Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Acute heart failure:Multiple clinical profiles and mechanisms require tailored therapy

Acute heart failure (HF) is the most common diagnosis at discharge in patients aged >65 years. It carries a dismal prognosis with a high in-hospital mortality and very high post-discharge mortality and re-hospitalization rates. It is a complex clinical syndrome that cannot be described as a single entity as it varies widely with respect to underlying pathophysiologic mechanisms, clinical presentations and, likely, treatments. It is the aim of this paper to describe some of the main clinical presentations of acute HF. Amongst them, we will consider de novo HF versus acutely decompensated chronic HF, HF caused, and/or worsened, by myocardial ischemia, acute HF with low, normal, or high systolic blood pressure, acute HF caused by lung congestion or fluid retention or fluid redistribution to the lungs, and acute HF with comorbidities (diabetes, anemia, renal insufficiency, etc.). Different pathophysiologic mechanisms and clinical presentations may coexist in the same patient. Identification and, whenever possible, treatment of underlying pathophysiologic mechanisms may become important for acute HF management. (C) 2010 Elsevier Ireland Ltd. All rights reserved

Cardiovascular and noncardiovascular comorbidities in patients with chronic heart failure

A broad spectrum of concomitant disorders may complicate heart failure adding further morbidity and mortality risk. Comorbidities may be subdivided into cardiovascular and noncardiovascular. The first group includes hypertension, coronary artery disease, peripheral artery disease, cerebrovascular disease, arrhythmias and valvular heart disease. Noncardiovascular comorbidities include respiratory, endocrine, metabolic, nutritional, renal, hematopoietic, neurological as well as musculoskeletal conditions. In recent years, advances in the treatment of heart failure have not been attended by important changes in management of its comorbidities. They now seem to be major causes of the poor prognosis of heart failure patients. In this review we provide an updated summary of the epidemiological, pathophysiological and clinical characteristics of comorbidities as well as their potential impact for heart failure treatment. J Cardiovasc Med 12:76-84 (C) 2011 Italian Federation of Cardiology

Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure

BACKGROUND The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. METHODS We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. RESULTS During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. CONCLUSIONS Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016 -002299-28.)