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Figure 1.
Consolidated Standards of Reporting Trials Diagram of the Effects of Selective Serotonin Reuptake Inhibition on Morbidity, Mortality, and Mood in Depressed Heart Failure Patients Study
Consolidated Standards of Reporting Trials Diagram of the Effects of Selective Serotonin Reuptake Inhibition on Morbidity, Mortality, and Mood in Depressed Heart Failure Patients Study

aFulfilled criteria of DSM-IV diagnosis of depression.

bWithdrew informed consent immediately after randomization prior to receiving study medication.

Figure 2.
Kaplan-Meier Curves for the Incidence of All-Cause Death or Hospitalization
Kaplan-Meier Curves for the Incidence of All-Cause Death or Hospitalization

According to a modified intention-to-treat analysis (4 patients who were randomized but did not take at least 1 dose of study medication were excluded). Median follow-up times were 560 days (interquartile range, 201-747 days) in the escitalopram group and 573 days (interquartile range, 306-747 days) in the placebo group. The median times at risk for the primary end point (all-cause death or all-cause hospitalization) were 148 days (interquartile range, 46-386 days) in the escitalopram group and 162 days (interquartile range, 42-377 days) in the placebo group. There were 116 patients in the escitalopram group with an event and 119 in the placebo group.

Figure 3.
Serial Changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) Sum Score
Serial Changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) Sum Score

The error bars indicate 95% CIs. The group sizes at baseline refer to all patients who had at least 1 MADRS follow-up assessment. Each item of the 10-item MADRS questionnaire yields a score of 0 to 6 resulting in an overall score from 0 to 60, with higher values indicating more severe depression. The effect of escitalopram vs placebo at 12 weeks was –0.9 (95% CI, –2.6 to 0.7; P = .26). The overall effect of escitalopram vs placebo across all MADRAS assessments was –0.9 (95% CI, –2.3 to 0.4; P = .16). The cutoff points are 0 to 6, which indicates normal; 7 to 19, mild depression; 20 to 34, moderate depression; and greater than 34, severe depression.26 Regression of an elevated MADRS sum score to a value of 10 or less has previously been proposed as a reasonable indicator of depression remission.24,32

aAssessment at 12 weeks was the prespecified secondary outcome.

Table 1.  
Baseline Characteristics of Study Participants
Baseline Characteristics of Study Participants
Table 2.  
Incidence of the Primary Composite Outcome and Secondary Time-to-Event Outcomes
Incidence of the Primary Composite Outcome and Secondary Time-to-Event Outcomes
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Taylor  CB, Youngblood  ME, Catellier  D,  et al; ENRICHD Investigators.  Effects of antidepressant medication on morbidity and mortality in depressed patients after myocardial infarction. Arch Gen Psychiatry. 2005;62(7):792-798.
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Spitzer  RL, Williams  JB, Gibbon  M, First  MB.  The Structured Clinical Interview for DSM-III-R (SCID): I, history, rationale, and description. Arch Gen Psychiatry. 1992;49(8):624-629.
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American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
22.
McMurray  JJ, Adamopoulos  S, Anker  SD,  et al; Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology; ESC Committee for Practice Guidelines.  ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2012;14(8):803-869.
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Güder  G, Störk  S, Gelbrich  G,  et al.  Nurse-coordinated collaborative disease management improves the quality of guideline-recommended heart failure therapy, patient-reported outcomes, and left ventricular remodelling. Eur J Heart Fail. 2015;17(4):442-452.
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Angermann  CE, Störk  S, Gelbrich  G,  et al; Competence Network Heart Failure.  Mode of action and effects of standardized collaborative disease management on mortality and morbidity in patients with systolic heart failure: the Interdisciplinary Network for Heart Failure (INH) study. Circ Heart Fail. 2012;5(1):25-35.
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Montgomery  SA, Åsberg  M.  A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382-389.
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Hawley  CJ, Gale  TM, Sivakumaran  T; Hertfordshire Neuroscience Research Group.  Defining remission by cut off score on the MADRS: selecting the optimal value. J Affect Disord. 2002;72(2):177-184.
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Kramer  DG, Trikalinos  TA, Kent  DM, Antonopoulos  GV, Konstam  MA, Udelson  JE.  Quantitative evaluation of drug or device effects on ventricular remodeling as predictors of therapeutic effects on mortality in patients with heart failure and reduced ejection fraction: a meta-analytic approach. J Am Coll Cardiol. 2010;56(5):392-406.
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Oremus  M, Don-Wauchope  A, McKelvie  R,  et al.  BNP and NT-proBNP as prognostic markers in persons with chronic stable heart failure. Heart Fail Rev. 2014;19(4):471-505.
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Original Investigation
June 28, 2016

Effect of Escitalopram on All-Cause Mortality and Hospitalization in Patients With Heart Failure and DepressionThe MOOD-HF Randomized Clinical Trial

Author Affiliations
  • 1Comprehensive Heart Failure Center and Department of Medicine I, University Hospital Würzburg, Wurzburg, Germany
  • 2Institute of Clinical Epidemiology and Biometry, University of Würzburg and Clinical Trial Center Würzburg, University Hospital Würzburg, Wurzburg, Germany
  • 3Department of Medicine and Cardiology and Heart Center, University Hospital Leipzig, Leipzig, Germany
  • 4Department of Cardiology, University Hospital Göttingen, Gottingen, Germany
  • 5Department of Internal Medicine, Cardiology, Charité-Campus Virchow-Klinikum, Universitätsmedizin Berlin, Berlin, Germany
  • 6Department of Cardiology, University Hospital Göttingen, Gottingen, Germany
  • 7German Heart Center Munich, Technical University München, Munich
  • 8Department of Medicine II, University Hospital Lübeck, Lubeck, Germany
  • 9Department of Medicine III, Saarland University Hospital, Homburg (Saar), Germany
  • 10Department of Cardiology, Theresienkrankenhaus (Academic Teaching Hospital of the University of Heidelberg), Heidelberg, Germany
  • 11University Heart Center Hamburg, Hamburg, Germany
  • 12Department of Cardiology, University Hospital Marburg, Marburg, Germany
  • 13Clinical Trial Center Leipzig, University of Leipzig, Leipzig, Germany
  • 14Department of Cardiology, University Hospital Nürnberg, Klinikum Nürnberg, Nurnberg, Germany
  • 15Department of Medical Psychology, Medical Sociology and Rehabilitation Sciences, Center of Mental Health, University of Würzburg, Wurzburg, Germany
  • 16Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Center of Mental Health, University Hospital Würzburg, Wurzburg, Germany
JAMA. 2016;315(24):2683-2693. doi:10.1001/jama.2016.7635
Abstract

Importance  Depression is frequent in patients with heart failure and is associated with adverse clinical outcomes. Long-term efficacy and safety of selective serotonin reuptake inhibitors in these patients are unknown.

Objective  To determine whether 24 months of treatment with escitalopram improves mortality, morbidity, and mood in patients with chronic systolic heart failure and depression.

Design, Setting, and Participants  The Effects of Selective Serotonin Re-Uptake Inhibition on Morbidity, Mortality, and Mood in Depressed Heart Failure Patients (MOOD-HF) study was a double-blind, placebo-controlled randomized clinical trial conducted at 16 tertiary medical centers in Germany. Between March 2009 and February 2014, patients at outpatient clinics with New York Heart Association class II-IV heart failure and reduced left ventricular ejection fraction (<45%) were screened for depression using the 9-item Patient Health Questionnaire. Patients with suspected depression were then invited to undergo a Structured Clinical Interview based on the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) to establish the diagnosis.

Interventions  Patients were randomized 1:1 to receive escitalopram (10-20 mg) or matching placebo in addition to optimal heart failure therapy. Study duration was 24 months.

Main Outcomes and Measures  The composite primary outcome was time to all-cause death or hospitalization. Prespecified secondary outcomes included safety and depression severity at 12 weeks of treatment (including the titration period), which were determined using the 10-item Montgomery-Åsberg Depression Rating Scale (total possible score, 0 to 60; higher scores indicate more severe depression).

Results  A total of 372 patients (mean age, 62 years; 24% female) were randomized and had taken at least 1 dose of study medication when the data and safety monitoring committee recommended the trial be stopped early. During a median participation time of 18.4 months (n = 185) for the escitalopram group and 18.7 months (n = 187) for the placebo group, the primary outcome of death or hospitalization occurred in 116 (63%) patients and 119 (64%) patients, respectively (hazard ratio, 0.99 [95% CI, 0.76 to 1.27]; P = .92). The mean Montgomery-Åsberg Depression Rating Scale sum score changed from 20.2 at baseline to 11.2 at 12 weeks in the escitalopram group and from 21.4 to 12.5 in the placebo group (between-group difference, −0.9 [95% CI,−2.6 to 0.7]; P = .26). Safety parameters were comparable between groups.

Conclusions and Relevance  In patients with chronic heart failure with reduced ejection fraction and depression, 18 months of treatment with escitalopram compared with placebo did not significantly reduce all-cause mortality or hospitalization, and there was no significant improvement in depression. These findings do not support the use of escitalopram in patients with chronic systolic heart failure and depression.

Trial Registration  isrctn.com Identifier: ISRCTN33128015

Introduction

Quiz Ref IDCompared with the general population, depression is 2- to 3-times more common in patients with cardiovascular disease.1 Patients with depression have worse outcomes after myocardial infarction,2 and physically healthy individuals with depression are at increased risk of developing coronary disease.3 Meta-analysis indicates that depression prevalence in patients with heart failure is 10% to 40%, depending on disease severity.4 Depression has been shown to be an independent predictor of mortality and rehospitalization in patients with heart failure,5,6 with incidence rates increasing in parallel with depression severity,6 and was found to be associated with poor quality of life,7 increased costs,8 and low treatment adherence.9

Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat depression. According to meta-analysis data, sertraline and escitalopram have better efficacy and patient acceptability than other new-generation antidepressants.10 In patients with coronary disease, randomized studies showed that SSRIs were safe and might improve depression, but had no beneficial effect on prognosis.1113 However, post hoc analyses from the Enhancing Recovery in Coronary Heart Disease trial12 indicated that prolonged SSRI treatment might reduce mortality and morbidity.14

Until now the Sertraline Against Depression and Heart Disease in Chronic Heart Failure (SADHART-CHF) study is the only randomized trial evaluating SSRIs in patients with heart failure.15 Compared with placebo, sertraline did not improve depression or cardiovascular status, but treatment duration was only 12 weeks. Assessment of the effects of SSRIs over a longer period seemed required to detect possible effects of these agents on long-term clinical outcomes in patients with heart failure.

Therefore, the Effects of Selective Serotonin Re-Uptake Inhibition on Morbidity, Mortality and Mood in Depressed Heart Failure Patients (MOOD-HF) study was designed to investigate long-term efficacy and safety of escitalopram in patients with chronic systolic heart failure and depression. We hypothesized that pharmacotherapy with this antidepressant would reduce the increased mortality and morbidity risk associated with comorbid depression in patients with heart failure.5,6

Methods
Study Design

MOOD-HF was a double-blind, placebo-controlled randomized clinical trial conducted at 16 tertiary medical centers in Germany. Study design information has been reported,16 and the full study protocol appears in Supplement 2. The study protocol was approved by the institutional ethics committee at each study site. All participants provided written informed consent prior to inclusion in the study. Patients were not compensated for study participation except for travel expenses. The trial was conducted according to the guideline for good clinical practice17 and the ethical principles of the Declaration of Helsinki 2002.18 The principal investigators oversaw the conduct of the trial and data analysis. The trial was reviewed by an independent data and safety monitoring committee. The eMethods in Supplement 1 provides more details.

Study Population

Adult attendees at heart failure outpatient clinics with an established diagnosis of heart failure (New York Heart Association class II-IV) and a left ventricular ejection fraction (LVEF) of less than 45% documented within the last 3 months were screened for depression using the 9-item Patient Health Questionnaire (PHQ-9).19 Those with a score of 12 points or higher (or ≥9 points by protocol amendment on June 30, 2011; Supplement 2) underwent a Structured Clinical Interview20 based on the Diagnostic and Statistical Manual of Mental Disorders (German version of the Fourth Edition; DSM-IV) (SCID) with a psychiatrist or psychosomatic specialist, which was scheduled at least 2 weeks later to exclude transient mood swings (eMethods in Supplement 1). Patients diagnosed with current major depression according to DSM-IV criteria21 during the SCID were then invited to participate in MOOD-HF and asked to provide signed informed consent. Other inclusion and exclusion criteria have been reported previously16 (and appear in the eMethods).

Study Treatments and Follow-up

The study design is shown schematically in eFigure 1 in Supplement 1. Eligible patients were randomized 1:1 to receive either escitalopram (10-20 mg once daily) or matching placebo for up to 24 months in addition to optimal heart failure care. Randomization strata were age, sex, depression severity, and time since the last hospitalization (eMethods). The starting dose was 5 mg once daily, increasing to 10 mg/d and 20 mg/d after 3 and 6 weeks; slower uptitration was permitted for tolerability reasons. The dose at 12 weeks was considered the maintenance dose. From December 5, 2011, the maximum dose was limited to 10 mg/d in patients aged 65 years or older based on the pharmaceutical manufacturer’s recommendation.

Tolerance-guided uptitration of heart failure pharmacotherapy22 and patient counseling and empowerment (with modules addressing heart failure signs and symptoms, lifestyle modifications, drug adherence, self-care, and self-supervision skills) occurred in parallel during telephone contacts and personal visits using previously reported effective care strategies.23,24 Maintenance therapy and the clinical status of patients were evaluated every 6 months.

After the final visit, patients were tapered off study medication and underwent a psychiatric closeout examination to clarify the need for continued antidepressant pharmacotherapy. The first patient was randomized on March 11, 2009, and the last on February 24, 2014. Final patient follow-up took place on September 2, 2014.

Psychometric and medical safety assessments were performed at each follow-up visit (eMethods in Supplement 1). Cardiologists used the 10-item Montgomery-Åsberg Depression Rating Scale (MADRS)25 to assess depression. Each item of the 10-item MADRS yields a score of 0 to 6 resulting in an overall score from 0 to 60, with higher values indicating more severe depression. Commonly used cutoff ranges are 0 to 6, normal; 7 to 19, mild depression; 20 to 34, moderate depression; and greater than 34, severe depression.26 Additional safety measures included weekly telephone monitoring of depressive symptoms and cardiac status during uptitration, and then bimonthly monitoring. Specialized nurses applied the 2-item PHQ27 during telephone calls, and immediately involved a psychiatrist or psychosomatic specialist if he/she suspected significant worsening of depression or suicidal ideations. Prescription of open-label antidepressant therapy was permitted only after consultation with the psychiatric core laboratory. After database closure, serum escitalopram levels were measured28 from serial serum samples stored at –80°C (eMethods).

Study End Points

The primary efficacy outcome was time to a first event of the composite of all-cause death or hospitalization (excluding planned hospitalization for noncardiac causes). Prespecified psychometric secondary outcomes included the MADRS sum score25 at 12 weeks, anxiety as assessed with the 7-item PHQ for generalized anxiety disorder,29 and health-related quality of life (assessed using the Kansas City Cardiomyopathy Questionnaire [KCCQ]).30 Other prespecified secondary outcomes were time-to-event variables as the individual components of the primary outcome, time to cardiovascular death or hospitalization for heart failure, escitalopram serum levels, heart failure pharmacotherapy, and parameters describing heart failure severity, cardiac status, and safety. In addition, various subgroup analyses of the primary outcome were performed.

Adjudication of time-to-event outcomes was performed by an independent end point adjudication committee using prespecified criteria. Committee members were blinded to initial treatment assignment and had no information on whether patients were taking study medication, taking an open-label antidepressant therapy, or not taking antidepressant drugs.

Sample Size

We estimated an annual rate for the primary outcome of 36% with placebo, and hypothesized a 25% relative reduction in primary outcome events with escitalopram, corresponding to a hazard ratio (HR) of ln(0.73)/ln(0.64) = 0.705 (eMethods in Supplement 1). Accordingly, 257 adjudicated end points were required to achieve 80% power with a type I error of .05. Total event rates after recruitment of 240 patients indicated a considerably higher than anticipated hospitalization rate (60%). Therefore, we recalculated that data for 414 patients (instead of the planned 70018) would be sufficient to achieve 80% power while also maintaining the HR (protocol amendment of August 6, 2012; eMethods).

Early Termination

Quiz Ref IDOn February 28, 2014, the steering committee stopped enrollment based on futility after a recommendation from the data and safety monitoring committee. The decision was made during the regular data review process and not based on a prespecified futility rule. After that date, the next scheduled appointment constituted the final study visit for patients who had participated in MOOD-HF for at least 6 months. Patients with shorter study participation continued until completing 6 months. Follow-up was completed on September 2, 2014.

Statistical Analysis

The full statistical analysis plan appears in Supplement 3. Analyses were performed on a modified intention-to-treat basis, which included all patients who took at least 1 dose of study medication. Baseline characteristics were summarized as mean and standard deviation (median and interquartile ranges if appropriate) for continuous variables and as counts (percentages) for categorical variables.

Time-to-event end points were analyzed by Cox regression. Results are presented as HRs with 95% CIs. Analyses were performed for each end point, both unadjusted and after adjusting for stratification at randomization. The prespecified primary hypothesis test was the adjusted modified intention-to-treat analysis of all-cause death and hospitalization. Kaplan-Meier time-to-event curves were generated. Changes in MADRS sum scores from baseline to 12 weeks were assessed by analysis of covariance. Generalized estimating equations were used for repeated measurement analyses of all consecutive MADRS assessments.

Analysis of covariance and ordinal or binary logistic regression models were used to analyze other quantitative ordinal and binary outcomes as appropriate. In each of these models, the follow-up measurement was the dependent variable, and treatment group and the respective baseline variable were predictors. For each of the tests, the binary subgroup variable and subgroup × treatment interaction term was added to the Cox model used in the primary analysis. Subgroup HRs and 95% CIs are reported from these models in which the respective subgroup category was defined as the reference category. P values for the interaction terms were reported (null hypothesis was equal HRs in the subgroups). Analyses of serious adverse event frequencies were adjusted for time alive and under observation. Statistical analyses were performed using SPSS version 23 (IBM Corp). Significance tests were 2-sided. P values <.05 were defined as statistically significant.

Results
Study Population

Screening using the PHQ-9 was performed on 11 086 patients; 2872 qualified to be further assessed using the SCID and 773 consented to be interviewed. Of the 508 patients with SCID-confirmed major depression, 376 met all inclusion criteria and were randomized; however, 4 withdrew consent prior to receiving any study medication. These 4 patients were prospectively excluded from all analyses (eTable 1 in Supplement 1).

Therefore, 372 patients (185 in the escitalopram group and 187 in the placebo group) who took at least 1 dose of study medication constituted the modified intention-to-treat population (Figure 1). Study treatment dosages were comparable at 12 weeks (mean [SD], 15.8 [6.4] mg of escitalopram and 14.9 [7.6] mg of placebo). The median participation times were 18.4 months in the escitalopram group and 18.7 months in the placebo group. No patient was lost to follow-up.

Baseline characteristics were balanced between groups (Table 1). Patients were predominantly male and on average 62 years of age with impaired LVEF and enlarged cavity size; the average MADRS sum scores at baseline indicated mild to moderate depression severity.25,26 Kansas City Cardiomyopathy Questionnaire assessment30 demonstrated substantial symptom burden and impaired disease-specific quality of life. The 7-item PHQ for generalized anxiety disorder and the Mini-Mental State Examination sum scores indicated moderate anxiety but no cognitive impairment.29,31 Most patients were receiving guideline-recommended heart failure medication regarding substance classes.22

Efficacy Outcomes

A primary end point event occurred in 116 patients (63%) in the escitalopram group and in 119 patients (64%) in the placebo group (HR, 0.99 [95% CI, 0.76 to 1.27], P = .92; Figure 2 and Table 2). No significant between-group differences were found for any time-to-event outcomes in the unadjusted or adjusted analyses (Table 2). Additional subgroup analyses showed no significant treatment × subgroup interactions (eFigure 2 in Supplement 1).

The mean (SD) baseline MADRS sum score changed from 20.2 (8.6) at baseline to 11.2 (8.1) at 12 weeks with escitalopram and from 21.4 (8.8) to 12.5 (7.6) with placebo (between-group difference, –0.9 [95% CI, –2.6 to 0.7], P = .26; Figure 3). Mean (SD) daily dosages of study medication were comparable in the 2 groups (15.8 [6.4] mg in the escitalopram group and 14.9 [7.6] mg in the placebo group). The overall between-group treatment difference across all MADRS assessments was –0.9 (95% CI, –2.3 to 0.4; P = .16).

Changes in the PHQ-9, the KCCQ, the 7-item PHQ for generalized anxiety disorder, and the Mini-Mental State Examination scores from baseline through 12 months appear in eTable 2 in Supplement 1. The PHQ-9 results confirmed comparable remission of depressive symptoms with both escitalopram and placebo. The KCCQ scores suggested clinically relevant improvements in health status and quality of life within groups. However, between-group differences did not reach statistical significance except for the KCCQ Symptom Scale, which was significantly higher in patients in the placebo group at 12 months. Anxiety decreased in both groups and there was no difference regarding the extent of improvement in anxiety between groups. Mini-Mental State Examination scores did not change.

Secondary and Exploratory Outcomes

The median escitalopram levels were in the therapeutic range of 15 ng/mL to 80 ng/mL28 throughout the trial. Treatment adherence was satisfactory; 86% of patients in the escitalopram group had serum levels of escitalopram above the lower detection limit of 6.3 ng/mL at study visit 3, 88% at study visit 4, 85% at study visit 5, and 73% at study visit 6 (eTable 3 in Supplement 1). At 12 weeks, 95% of patients were receiving angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers and β-blockers. The proportion of patients receiving guideline-recommended target doses22 increased during the first 12 weeks of the study (eTable 4). Uptitration of heart failure medication did not differ between groups.

Changes in heart failure severity and cardiac status from baseline to 6 and 12 months appear in eTable 5 in Supplement 1. In both groups, LVEF improved comparably. However, there was a faster decrease in N-terminal pro-B-type natriuretic peptide levels in the placebo group, and only patients in this group showed a reduction in left ventricular end-diastolic diameter, resulting in significant between-group differences at 6 and 12 months.

Exploratory analysis suggested that irrespective of treatment allocation, remission of depression symptoms, or marked improvement after 6 weeks did not decrease the HR for the primary outcome (eFigure 3 in Supplement 1). Furthermore, higher baseline MADRS scores appeared to be associated with worse outcomes in patients in the escitalopram group compared with those in the placebo group (eFigure 4 and eFigure 5).

Tolerability and Safety

In the escitalopram group, the proportion of patients discontinuing treatment after 6 weeks was 11% and after 12 weeks was 15% compared with 5% and 7%, respectively, in the placebo group (P = .04 at 6 weeks and P = .02 at 12 weeks). Throughout the study, participation was comparable in the 2 treatment groups; the HR for study withdrawal, discontinuation of study medication, and open-label antidepressant therapy was similar in both groups (eTable 6 in Supplement 1). Overall, there were no between-group differences in safety parameters and serious adverse event rates except for worsening depression, which occurred more often in patients in the placebo group (eTable 7 and eTable 8).

Discussion

This study involving 372 patients with chronic systolic heart failure and depression showed that escitalopram was well tolerated, but failed to demonstrate a difference between the effects of escitalopram compared with placebo on the elevated mortality and morbidity risk known to be associated with this comorbidity.

These results are similar to those of the Sertraline Antidepressant Heart Attack Randomized Trial11 and the Enhancing Recovery in Coronary Heart Disease study,12 both of which enrolled patients with coronary disease and depression and found no beneficial effects with 6 months of antidepressant treatment. Although the efficacy of escitalopram for treating primary depression is considered superior to that of sertraline,10 and although the treatment duration in the current trial was extended to 24 months compared with only 12 weeks in the SADHART-CHF trial,15 treatment with escitalopram had no beneficial effect in our patients who were diagnosed as having a major depressive disorder according to the DSM-IV but had baseline MADRS scores indicative of only mild to moderate depression.26

To our knowledge, this study was the first to investigate the composite of all-cause mortality and hospitalization in a population with heart failure treated with escitalopram. Although the trial was terminated early, mean treatment duration was more than 18 months in each group, and the results are based on a sizable number of adjudicated outcome events. Furthermore, the lack of overlap between the HR for the primary end point in the trial and the HR used in the sample size calculation suggests that if escitalopram did have any therapeutic efficacy, this effect was significantly smaller than the effect postulated in the trial hypothesis.

Quiz Ref IDThe concordant changes in MADRS and PHQ-9 sum scores observed in both groups in this study are in line with SADHART-CHF,15 but are contrary to evidence from patients with coronary disease,1114 in whom SSRI therapy was (compared with placebo) associated with significantly greater improvement in depressive symptoms. Given that escitalopram levels were always in the therapeutic range28 in our study, the results are likely to indicate an absence of therapeutic efficacy. In addition, the exploratory analysis suggested that remission or improvement of depressive symptoms was not associated with better clinical outcomes. Therefore, the incidence rates of the composite primary outcome appeared to be independent of the response to escitalopram or placebo. Contrary to expectations, other exploratory analysis findings showed that the frequency of the primary composite outcome might even increase with escitalopram treatment in patients with heart failure in whom higher MADRS scores indicate more severe depression.

Quiz Ref IDThese observations support the concept of alternative pathophysiological mechanisms for mood disorders in somatic illnesses, with depressive symptoms less responsive or, as in both SADHART-CHF15 and our study, unresponsive to sertraline or escitalopram. Placebo-controlled trials of antidepressants tended to exclude patients with severe somatic illnesses. These observations suggest that the efficacy results of these studies may not necessarily be transferable to all individuals in whom antidepressants are prescribed in clinical practice.

Improved LVEF, decreased N-terminal pro-B-type natriuretic peptide levels, lower New York Heart Association class, and higher KCCQ scores (as observed in both groups during the study) predict better survival.22,3335 In this study, mortality rates were low in both groups, particularly compared with those reported from SADHART-CHF,15 and within the range reported from the Heart Failure-A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) study or the Patient-Centered Disease Management for Heart Failure trial, which both enrolled unselected patients with or without depression.36,37

In contrast, hospitalization rates in this study were high, possibly as a result of recruiting patients from heart failure outpatient clinics at tertiary care centers, the majority of whom had experienced at least 1 hospitalization for heart failure during the year before randomization and were thus at high risk of recurrent adverse outcomes.22 We found in a previous study38 evaluating enhanced heart failure care (similar to that offered to all participants in MOOD-HF) that even though mortality decreased significantly more in patients who were depressed compared with those who were not depressed, hospitalization rates remained comparably high. Possible mechanisms by which mortality could have been reduced include (1) tolerance-guided uptitration of heart failure medication, (2) practical training in self-care, and (3) regular monitoring of treatment adherence by nurses specialized in the care of patients with heart failure. Interestingly, the psychosocial support provided in the SADHART-CHF study did not appear to be associated with comparable clinical effects.15

More recently, Freedland et al39 demonstrated that integrative cognitive behavior therapy effectively improved depression in a younger population with heart failure, but not self-care and physical functioning. This finding is remarkable in view of the present and previous15 negative results with SSRI therapy and the Patient-Centered Disease Management for Heart Failure study, in which multidisciplinary patient-centered disease management did not improve patient health status; however, mortality was lower and mood improved more in participants who were depressed.36 Telephone-based collaborative care strategies have been shown to enhance health-related quality of life, physical functioning, and mood symptoms in patients with cardiovascular disease and heart failure.40

Given that sample size and observation time were limited in most of these trials, clinical outcomes could not be studied and the type and intensity of the interventions varied. More research is needed to identify efficacious combinations of care modules for patients with depression and heart failure. Quiz Ref IDCurrently available evidence suggests that a good approach could be to combine classic collaborative disease management strategies to optimize heart failure pharmacotherapy, self-supervision, and drug adherence with physical training, which reduced mortality and depression in the HF-ACTION trial,37 and with cognitive behavior therapy, which favorably affects patients with depression.39

Adverse effects at the initiation of SSRI therapy11 led to higher early withdrawal rates in patients in the escitalopram group in our study; however, overall tolerability was comparable between groups. There were no between-group differences in additional safety parameters. However, there was a nonsignificant trend toward a greater risk of primary outcome events in patients in the escitalopram group who were older or had more severe heart failure, depressive symptoms, or cognitive impairment. In an exploratory analysis, increasingly higher event rates were observed with increasing baseline MADRS scores in patients treated with escitalopram. Furthermore, N-terminal pro-B-type natriuretic peptide levels decreased more slowly while patients were taking escitalopram, left ventricular cavity size did not decrease as it did in patients in the placebo group, and there was a trend toward lower health-related quality of life as assessed by the KCCQ. Interpretation of these secondary and exploratory findings requires great caution, but the possibility of unfavorable effects with longer-term escitalopram therapy on cardiac status and health-related quality of life cannot be ruled out.

Limitations

An important limitation of this study is its lack of generalizability. Numerous patients were not randomized because of contraindications, ethnicity was predominantly white, and all study centers were located in Germany. Furthermore, patients seen at heart failure outpatient clinics of tertiary care centers typically belong to a higher risk category, but at the same time receive the best possible heart failure care.22 In addition, many patients could not be randomized because of contraindications, and only patients with heart failure and reduced LVEF were eligible. Therefore, these results cannot be extended beyond the patient population studied.

The results also do not provide information on the use of escitalopram in important subgroups that have been identified as being particularly resistant to antidepressant pharmacotherapy, such as women, black adults, and older persons (aged ≥65 years). Excellent adherence in patients in the escitalopram group suggests that they may also have been particularly motivated to follow other treatment recommendations. Furthermore, our study did not assess escitalopram alone. Participants likely benefited from the enhanced heart failure care provided in both treatment groups.

There were also extensive safety measures incorporated into the trial design, such as psychometric and medical assessments at each visit, telephone monitoring, and psychiatric or psychosomatic expertise (readily available on request). All of these, plus the allowance for open-label antidepressant therapy and unscheduled psychiatric consultations in the study protocol, could have blunted between-group differences in outcomes by diminishing treatment effects. However, the consultation rates and the proportion of patients taking open-label antidepressants were low and similar in patients in the escitalopram and placebo groups. In addition, it seems possible that both groups in this study showed regression to the mean (ie, their depressive symptoms improved without any treatment).

Conclusions

In patients with chronic heart failure with reduced ejection fraction and depression, 18 months of treatment with escitalopram compared with placebo did not significantly reduce all-cause mortality or hospitalization, and there was no significant improvement in depression. These findings do not support the use of escitalopram in patients with chronic systolic heart failure and depression.

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Article Information

Group Information: A complete list of the MOOD-HF Study Investigators and Committee Members appears in Supplement 1.

Corresponding Author: Christiane E. Angermann, MD, Medicine and Cardiology, University and University Hospital Würzburg, Department of Medicine I, Cardiology and Comprehensive Heart Failure Center Würzburg, Straubmühlweg 2a, 97078 Wurzburg, Germany (angermann_c@ukw.de).

Author Contributions: Drs Angermann, Gelbrich, and Ertl had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Angermann, Gelbrich, Deckert, Ertl.

Acquisition, analysis, or interpretation of data: Angermann, Gelbrich, Störk, Gunold, Edelmann, Wachter, Schunkert, Graf, Kindermann, Haass, Blankenberg, Pankuweit, Prettin, Gottwik, Böhm, Faller, Deckert, Ertl.

Drafting of the manuscript: Angermann, Böhm, Ertl.

Critical revision of the manuscript for important intellectual content: Angermann, Gelbrich, Störk, Gunold, Edelmann, Wachter, Schunkert, Graf, Kindermann, Haass, Blankenberg, Pankuweit, Prettin, Gottwik, Böhm, Faller, Deckert, Ertl.

Statistical analysis: Gelbrich.

Obtained funding: Angermann, Ertl.

Administrative, technical, or material support: Prettin, Faller, Deckert.

Study supervision: Angermann, Gelbrich, Prettin, Gottwik, Böhm, Ertl.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Angermann reported receiving grants, personal fees, nonfinancial support, and other from ResMed; grants, personal fees, and other from Novartis; personal fees and other from Servier; grants and personal fees from Thermo Fisher, Boehringer Ingelheim, and Vifor; personal fees, grants, and nonfinancial support from Lundbeck AS; nonfinancial support from the University Hospital Würzburg and the Comprehensive Heart Failure Center Würzburg; and grants from the German Ministry for Education and Research. Dr Gelbrich reported receiving grants from University Hospital Würzburg, University Göttingen, and Reha-Klinik Roter Hügel Bayreuth; and personal fees from Charité-Universitätsmedizin Berlin. Dr Störk reported receiving grants from the Federal Ministry for Education and Research, Boehringer, and Santhera; grants and personal fees from Servier, Pfizer, Novartis, Roche Diagnostics, and Thermo Fisher/Brahms; and personal fees from AstraZeneca, Genzyme, Medtronic, and Bayer. Dr Edelmann reported receiving grants from the German Research Foundation; personal fees from Berlin-Chemie, Novartis, and Servier; and reimbursement of travel expenses from Servier, Pfizer, AstraZeneca, Biotronic, and Novartis. Dr Wachter reported receiving personal fees and other from Novartis, Servier, Bayer, CVRx, Medtronic, and Johnson & Johnson; grants, personal fees, and other from Boehringer Ingelheim; grants from the European Union, the German Ministry for Education and Research; and personal fees Bristol-Meyers Squibb and Pfizer. Dr Schunkert reported receiving grants and personal fees from Amgen, AstraZeneca, Brahms GmbH, Sanofi-Aventis, Medtronic, Pfizer, Boston Scientific, Merck Sharp & Dohme, Takeda, Bayer Vital, Mitsubishi Pharma, Novartis, St Jude, Daiichi Sankyo, Cordis, Genzyme, and Synlab. Dr Kindermann reported receiving grants from the German Heart Foundation, Saarland University, and Friede-Springer-Stifung; personal fees and other from Vifor, Boehringer Ingelheim, and Novartis; and personal fees from Servier and Bayer. Dr Blankenberg reported receiving grants and personal fees from Abbott, Abbott Diagnostics, Bayer, Boehringer Ingelheim, Thermo Fisher, and Siemens; and personal fees from Medtronic, Pfizer, Roche, Siemens Diagnostics, and Novartis. Dr Deckert reported receiving support from the Germany Ministry of Education and Research. Dr Ertl reported receiving grants from the German Ministry of Education and Research; nonfinancial support from Lundbeck; grants from Bayer; and grants and personal fees Novartis and Boehringer Ingelheim. Drs Gunold, Graf, Haas, Pankuweit, Prettin, Gottwik, Böhm, and Faller reported having no disclosures.

Funding/Support: The study was funded by the German Ministry of Education and Research and Lundbeck AS Denmark. The Departments of Cardiology, to which investigators enrolling patients in the Effects of Selective Serotonin Re-Uptake Inhibition on Morbidity, Mortality, and Mood in Depressed Heart Failure Patients (MOOD-HF) were affiliated received case payment from the German Ministry of Education and Research and cofunding from Lundbeck AS Denmark, which was distributed by the Administrative Office of the Würzburg University Hospital. Case payments were calculated ex ante based on the expected net costs for 24 months of study participation per patient and data entry into the central data base. Case payments included funds for performing the Structured Clinical Interview based on the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) for the diagnosis of depression and for psychiatric emergency interventions, which were transferred to the partnering Departments of Psychiatry or Psychosomatic Medicine. The Institute of Clinical Epidemiology and Biometry, University of Würzburg, and the Clinical Trial Centre, University of Leipzig, received funding for biometry, statistical analyses, and study management.

Role of the Funder/Sponsor: The German Ministry of Education and Research and Lundbeck AS Denmark had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank all patients who consented to be screened for MOOD-HF and those who participated in this study. Patients were not compensated for participation. We also thank the principal investigators and their multidisciplinary teams, and the members of the steering committee, the data and safety monitoring committee, the independent end point adjudicating committee for their work, the heart failure specialist nurses for their patient care and support of study logistics, the MOOD-HF study teams at the Clinical Trial Centre Leipzig and at the Comprehensive Heart Failure Center Würzburg for high-quality study and data management, and the Competence Network Heart Failure for help to implement this study in its study network. English-language editing support was provided by Nicola Ryan, BSc, an independent medical writer, who received financial compensation from the University of Würzburg.

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