Sadhart trial

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 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 On long-term follow-up mean of days , there was no difference between the two arms in all-cause mortality 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. Sertraline is a safe treatment for recurrent depression among patients recently hospitalized for ACS. TCAs can treat depression, but their use has been associated with orthostatic hypotension, QT prolongation, and arrhythmic deaths, and thus their use in post-ACS depression is controversial.

This study therefore sought to investigate the role of a different class of antidepressents, namely SSRIs. The study was not powered to detect differences in depression scores; thus unsurprisingly there were no significant differences in the study's secondary outcome measures, namely the Hamilton Depression and Clinical Global Impression ratings.

A subgroup analysis, however, identified improvements in depression ratings among the subgroup of patients who had experienced an episode of major depression prior to their ACS. Non-completers were participants who discontinued study drug prior to weeks. A total of participants were randomized to sertraline. Of these, were classified as completers. In the placebo group, participants of the randomized completed the week treatment period and received study drug for The remaining 83 participants were non-completers and stopped study drug after The reasons for study drug withdrawal are given in Figure 1.

Figure 2 displays the trajectory of improvement in the raw total scores of HDRS across the treatment phase. Based on raw HDRS scores. This plot displays the change in HDRS total scores by week in the study.

A total of 8. The HDRS scores at baseline vs. The results were similar to the intention-to-treat analysis. The mean change in HDRS from baseline to weeks was There was no difference in change scores between groups 1. Again, there was no treatment by dose interaction.

In the sertraline group, the composite cardiovascular status worsened in In the placebo group, No differences were observed between groups in individual components of the composite score, including all cause mortality, cardiovascular death, non-fatal cardiovascular events, heart failure hospitalization, or combinations of these outcomes Table 3.

The total number of days alive during the week acute phase was similar in both groups, The distribution of change in NYHA class was also similar among groups. NYHA class worsened in 61 An as per-protocol analysis including only those participants who completed weeks of treatment was also performed. The results for change in HDRS and composite cardiovascular score were similar to the findings of the intention-to-treat analysis.

Serious adverse events were not statistically different between the groups Table 4. Two participants in the placebo group developed significant suicidal ideations during the acute treatment phase.

There were no suicide attempts or completed suicides. All cause mortality was not different between groups. A total of 68 participants In the Cox model adjusted for site, the hazard ratio for survival was not significantly different between the two treatment groups HR 1. Non-fatal cardiovascular events were also similar Table 5.

Multiple reasons may be responsible for the lack of an observed additive benefit with sertraline. Placebo effects are common in anti-depressant trials. The placebo response in this study may have been enhanced by the nursing support provided to all participants. An additive benefit for sertraline on depression scores was not detected. It is possible that the close cardiovascular follow-up coupled with the nursing staff interactions improved mood disorders to a degree sufficient to blunt any sertraline effect.

It is also possible that the mechanism of depression and mood disorders differs in the heart failure population, such that their response to traditional anti-depressant pharmacotherapy is inadequate.

The level of depression in our study may not have been severe enough to respond to sertraline therapy. Additionally, the pharmacokinetics of many drugs may be altered in the setting of acute decompensation; it is possible that higher doses of sertraline may be needed in patients with a recent episode of acute decompensated heart failure to overcome the lower absorption that can occur in states of significant volume overload or reduced cardiac output and decreased gastrointestinal perfusion states.

There are no data evaluating the extent to which sertraline pharmacokinetics may be altered in acute heart failure, but this hypothesis may be worth exploring in future studies. Similarly, in the SADHART trial of sertraline in patients with acute myocardial infarction or unstable angina, sertraline's overall effect size on the depression endpoint was small and only significant in the subset of patients with recurrent depression These findings may reflect a true lack of efficacy for sertraline in these populations whose depression may not be severe enough to benefit from sertraline or other antidepressants These data indicate that heart failure patients with evidence of depression may benefit from psychosocial supportive care delivered by clinically experienced personnel.

The use of antidepressant agents should likely be reserved for patients who do not respond to supportive care. This mortality rate is higher than would be expected based on the population's heart failure characteristics alone, considering the annual mortality rate reported in a similar outpatient heart failure population with primarily NYHA class II and III symptoms was 8.

This elevated short-term mortality rate may be due to the presence of depression, and it reinforces the need to find more effective treatment and management approaches for depression in patients with heart failure. Sertraline did not influence short or long-term cardiovascular events or survival in this study as compared to the placebo.

The proportion of participants whose cardiovascular status worsened, improved, or was unchanged was similar among treatment groups. Fatal and non-fatal cardiovascular events were also similar between groups. Thus, the ancillary properties of SSRIs 16 - 24 did not translate into cardiovascular benefit, at least in this short-term study.

A large, ongoing trial will provide further evidence to guide the management of patients with heart failure and depression The primary endpoint is the time to first death or hospitalization Nurse support may have contributed to the placebo response and improvement in depression scores, limiting the ability to detect a difference between groups.

The non-completer rate was approximately twice the rate assumed in the sample size calculations. However, even a larger sample would be unlikely to affect the results, given the small observed differences between groups. Finally, a short-term duration of therapy may have been insufficient to fully demonstrate the potential effects of sertraline on cardiovascular outcomes.

In conclusion, depression in patients with heart failure is associated with substantial mortality. Sertraline did not adversely affect cardiovascular outcomes in this population, and it may be an appropriate therapeutic strategy in patients who remain depressed despite non-pharmacologic interventions and who otherwise have an indication for sertraline.

Many patients with depression and heart failure who have coronary heart disease may be candidates for depression treatment on the basis of their coronary heart disease alone Further research is needed to determine the optimal combination of pharmacologic and non-pharmacologic treatment of depression in patients with heart failure. Financial Disclosures:. Silva receives honoraria from Pfizer, Inc. Silva also received salary support through the NIMH research grant.

He also received salary support through the NIMH research grant. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

National Center for Biotechnology Information , U. J Am Coll Cardiol. Author manuscript; available in PMC May Christopher M.