MOOD-HF: SSRI ineffective in heart failure with depression




SAN DIEGO – Patients with major depressive disorder and heart failure with reduced ejection fraction fared no better with a selective serotonin reuptake inhibitor than with placebo in terms of heart failure outcomes or improved psychological well being in MOOD-HF, the first large randomized trial to examine the issue.

“MOOD-HF does not provide a rationale for the use of escitalopram in patients with systolic heart failure and comorbid depression. MOOD-HF suggests, however, that optimal heart failure management resulting in improved signs and symptoms might possibly be a means to ameliorate comorbid depression,” Dr. Christiane E. Angermann said at the annual meeting of the American College of Cardiology.

Dr. Christiane E. Angermann

Dr. Christiane E. Angermann

Moreover, exploratory secondary analysis suggested “a very subtle long-term effect of the antidepressant that may not be so favorable” in patients with more severe heart failure, she added.

“It seems that some of our patients take antidepressants in vain, and we should care more about the heart failure medications,” said Dr. Angermann, chairman of the MOOD-HF trial and director of clinical research at the Comprehensive Heart Failure Center at the University of Wurzburg (Germany).

MOOD-HF was an ambitious clinical trial conducted at 16 German academic medical centers. The study began with the screening – via the Patient Health Questionnaire–9 – of more than 11,000 patients who had heart failure with reduced ejection fraction. A psychiatrist using the Structured Clinical Interview for Depression eventually diagnosed a subgroup as having major depressive disorder. Ultimately, 372 patients with an average left ventricular ejection fraction of 35% were randomized in double-blind fashion to escitalopram (Lexapro) or placebo for a planned 24 months.

The study rationale stemmed from the well-established finding that depression is three to five times more common in heart failure patients than in the general population, and that the severity of depression in these patients shows a dose-response relationship with their risks of all-cause mortality and heart failure hospitalization. The primary study hypothesis in MOOD-HF was that treating the comorbid depression would result in a reduced risk of all-cause mortality and unplanned hospitalization for any cause.

“Never before had an ethics committee been persuaded to allow patients with major depressive disorder to be on a placebo for 2 years,” said Dr. Angermann. “It took a lot of discussion with the psychiatrists, addressing whether these were depressed patients with comorbid heart failure or patients with heart failure and comorbid depression. We ended up agreeing that since these patients mostly die from heart failure, therefore this is the main disease. And since there was no evidence from other cardiovascular studies that antidepressants were of use, we were allowed to do the study,” she explained.

The trial was halted early for futility at the request of the data safety monitoring board after a median of 18 months. At that point, the primary composite endpoint of death or unplanned hospitalization had occurred in 116 patients in the escitalopram group and 119 on placebo.

A key secondary endpoint – improvement in the Montgomery-Asberg Depression Rating Scale (MADRS) at 12 weeks – was also a virtual dead heat. From a baseline score of 21, both the escitalopram and placebo groups showed a clinically meaningful improvement of roughly 9 points. The improvement in MADRS scores in the control group piqued investigators’ interest because no psychotherapy or counseling was involved in the trial.

The target dose of escitalopram was 20 mg/day, with uptitration to that goal taking place over the first 12 weeks. The mean dose of the antidepressant at week 12 was 13.7 mg/day. During the course of the study, however, the target dose dropped to 10 mg/day in patients over age 65 in accordance with updated regulatory guidance regarding possible proarrhythmic QTc prolongation in older patients. As it turned out, QTc prolongation was not an issue in MOOD-HF. Indeed, there was no difference between the two groups in terms of any serious adverse events. Adherence to the study medication was good, Dr. Angermann continued.

While the dose of escitalopram was being uptitrated during the first 12 weeks, so was guideline-directed medical therapy for heart failure in both study arms. The patients improved from being at 56% of the recommended dose of ACE inhibitor/angiotensin receptor blocker therapy at baseline to 64%, and from 58% of the target dose of beta-blocker therapy to 63%. That, rather than the antidepressant, appeared to be responsible for the improvement in heart failure, she said.

Both study arms showed similar improvements over time in New York Heart Association functional class and left ventricular ejection fraction. But levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) – an important biomarker of heart failure severity – improved only in the placebo-treated controls. The same held true for reduction in left ventricular end diastolic diameter.


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