HOLLYWOOD, FLA. — Sertraline did not significantly improve depressive symptoms or cardiovascular status among depressed patients with heart failure, compared with placebo in a 12-week, randomized, double-blind study.
A second, posthoc analysis of the data indicates that patients who achieve remission of depression experience prognostic and functional improvements, including statistically fewer mean cardiovascular events during long-term follow-up, compared with nonremitters.
Dr. Wei Jiang presented results of both the primary and secondary analyses of the Sertraline Antidepressant Heart Attack Randomized Trial in Congestive Heart Failure (SADHART-CHF) at a meeting of the New Clinical Drug Evaluation Unit (NCDEU) sponsored by the National Institute of Mental Health.
She and her associates assessed depressive symptoms, cardiovascular status, and long-term mortality rates in 234 patients who were randomized to sertraline (Zoloft, Pfizer Inc.) and an additional 235 who received placebo. At the end of the 12-week trial, there were 144 patients remaining on treatment and 146 others in the placebo group.
In an intent-to-treat analysis, there was a significant reduction in Hamilton Depression Rating Scale scores in both groups, compared with baseline. However, no significant differences were found between groups in these Hamilton scores, composite cardiovascular scores, fatal or nonfatal cardiovascular events, or results of the Kansas City Cardiomyopathy Questionnaire. In addition, long-term survival did not differ significantly between groups.
The null findings might result from an effect of a nurse-facilitated supportive intervention for all participants, Dr. Jiang said. “But a placebo effect cannot be ruled out.”
Dr. Jiang receives research support from the NIMH (sponsor of the study), the National Heart, Lung, and Blood Institute, and from Pfizer for an unrelated study. Pfizer's only role in SADHART-CHF was to supply the sertraline, she added.
“We spent 6 years doing the study, and now we are stuck. There is no antidepressant we can recommend to cardiologists for this population. Other than sertraline, almost all other classes of antidepressants … have cardiovascular concerns,” said Dr. Jiang, who is on both the internal medicine and the psychiatry and behavioral sciences faculties at Duke University, Durham, N.C.
The search for a safe and effective treatment for depression is important and should continue, Dr. Jiang said, because depression is “highly prevalent” in patients with heart failure. A 22% prevalence of depression was found in a meta-analysis, for example (J. Am. Coll. Cardiol. 2006;48:1527-37).
This study suggested that there was an increased risk for death and secondary cardiac events in depressed versus nondepressed patients (risk ratio 2.1).
The 469 participants in the primary analysis were 45 years or older, had a New York Heart Association classification of II or higher, and a left ventricular ejection fraction of 45% or less. Mean age was 63 years in the treatment cohort and 62 years in the placebo group. Men comprised 57% and 62%, respectively, of these cohorts.
Those randomized to treatment received sertraline between 50 mg/day and 200 mg/day or matched placebo. The average sertraline dose was 69 mg/day and 75 mg/day for placebo. “That is too low,” a meeting attendee said during a question-and-answer session. “That is what we thought, also,” Dr. Jiang said. “I agree with you, but we felt many patients would drop out [if dosing were higher]. Remember that 41% of the sertraline arm dropped out.”
The same person commented further that sertraline might have been more effective at a higher dose. “There are studies showing 50 mg is enough, so I don't know the right answer,” she replied.
Dr. Jiang also presented results of a posthoc analysis of remission using Hamilton Depression scores. Remission was associated with prognostic and functional improvement in depressed heart failure patients during the 12-week intervention phase. In addition, there was a statistical difference in mean overall cardiovascular events between that favored remitters (1.11) versus nonremitters (1.66) during follow-up.
Again, there was no significant difference in long-term survival between the 208 remitters and 194 nonremitting patients (mean survival of 866 days versus 793 days). The remaining 67 patients were classified as early terminators because they dropped out of the study prior to the first treatment.
Achievement of remission should be a target for additional studies of patients with heart failure and comorbid depression, Dr. Jiang said.
In addition, more data are needed to identify factors that might indicate which heart failure patients are likely to respond to different antidepressant modalities, she said.