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

Detection of acute ischemia from the EASI-derived 12-lead electrocardiogram and from the 12-lead electrocardiogram acquired in clinical practice

ST-segment measurements in the standard 12-lead electrocardiogram (ECG) of patients with acute coronary syndromes are crucial for these patients' management. Our objective was to determine whether the 12-lead ECG derived from the 3-lead EASI system can attain a level of diagnostic performance similar to that of the Mason-Likar (ML) 12-lead ECG acquired in clinical practice (CP) by paramedics and emergency department technicians. Using 120-lead body surface potential maps recorded before and during balloon inflation angioplasty from 88 patients (divided into "responders" and "nonresponders"), and electrode placement data from 60 applications of precordial leads in CP, we generated for the "nonischemic" and "ischemic' states of each patient the following lead sets: the ML 12-lead ECG, the EASI-derived 12-lead ECG, and 60 sets of 12-lead CP ECGs. We extracted ST deviations at J + 60 milliseconds, summed them for all 12 leads of each lead set to obtain Sigma ST, and, by using the bootstrap method, determined the mean sensitivity and specificity for recognizing the "ischemic' state at various thresholds of Sigma ST. Results were displayed as receiver operating characteristics, and the area under these curves (AUC) +/- SE was used as the measure of diagnostic performance. AUC SE for all patients were ML ECG, 0.66 +/- 0.03; EASI ECG, 0.64 +/- 0.03; and CP ECG, 0.67 +/- 0.03. Corresponding results for responders only were 0.81 +/- 0.04 for ML ECG, 0.78 +/- 0.04 for EASI ECG, and 0.81 +/- 0.04 for CP ECG. The differences between the AUCs for the different lead sets were not significant (P >.05). Thus, the EASI-derived 12-lead ECG is as good for detecting acute ischemia as is the 12-lead ECG acquired in CP. (c) 2007 Elsevier Inc. All rights reserved

Difference vectors to describe dynamics of the ST segment and the ventricular gradient in acute ischemia

Background: The ECG is important in the diagnosis and triage of the acute coronary syndrome (ACS), especially in the hyperacute phase, the "golden hours," during which myocardial salvage possibilities are largest. An important triaging decision to be taken is whether or not a patient requires primary PCI, for which, as mentioned in the guidelines, the presence of an ST elevation (STE) pattern in the ECG is a major criterion. However, preexisting non-zero ST amplitudes (diagnostic, but also non-diagnostic) can obscure or even preclude this diagnosis. Methods: In this study, we investigated the potential diagnostic possibilities of ischemia detection by means of changes in the ST vector, Delta ST, and changes in the VG (QRST integral) vector, Delta VG. We studied the vectorcardiograms (VCGs) synthesized of the ECGs of 84 patients who underwent elective PTCA. Mean +/- SD balloon occlusion times were 260 +/- 76 s. The ECG ischemia diagnosis (ST elevation, STE, or non-ST-elevation, NSTE), magnitudes and orientations of the ST and VG vectors, and the differences Delta ST and Delta VG with the baseline ECG were measured after 3 min of balloon occlusion. Results: Planar angles between the Delta ST and Delta VG vectors were 14.9 +/- 14.0 degrees. Linear regression of Delta VG on Delta ST yielded Delta VG = 324. Delta ST (r = 0.85; P 0.05 mV, and the corresponding Delta VG > 16.2 mV.ms as ischemia thresholds. The classical criteria characterized the ECGs of 46/84 (55%) patients after 3 min of occlusion as STE ECGs. Combined application of the Delta ST and Delta VG criteria identified 73/84 (87%) of the patients as ischemic. Conclusion: Differential diagnosis by Delta ST and Delta VG (requiring an earlier made non-ischemic baseline ECG) could dramatically improve ECG guided detection of patients who urgently require catheter intervention. (C) 2013 Elsevier Inc. All rights reserved

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.)