Board at Duke University Medical Center, where all assessments were performed. Written informed consent was obtained from all participants before their participation.

After 20 min of seated relaxation, blood was collected from an antecubital vein in a 5-ml phlebotomy tube containing ethylenediaminetetraacetic acid. Samples were placed on ice and were cold-centrifuged at 1,000 g for 10 min. The resulting plasma was pipetted into plastic vials and frozen and maintained at 80 C until assay. On the day of NT-pro BNP analysis, samples were thawed in a room temperature water bath and then mixed thoroughly. NT-pro BNP measurements were performed within 4 hours of thawing using an electrochemiluminescence immunoassay in accordance with the manufacturer's instructions (Elecsys pro BNP, Roche Diagnostics Corporation, Indianapolis, Indiana). The analytical measurement range for the assay is 5 to 35,000 pg/ml, and typical day-to-day imprecision has a coefficient of variation of less than 5%.

LVEF was determined by 2-dimensional echocardiography. Apical 4- and 2-chamber images of the heart were acquired by a single sonographer using an Acuson (Mountain View, California) ultrasound machine and were stored as digital loops. The endocardial borders of the left ventricle in the 2 views were traced by a single experienced echocardiography specialist (A.L.H.) using customized off-line software (Access Point 2000, Freeland Systems, LLC, Westfield, Indiana), and ventricular volumes and LVEF were computed using the biapical Simpson's rule.

The Beck Depression Inventory (BDI) is a 21-item self-report measure of depressive symptomatology (14). A score of 10 or more is considered indicative of clinically significant levels of depressive symptoms (15). Although the BDI is not used to diagnose clinical depression, it is a well-validated instrument for assessing the severity of depressive symptoms. Moreover, elevated symptoms of depression measured by the BDI are associated with an increased risk of adverse events in cardiac patients, including patients with HF ( [3], [7], [16] and [17]). These studies also document that the cut point of a BDI score of 10 or more is applicable in cardiac patient populations, where it has been associated with poorer prognosis ( [3], [16] and [17]).

On the 1-year anniversary ( 2 weeks) of participants' baseline assessments, 147 surviving participants repeated the BDI to reassess their depression symptoms. Medical records also were examined to document current health status, hospitalizations during the past year, and antidepressant medication use.

Participants' medical records were reviewed on a yearly basis, over a median of 5 consecutive years from baseline (with a range of 4 to 7 years and no losses to follow-up) on the anniversary of their baseline assessments by trained research assistants blinded to patients' depression status. Patients also were contacted annually by mail and asked to indicate whether they had been hospitalized during the past year and provided consent for retrieval of their hospitalization records. The primary end point was defined as the time to cardiovascular hospitalization or death (whichever occurred first) within the follow-up period. Patient mortality was verified through hospital and emergency medical services records. Cardiovascular hospitalizations included hospitalizations for MI, stroke, treatment for worsening heart failure, cardiac surgery including coronary artery bypass grafts, and heart transplantation. To develop a fuller understanding of the relationship of depression and clinical outcomes, we also considered all-cause hospitalization or mortality as a secondary composite end point.

Cox proportional hazards regression models were used to examine the relationship between baseline characteristics and events (death and hospitalizations) during the median 5-year follow-up (with range of 4 to 7 years and no losses to follow-up). Age, HF cause, NT-pro BNP level, LVEF, baseline BDI score, 1-year change in BDI score (BDI score at 1 year minus baseline BDI score), and antidepressant medication use had planned inclusion in the primary model. Hospitalizations occurring during the first year were used as an indicator of medical status for that year and also were included in the planned primary proportional hazards regression model to address the possibility that clinical events during the first year of follow-up could drive changes in depression symptoms during the interval between baseline and the reassessment 1 year later. To minimize the possible influence of clinical events during the first year on subsequent 1-year BDI scores, outcomes were considered as clinical events occurring at least 1 year after initial baseline assessments. Thus, outcomes were defined as death or hospitalizations occurring only after the first year of follow-up data had been collected (including 1-year BDI score) for each participant. Secondary sensitivity analyses for the evaluation of robustness of findings from the planned model allowed other potential explanatory factors (including New York Heart Association functional class; diabetes, hypertension; hypercholesterolemia; myocardial infarction; tobacco use; glomerular filtration rate [modified Cockcroft-Gault equation]; implantable defibrillator; and treatment with a beta-blocker, diuretic, angiotensin converting enzyme inhibitor, nitrate, warfarin, or statin) to be available for entry into the planned model by stepwise selection (significance level entry/exit = 0.1). For Cox regression analyses, baseline NT-pro BNP and BDI scores were trimmed at the ninety-fifth percentiles to prevent excessive influence of outliers; NT-pro BNP was expressed as NT-pro BNP/1,000 and age was expressed as age/10. Descriptive statistics were means with standard deviations for continuous variables and counts with percentages for categorical variables. Also, Student t tests and chi-square tests were used for the comparison of characteristics of study participants who died before or were otherwise unavailable for reassessment of depressive symptoms, with those comprising the study sample (n = 147) evaluated using the Cox regression analyses.

Demographic and clinical characteristics of the study sample are shown in Table 1. The mean age at baseline was 57 years, with a range of 27 to 88 years. Most patients were male (70%), and approximately half were minorities. Most patients had New York Heart Association functional class II (59%) or class III (37%) levels, and most patients were taking a beta-blocker (88%) or an angiotensin converting enzyme inhibitor (86%). Twenty percent of patients were taking antidepressant medication (selective serotonin reuptake inhibitors, tricyclic or tetracyclic agents, and monoamine-oxidase inhibitors) at baseline, and the average BDI score at baseline was 10 (SD: 6, range: 0 to 37). The study sample consisted of 147 patients, which represents 83% of the 177 patients who survived 1 year after baseline assessments from our original study (3). Compared with the survivors, patients who died during the first year of follow-up (n = 27) had, at baseline, higher resting heart rates (p = 0.021), lower LVE Fs (p = 0.028), higher NT-pro BNP levels (p = 0.0001), and were less likely to be taking nitrates (p = 0.041). Cox proportional-hazards regression analyses revealed that only NT-pro BNP and LVEF were related to death (all p < 0.01) within the first year after baseline assessments. There were few differences in any of the demographic or clinical characteristics of the 30 patients who survived at least 1 year, but who were unavailable for follow-up compared with the remaining 147 patients, with the exceptions of their having higher baseline systolic blood pressure (p = 0.011), higher NT-pro BNP levels (p = 0.021), lower hemoglobin levels (p = 0.015), and being more likely to be diabetic (p = 0.024). It is of note that there were no differences in baseline BDI score between the present study sample (n = 147) and those 30 patients who were unavailable for 1-year follow-up (10.2 6.9 vs. 10.9 6.4, respectively, p = 0.579).