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

Left Atrial Remodeling is Associated with Left Ventricular Remodeling in Patients with Reperfused Acute Myocardial Infarction

Background: Left atrial volume (LAV) has been established as a sensitive marker of left ventricular (LV) diastolic function and as an independent predictor of mortality in patients with acute myocardial infarction (AMI). LA remodeling and its determinants in the setting of AMI have not been much studied. Methods: We studied 53 patients with anterior AMI and a relatively preserved LV systolic function, who underwent complete reperfusion and received guidelines guided antiremodeling drug management. LA and LV remodeling were assessed using 2D echocardiography at baseline and 6 months. LAV indexed for BSA (LAVi) was used as the index of LA size and further LA remodeling. Results: LAVi increased signifi cantly at 6 months compared to baseline [28.1 (23.0-34.5) vs 24.4 (19.5- 31.6) ml/m2, p=0.002] following LV end diastolic-volume index change [56.8 (47.6-63.9) vs 49.5 (42.0-58.4) ml/m2, p=0.0003]. Other standard LV diastolic function indices did not show any signifi cant change. Univariateanalysis showed a strong positive correlation of LAVi change with BNP levels at discharge, LV mass index and LV volumes indices change, throughout the follow up period. Multivariate regression analysis revealed that BNP plasma levels was the most important independent predictor of LA remodeling (b-coef.=0.630, p=0.001). Conclusions: Despite current antiremodeling strategies in patients with AMI, LA remodeling is frequently asssociated with LV remodeling. Additionally LAVi change in the mid-term reflects better than standard echocardiographic indices LV diastolic filling impairment

Atrial fibrillation in hypertrophic cardiomyopathy: A turning point towards increased morbidity and mortality

Background: Atrial fibrillation (AF) is the most common arrhythmic event in patients with hypertrophic cardiomyopathy (HCM). The aim of this study was to identify the clinical impact and prognostic significance of AF on a large cohort of patients with HCM. Methods: Echocardiographic and clinical correlates, risk factors for AF and thromboembolic stroke and the prognostic significance of AF were evaluated in 509 patients with an established diagnosis of HCM. Results: A total of 119 patients (23.4%) were diagnosed with AF during the index evaluation visit. AF patients had a higher prevalence of stroke and presented with worse functional impairment. Left atrial diameter (LA size) was a common independent predictor of the arrhythmia (OR: 2.2, 95% CI 1.6-3.3) and thromboembolic stroke (OR: 1.6, 95% CI 1.01-2.40). AF was an important risk factor for overall mortality (HR=3.4, 95% CI: 1.7-6.5), HCM-related mortality (HR=3.9, 95% CI: 1.8-8.2) and heart failure-related mortality (HR=6.0, 95% CI: 2.0-17.9), even after adjusting for statistically significant clinical and demographic risk factors. However, AF did not affect the risk for sudden death. Conclusions: LA size is an independent predictor of both AF and thromboembolic stroke. Moreover, patients with AF, regardless of type, have significantly higher mortality rates than patients without AF

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.)