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Sertraline Against Depression and Heart Disease in Chronic Heart Failure - SADHART-CHF
Description:
Depression is a common comorbidity in patients with chronic heart failure (CHF). The SADHART-CHF trial sought to study if treatment with an antidepressant, sertraline (a selective serotonin reuptake inhibitor [SSRI]) would be associated with benefit in patients with CHF and depression.
Hypothesis:
Sertraline will be associated with a significant improvement in cardiovascular outcomes in patients with CHF and depression, as compared with placebo.
Study Design
- Blinded
- Parallel
- Placebo Controlled
- Randomized
Patient Populations:
- Age ≥45 years
- Left ventricular EF ≤45% (within the previous 6 months)
- NYHA class II-IV symptoms
- Major depressive disorder
Number of enrollees: 469
Duration of follow-up: 12 weeks
Mean patient age: 62 years
Percentage female: 41%
Ejection fraction: 31% NYHA class: II (28%), III (48%), IV (24%)
Exclusions:
- Significant cognitive impairment
- Alcohol or drug dependence within the previous year
- Psychoses
- Bipolar disorder
- Severe personality disorder
- Suicidal ideation
- Life-threatening comorbidity
- Current use of antipsychotic or antidepressant medications
Primary Endpoints:
- Change in HDRS score from baseline
- Change in composite CV status from baseline
Drug/Procedures Used:
Patients with chronic systolic CHF were randomized to receive either sertraline or placebo for 12 weeks. The initial dose was 50 mg/day and was increased in 50 mg/day increments based on the results of the Beck Depression Inventory (BDI) total score and the clinical opinion of the examining investigator, to a maximum of 200 mg/day. The minimum dose was 50 mg/day. All participants also received nurse-facilitated support, designed to build rapport and trust with the study participants, ascertain compliance with the study protocol, reevaluate depression status, monitor suicidal ideation, and consult with study physicians on appropriate patient management.
Concomitant Medications:
Beta-blockers (84%), angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (79%), diuretic (62%), and statin (69%)
Principal Findings:
A total of 469 patients were randomized, 234 to sertraline, and 235 to placebo. Baseline characteristics were fairly similar between the two arms. The majority of patients had New York Heart Association (NYHA) class III or IV symptoms (72%), with a mean ejection fraction (EF) of 31%. The mean BDI total score was 6.9, with a corresponding Hamilton Depression Rating Scale (HDRS) total score of 18.3. About 18% of patients carried a prior diagnosis of major depression, and about 7% were already on antidepressants on recruitment. Implantable cardioverter-defibrillators (ICDs) were present in about 19% of the patients.
There was a significant reduction in the mean HDRS score in both arms at 12 weeks. However, this was similar between the sertraline and placebo arms (mean change = -7.1% vs. -6.8%, p = 0.89). The proportion of patients classified as worsened, improved, or unchanged for the co-primary endpoint of composite cardiovascular status was similar between the two arms at the end of follow-up (p = 0.78). This included all-cause mortality (7.7% vs. 6.8%, p = 0.58), cardiovascular (CV) death (6.8% vs. 4.3%, p = 0.59), arrhythmia (1.7% vs. 2.6%, p = 0.53), exacerbation of CHF (8.1% vs. 12.8%, p = 0.1), and acute myocardial infarction (MI) (0.4% vs. 0%). CHF hospitalization or death was also similar between the two arms (15.8% vs. 19.2%, p = 0.34).
A significantly higher proportion of participants in the sertraline arm withdrew from the treatment phase because of side effects that were believed to be study drug related compared with the placebo arm (11.5% vs. 6.0%, p = 0.03). Nausea and dizziness were the most common side effects reported, with a higher frequency in the sertraline arm. Serious adverse events were not statistically different between the two arms, including CV (35.6% vs. 37.1%, p = 0.79) and psychiatric (0% vs. 1%, p = 0.16) at 12 weeks.
On long-term follow-up (mean of 798 days), there was no difference between the two arms in all-cause mortality (29.1% vs. 26%), or any of the other CV outcomes noted above (p > 0.05 for all).
Interpretation:
The results of the SADHART-CHF trial indicate that there is no CV or psychiatric benefit derived at 12 weeks from the routine use of sertraline in patients with chronic systolic CHF and depression. Moreover, sertraline is associated with a higher incidence of drug cessation due to side effects, mainly nausea and dizziness. Serious side effects were similar between the two arms. Long-term follow-up of these patients revealed no difference in mortality or CV outcomes. These results are similar to those of the SADHART trial, showing no benefit with the use of sertraline over placebo in post-MI and unstable angina patients with depression.
Nurse-facilitated support provided in both arms in this trial may be a reason for the significant response in the HDRS scale noted in the placebo response from baseline, thus biasing the primary endpoint towards the null. It is further possible that only patients with severe coexisting depression, or those with post-traumatic stress disorder-like symptoms from ICD firing, may benefit from antidepressant use. This will need to be studied in further trials.
References:
O’Connor CM, Jiang W, Kuchibhatla M, et al. Safety and efficacy of sertraline for depression in patients with heart failure: results of the SADHART-CHF (Sertraline Against Depression and Heart Disease in Chronic Heart Failure) trial. J Am Coll Cardiol 2010;56:692-9.
Keywords: Nausea, Myocardial Infarction, Depressive Disorder, Major, Serotonin Uptake Inhibitors, Follow-Up Studies, Comorbidity, Stress Disorders, Post-Traumatic, Sertraline, Dizziness, Research Personnel, Heart Failure, Suicidal Ideation, Patient Compliance, Defibrillators, Implantable
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