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

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

JAMA. 2016;315(24):2683-2693.

Sustained efficacy of pulmonary artery pressure to guide adjustment of chronic heart failure therapy: complete follow-up results from the CHAMPION randomised trial

Background

In the CHAMPION trial, significant reductions in admissions to hospital for heart failure were seen after 6 months of pulmonary artery pressure guided management compared with usual care. We examine the extended efficacy of this strategy over 18 months of randomised follow-up and the clinical effect of open access to pressure information for an additional 13 months in patients formerly in the control group.

Methods

The CHAMPION trial was a prospective, parallel, single-blinded, multicentre study that enrolled participants with New York Heart Association (NYHA) Class III heart failure symptoms and a previous admission to hospital. Patients were randomly assigned (1:1) by centre in block sizes of four by a secure validated computerised randomisation system to either the treatment group, in which daily uploaded pulmonary artery pressures were used to guide medical therapy, or to the control group, in which daily uploaded pressures were not made available to investigators. Patients in the control group received all standard medical, device, and disease management strategies available. Patients then remained masked in their randomised study group until the last patient enrolled completed at least 6 months of study follow-up (randomised access period) for an average of 18 months. During the randomised access period, patients in the treatment group were managed with pulmonary artery pressure and patients in the control group had usual care only. At the conclusion of randomised access, investigators had access to pulmonary artery pressure for all patients (open access period) averaging 13 months of follow-up. The primary outcome was the rate of hospital admissions between the treatment group and control group in both the randomised access and open access periods. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, numberNCT00531661.

Findings

Between Sept 6, 2007, and Oct 7, 2009, 550 patients were randomly assigned to either the treatment group (n=270) or to the control group (n=280). 347 patients (177 in the former treatment group and 170 in the former control group) completed the randomised access period in August, 2010, and transitioned to the open access period which ended April 30, 2012. Over the randomised access period, rates of admissions to hospital for heart failure were reduced in the treatment group by 33% (hazard ratio [HR] 0·67 [95% CI 0·55–0·80]; p<0·0001) compared with the control group. After pulmonary artery pressure information became available to guide therapy during open access (mean 13 months), rates of admissions to hospital for heart failure in the former control group were reduced by 48% (HR 0·52 [95% CI 0·40–0·69]; p<0·0001) compared with rates of admissions in the control group during randomised access. Eight (1%) device-related or system related complications and seven (1%) procedure-related adverse events were reported.

Interpretation

Management of NYHA Class III heart failure based on home transmission of pulmonary artery pressure with an implanted pressure sensor has significant long-term benefit in lowering hospital admission rates for heart failure.

By William T Abraham (et al), The Lancet, Volume 387, No. 10017, p453–461, 30 January 2016

Alcohol consumption and cardiovascular disease, cancer, injury, admission to hospital, and mortality: a prospective cohort study

Background

Alcohol consumption is proposed to be the third most important modifiable risk factor for death and disability. However, alcohol consumption has been associated with both benefits and harms, and previous studies were mostly done in high-income countries. We investigated associations between alcohol consumption and outcomes in a prospective cohort of countries at different economic levels in five continents.

Methods

We included information from 12 countries participating in the Prospective Urban Rural Epidemiological (PURE) study, a prospective cohort study of individuals aged 35–70 years. We used Cox proportional hazards regression to study associations with mortality (n=2723), cardiovascular disease (n=2742), myocardial infarction (n=979), stroke (n=817), alcohol-related cancer (n=764), injury (n=824), admission to hospital (n=8786), and for a composite of these outcomes (n=11 963).

Findings

We included 114 970 adults, of whom 12 904 (11%) were from high-income countries (HICs), 24 408 (21%) were from upper-middle-income countries (UMICs), 48 845 (43%) were from lower-middle-income countries (LMICs), and 28 813 (25%) were from low-income countries (LICs). Median follow-up was 4·3 years (IQR 3·0–6·0). Current drinking was reported by 36 030 (31%) individuals, and was associated with reduced myocardial infarction (hazard ratio [HR] 0·76 [95% CI 0·63–0·93]), but increased alcohol-related cancers (HR 1·51 [1·22–1·89]) and injury (HR 1·29 [1·04–1·61]). High intake was associated with increased mortality (HR 1·31 [1·04–1·66]). Compared with never drinkers, we identified significantly reduced hazards for the composite outcome for current drinkers in HICs and UMICs (HR 0·84 [0·77–0·92]), but not in LMICs and LICs, for which we identified no reductions in this outcome (HR 1·07 [0·95–1·21]; pinteraction<0·0001).

Interpretation

Current alcohol consumption had differing associations by clinical outcome, and differing associations by income region. However, we identified sufficient commonalities to support global health strategies and national initiatives to reduce harmful alcohol use.

Funding

Population Health Research Institute, the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, AstraZeneca (Canada), Sanofi-Aventis (France and Canada), Boehringer Ingelheim (Germany and Canada), Servier, GlaxoSmithKline, Novartis, King Pharma, and national or local organisations in participating countries.

Alcohol consumption and cardiovascular disease, cancer, injury, admission to hospital, and mortality: a prospective cohort study by Andrew Smyth et al.

Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data

Objective To clarify the impact of digoxin on death and clinical outcomes across all
observational and randomised controlled trials, accounting for study designs and methods.
Data sources and study selection Comprehensive literature search of Medline, Embase,
the Cochrane Library, reference lists, and ongoing studies according to a prospectively
registered design (PROSPERO: CRD42014010783), including all studies published from
1960 to July 2014 that examined treatment with digoxin compared with control (placebo or
no treatment).
Data extraction and synthesis Unadjusted and adjusted data pooled according to study
design, analysis method, and risk of bias.
Main outcome measures Primary outcome (all cause mortality) and secondary outcomes
(including admission to hospital) were meta-analysed with random effects modelling.
Results 52 studies were systematically reviewed, comprising 621,845 patients. Digoxin
users were 2.4 years older than control (weighted difference 95% confidence interval 1.3 to
3.6), with lower ejection fraction (33% v 42%), more diabetes, and greater use of diuretics
and anti-arrhythmic drugs. Meta-analysis included 75 study analyses, with a combined total
of 4,006,210 patient years of follow-up. Compared with control, the pooled risk ratio for
death with digoxin was 1.76 in unadjusted analyses (1.57 to 1.97), 1.61 in adjusted
analyses (1.31 to 1.97), 1.18 in propensity matched studies (1.09 to 1.26), and 0.99 in
randomised controlled trials (0.93 to 1.05). Meta-regression confirmed that baseline
differences between treatment groups had a significant impact on mortality associated with
digoxin, including markers of heart failure severity such as use of diuretics (P=0.004).
Studies with better methods and lower risk of bias were more likely to report a neutral
association of digoxin with mortality (P<0.001). Across all study types, digoxin led to a small
but significant reduction in all cause hospital admission (risk ratio 0.92, 0.89 to 0.95;
P<0.001; n=29,525).
Conclusions Digoxin is associated with a neutral effect on mortality in randomised trials
and a lower rate of admissions to hospital across all study types. Regardless of statistical
analysis, prescription biases limit the value of observational data.

Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data by Oliver J Ziff, et al. BMJ2015; 351 (Published 30 August 2015)