Depression is prevalent in patients with heart failure and is associated with a significant increase in hospitalizations and death. Primary results of the Sertraline Against Depression and Heart Disease in Chronic Heart Failure (SADHART-CHF) trial revealed that sertraline and placebo had comparable effects on depression and cardiovascular outcomes. In this study, we explored whether remission from depression was associated with better survival and aimed to characterize participants who remitted during the trial. Based on depression response during the 12-week treatment phase, SADHART-CHF participants were divided into 2 groups: (1) remission, defined as participants whose last measured Hamilton Depression Rating Scale (HDRS) score was <8, and (2) nonremission, defined as participants whose last measured HDRS score was ≥8. Patients who dropped out before having any repeat HDRS were not included. Baseline characteristics and survival differences up to 5 years were evaluated between the remission and nonremission groups. Of the 469 SADHART-CHF participants, 208 (44.3%) achieved remission, 194 (41.4%) remained depressed, and 67 (14.3%) dropped out or died without any repeat HDRS assessment. Patients in the remission group had significantly fewer cardiovascular events than those in the nonremission group (1.34 ± 1.86 vs 1.93 ± 2.71, adjusted p = 0.01). Men patients were more likely to remit than women patients (56.5 vs 44.8%, p = 0.02). The remission group had milder depressive symptoms at baseline compared to the nonremission group (HDRS 17.0 ± 5.4 vs 19.6 ± 5.5, Beck Depression Inventory scale 17.9 ± 6.5 vs 20.3 ± 7.2, p <0.001 for the 2 comparisons). In conclusion, this study indicates that remission from depression may improve the cardiovascular outcome of patients with heart failure.
Depression is a common and well-documented co-morbidity in patients with heart failure (HF). It is associated with substantial morbidity and mortality and with lower quality of life and functional status. The adverse relation of depression to HF is independent of HF cause and other conventional risk factors. Sertraline appeared to be safe in depressed patients with HF ; however, it did not demonstrate any superiority over placebo for depression and HF survival in the Sertraline Against Depression and Heart Disease in Chronic Heart Failure (SADHART-CHF) trial. Recently, Carney et al and Glassman et al reported that patients with ischemic heart disease whose depression significantly decreased during the study periods that was not necessarily related to the trial intervention had better survival than those patients whose depression persisted. Whether this phenomenon applies to patients with HF is unknown. This study therefore aimed to explore if remission is associated with better cardiovascular outcome of patients with HF and major depressive disorder and to examine characteristics that may differentiate patients whose depression remitted from ones whose depression remained during the trial.
Methods
The SADHART-CHF database was used for this analysis. A detailed method of the SADHART-CHF trial has been previously published. SADHART-CHF was a randomized double-blind study of sertraline versus matching placebo in patients with HF and co-morbid major depression. In addition, all participants received nurse-facilitated support (NFS). Primary end points of the SADHART-CHF trial were change across time in severity of depression as measured by the Hamilton Depression Rating Scale (HDRS) total score and change in composite cardiovascular status. The protocol was reviewed and approved by the local institutional review board at each participating center, and all participants provided written, voluntary, informed consent before enrollment.
SADHART-CHF trial patients were randomized 1:1 to sertraline 50 mg/day or matched placebo for a 12-week acute treatment phase. Study drug dose was titrated up in 50-mg/day increments every 2 weeks with a maximum dose of 200 mg/day, depending on severity of depressive symptoms and tolerability of participants to the study drug. Participants who were unable to tolerate the 50-mg/day dose were allowed to remain in the study provided a minimum 25-mg/day dose was tolerated. The study medication was tapered off after the 12-week acute treatment phase. All participants, regardless of acute-phase completion, entered the long-term follow-up phase and were contacted at 6 months 12 months, and annually thereafter to evaluate clinical events and vital status. The long-term follow-up phase continued until the last enrolled participant completed a 6-month follow-up.
All participants received NFS as a mechanism to ascertain safety and study compliance. Primary goals for the research personnel applying supportive measures were to increase recruitment and assessment of participants, to ascertain safety of participants, and to increase participant compliance and retention. Such support was provided by nurses and other study personnel with experience or training in clinical psychiatry and supervised by the study psychiatrist. Supportive measures included ≥10 hours of active interaction between research personnel and study participants during the 12-week acute phase. The interaction consisted of 3 face-to-face visits (1 during recruitment/baseline assessment followed by 2 visits conducted primarily in participants’ homes) and 4 follow-up telephone contacts. Research personnel aimed to provide psychological support and conduct medical and psychiatric health evaluations. Personnel were instructed to provide active and empathetic listening and validation skills and soothing and other emotional support strategies. Research personnel were asked not to push for dialog with participants who were more reserved and aimed to establish an individual interpersonal relationship with each participant.
For the present study, SADHART-CHF participants were divided into 2 groups, irrespective of treatment assignment: (1) remission, defined as participants whose last measured HDRS score was <8, and (2) nonremission, defined as participants whose last measured HDRS score was ≥8. Patients who dropped out before having any repeat HDRS were not included in this study.
Primary end points of this analysis were survival or time to death and rate of recurrent cardiovascular events and/or death until last follow-up. Cardiovascular events were adjudicated by a blinded clinical events committee as a component of the primary trial. Clinical characteristics examined among these groups included effects of randomization, dosing of study medication, and depressive symptomatology measured by the HDRS and the Beck Depression Inventory (BDI) scale. Baseline depressive symptomatology was examined in 3 ways (1) severity of depression based on HDRS scores (mild ≤17, moderate 18 to 22, severe ≥23), (2) overall HDRS and BDI scores, and (3) depressive symptom dimension, i.e., cognitive/affective (items 2, 3, 5, 6, 7, 8, 9, 12, and 14), somatic/affective (items 1, 4, 10, 11, 13, 15, 16, 17, 21, and 22), and appetitive (items 18 and 19/20) based on the BDI scale. Comparative analysis of baseline characteristics was performed on remission status with respect to treatment assignment. Change in HDRS by remission status over the 12-week treatment period was analyzed by random coefficient models. The final model included treatment, remission status, time in weeks, and the square of time and the interaction of each of these 2 time variables with remission status and study site. The model also included the random effects of patient, patient-by-time interaction, and square of patient-by-time interaction. All participants (remission and nonremission groups) were included in the analysis. Cox proportional regression modeling was used to evaluate survival differences between participants classified in the remission and nonremission groups. Data were censored at time to death. Logistic regression analysis was used to test differences of cardiovascular events between groups. Baseline HDRS scores, treatment assignment (sertraline or placebo), age, gender, baseline left ventricular ejection fraction, New York Heart Association (NYHA) class, ischemic cause, and study site were included in the regression model. Assumptions of the model were assessed using standard techniques. Logistic regression was also used to determine which subsets of patients were likely to remit over the 12-week treatment phase. Investigated characteristics were gender, baseline HDRS scores (≤17 vs >17), BDI scores (≤16 vs >16), and somatic/affective scores (lower vs higher than or equal to mean). Statistical analyses using SAS 9.1 (SAS Institute, Cary, North Carolina) were performed by statistical personnel within Duke University Medical Center (Durham, North Carolina).
Results
In total 469 participants were enrolled in SADHART-CHF at Duke University Medical Center and 3 Duke Health System affiliates from August 13, 2003 to March 3, 2008. The primary analysis of SADHART-CHF has been previously reported. Of the 469 SADHART-CHF participants, 208 patients (44.3%) had HDRS scores that improved to <8, whereas 194 (41.4%) patients had a HDRS ≥8 at the end of 12-week intervention. There were 67 subjects (14.3%) who did not have any repeat HDRS during the 12-week acute phase intervention and were excluded from this study. These participants had higher NYHA class HF than the other 2 groups (NYHA class II 17.9 vs 29.9, p <0.05). Ten patients (14.9%) died before any repeat HDRS assessment.
Most baseline characteristics were similar between the remission and nonremission groups with respect to sertraline or placebo assignment ( Table 1 ). More men remitted than women (64.4 vs 53.1%, p = 0.02), although differences between groups were not statistically significant. Hospitalization due to HF exacerbation within 1 year before enrollment was higher in the nonremission group (p = 0.03; Table 1 ).
| Characteristics | Remission Group | Nonremission Group | p Value ⁎ | ||
|---|---|---|---|---|---|
| Sertraline (n = 106) | Placebo (n = 102) | Sertraline (n = 90) | Placebo (n = 104) | ||
| Age (years), mean ± SD | 63.0 ± 9.9 | 61.2 ± 9.8 | 61.9 ± 10.5 | 62.0 ± 11.3 | 0.52 |
| Men | 62.3% | 66.7% | 50.0% | 55.8% | 0.09 |
| Race | 0.71 | ||||
| White | 52.8% | 55.9% | 56.7% | 60.6% | |
| Black | 40.6% | 35.3% | 40.0% | 34.6% | |
| Other | 6.6% | 8.9% | 3.3% | 4.8% | |
| Left ventricular ejection fraction, mean ± SD | 31.5 ± 8.9 | 29.7 ± 10.2 | 32.2 ± 9.7 | 29.8 ± 10.1 | 0.20 |
| New York Heart Association class | 0.56 | ||||
| II | 32.8% | 27.5% | 32.2% | 27.9% | |
| III | 51.9% | 51.1% | 43.3% | 45.2% | |
| IV | 16.0% | 21.6% | 24.4% | 26.9% | |
| Ischemic cause | 68.9% | 67.7% | 68.9% | 69.2% | 0.99 |
| ≥1 heart failure hospitalization in previous 12 months | 57.6% | 62.4% | 52.2% | 72.1% | 0.03 |
| Previous myocardial infarction | 52.8% | 44.1% | 51.1% | 43.3% | 0.41 |
| History of hypertension | 93.4% | 83.3% | 87.8% | 83.7% | 0.10 |
| Hyperlipidemia | 83.0% | 73.5% | 71.1% | 82.7% | 0.09 |
| Diabetes mellitus | 55.7% | 45.1% | 51.1% | 47.1% | 0.43 |
| Current smoking | 32.1% | 24.5% | 24.4% | 28.9% | 0.82 |
| Previous coronary bypass | 36.8% | 31.4% | 28.9% | 32.7% | 0.69 |
| Pacemaker | 7.6% | 3.9% | 8.9% | 5.8% | 0.52 |
| Implantable cardioverter–defibrillator | 14.2% | 13.7% | 22.2% | 22.1% | 0.20 |
| Inpatient at enrollment | 70.8% | 79.4% | 72.2% | 79.8% | 0.29 |
| Baseline medications | |||||
| Angiotensin-converting enzyme inhibitor | 68.9% | 76.5% | 72.2% | 68.3% | 0.54 |
| Angiotensin receptor blocker | 9.4% | 9.8% | 10.0% | 5.7% | 0.67 |
| β Blocker | 84.9% | 84.3% | 91.1% | 83.7% | 0.43 |
| Aspirin | 86.8% | 80.4% | 81.1% | 84.6% | 0.57 |
| Digoxin | 14.2% | 18.6% | 15.6% | 18.3% | 0.79 |
| Statin | 72.6% | 65.7% | 71.1% | 69.2% | 0.73 |
| Loop diuretic | 60.4% | 59.8% | 61.1% | 61.5% | 0.99 |
| Calcium channel blocker | 8.5% | 4.9% | 13.3% | 10.6% | 0.22 |
| Baseline Hamilton Depression Rating Scale, mean ± SD (range) | 16.9 ± 5.6 (6–30) | 17.1 ± 5.2 (7–30) | 19.6 ± 5.8 (5–35) | 19.5 ± 5.2 (7–33) | 0.0002 |
| Depression severity (Hamilton Depression Rating Scale score) | <0.0001/0.96 † | ||||
| ≤17 | 31.6% | 30.5% | 16.4% | 21.5% | |
| 18–22 | 24.8% | 24.1% | 25.6% | 25.6% | |
| ≥23 | 18.5% | 17.4% | 29.4% | 34.8% | |
| Baseline Beck Depression Inventory, mean ± SD (range) | 18.3 ± 6.9 (9–40) | 17.6 ± 6.2 (8–34) | 21.3 ± 7.2 (9–41) | 19.5 ± 5.3 (7–40) | 0.0009 |
| Depressive symptom dimension (Beck Depression Inventory) | |||||
| Cognitive/affective | 4.4 ± 3.7 (0–19) | 4.0 ± 3.4 (0–21) | 5.5 ± 4.0 (0–16) | 4.6 ± 4.1 (0–19) | 0.07 |
| Somatic/affective | 11.8 ± 3.9 (5–26) | 11.5 ± 3.7 (3–21) | 13.7 ± 4.5 (4–28) | 12.4 ± 4.0 (4–24) | 0.003 |
| Appetitive | 2.1 ± 1.7 (0–7) | 2.0 ± 1.8 (0–6) | 2.1 ± 1.6 (0–6) | 2.4 ± 1.9 (0–7) | 0.28 |
| Antidepressant use before enrollment | 6.6% | 4.9% | 8.9% | 8.0% | 0.73 |
| History of major depressive disorder | 15.1% | 8.8% | 22.2% | 16.4% | 0.08 |
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