title: Acute Treatment With Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure: The ATOMIC-AHF Study.
abstract: BACKGROUND
  Omecamtiv mecarbil (OM) is a selective cardiac myosin activator that increases myocardial function in healthy volunteers and in patients with chronic heart failure.
  
  
  OBJECTIVE
  This study evaluated the pharmacokinetics, pharmacodynamics, tolerability, safety, and efficacy of OM in patients with acute heart failure (AHF).
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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).
authors.affiliation: School of Medicine, University of California San Francisco, San Francisco, California; Section of Cardiology, San Francisco Veterans Affairs Medical Center, San Francisco, California. Electronic address: john.teerlink@ucsf.edu.
authors.forename: John R
authors.initials: JR
authors.lastname: Teerlink
authors.affiliation: Division of Cardiology, Duke University School of Medicine, Durham, North Carolina.
authors.forename: G Michael
authors.initials: GM
authors.lastname: Felker
authors.affiliation: British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom.
authors.forename: John J V
authors.initials: JJV
authors.lastname: McMurray
authors.affiliation: Department of Heart Diseases, Medical University, Clinical Military Hospital, Wroclaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Ponikowski
authors.affiliation: Division of Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Metra
authors.affiliation: Department of Cardiology, Athens University Hospital Attikon, Athens, Greece.
authors.forename: Gerasimos S
authors.initials: GS
authors.lastname: Filippatos
authors.affiliation: Canadian VIGOUR Centre at the University of Alberta, Edmonton, Canada.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Ezekowitz
authors.affiliation: Cardiology Division, University of Bergen, Bergen, Norway; Cardiology Division, Stavanger University Hospital, Stavanger, Norway.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Dickstein
authors.affiliation: National Heart and Lung Institute, Royal Brompton and Harefield Hospitals, Imperial College, London, United Kingdom.
authors.forename: John G F
authors.initials: JGF
authors.lastname: Cleland
authors.affiliation: Amgen, Inc., Thousand Oaks, California.
authors.forename: Jae B
authors.initials: JB
authors.lastname: Kim
authors.affiliation: Amgen, Inc., Thousand Oaks, California.
authors.forename: Lei
authors.initials: L
authors.lastname: Lei
authors.affiliation: Amgen, Inc., Thousand Oaks, California.
authors.forename: Beat
authors.initials: B
authors.lastname: Knusel
authors.affiliation: Cytokinetics, Inc., South San Francisco, California.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Wolff
authors.affiliation: Cytokinetics, Inc., South San Francisco, California.
authors.forename: Fady I
authors.initials: FI
authors.lastname: Malik
authors.affiliation: Amgen, Inc., Thousand Oaks, California.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Wasserman
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004452:Echocardiography; D005260:Female; D005500:Follow-Up Studies; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects*; D011446:Prospective Studies; D013318:Stroke Volume / Q000187:drug effects / Q000502:physiology*; D016896:Treatment Outcome; D014336:Troponin / Q000097:blood; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology*; D055815:Young Adult
chemical_list: D014336:Troponin; C547293:omecamtiv mecarbil; D014508:Urea
keywords: arrhythmia; cardiac myosin activator; dyspnea; inotrope