Acute Treatment With Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure: The ATOMIC-AHF Study

• Published in: Journal of the American College of Cardiology 2016-03, Vol.67 (12), p.1444-1455
• Main Authors: Teerlink, John R, Felker, G Michael, McMurray, John J V, Ponikowski, Piotr, Metra, Marco, Filippatos, Gerasimos S, Ezekowitz, Justin A, Dickstein, Kenneth, Cleland, John G F, Kim, Jae B, Lei, Lei, Knusel, Beat, Wolff, Andrew A, Malik, Fady I, Wasserman, Scott M
• Format: Article
• Language: English
• Subjects: Acute coronary syndromes; Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Cardiology; Committees; Confidence intervals; Dose-Response Relationship, Drug; Double-Blind Method; Echocardiography; Female; Follow-Up Studies; Heart attacks; Heart failure; Heart Failure - blood; Heart Failure - drug therapy; Heart Failure - physiopathology; Heart rate; Heart Ventricles - diagnostic imaging; Heart Ventricles - drug effects; Heart Ventricles - physiopathology; Humans; Infusions, Intravenous; Male; Middle Aged; Mortality; Myocardial Contraction - drug effects; Plasma; Prospective Studies; Stroke; Stroke Volume - drug effects; Stroke Volume - physiology; Treatment Outcome; Troponin - blood; Urea - administration & dosage; Urea - analogs & derivatives; Urea - pharmacokinetics; Ventricular Function, Left - drug effects; Ventricular Function, Left - physiology; Young Adult
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2016.01.031

Omecamtiv mecarbil (OM) is a selective cardiac myosin activator that increases myocardial function in healthy volunteers and in patients with chronic heart failure. This study evaluated the pharmacokinetics, pharmacodynamics, tolerability, safety, and efficacy of OM in patients with acute heart failure (AHF). Patients admitted for AHF with left ventricular ejection fraction ≤40%, dyspnea, and elevated plasma concentrations of natriuretic peptides were randomized to receive a double-blind, 48-h intravenous infusion of placebo or OM in 3 sequential, escalating-dose cohorts. In 606 patients, OM did not improve the primary endpoint of dyspnea relief (3 OM dose groups and pooled placebo: placebo, 41%; OM cohort 1, 42%; cohort 2, 47%; cohort 3, 51%; p = 0.33) or any of the secondary outcomes studied. In supplemental, pre-specified analyses, OM resulted in greater dyspnea relief at 48 h (placebo, 37% vs. OM, 51%; p = 0.034) and through 5 days (p = 0.038) in the high-dose cohort. OM exerted plasma concentration-related increases in left ventricular systolic ejection time (p < 0.0001) and decreases in end-systolic dimension (p < 0.05). The adverse event profile and tolerability of OM were similar to those of placebo, without increases in ventricular or supraventricular tachyarrhythmias. Plasma troponin concentrations were higher in OM-treated patients compared with placebo (median difference at 48 h, 0.004 ng/ml), but with no obvious relationship with OM concentration (p = 0.95). In patients with AHF, intravenous OM did not meet the primary endpoint of dyspnea improvement, but it was generally well tolerated, it increased systolic ejection time, and it may have improved dyspnea in the high-dose group. (Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure [ATOMIC-AHF]; NCT01300013).