title: Safety and tolerability of omecamtiv mecarbil during exercise in patients with ischemic cardiomyopathy and angina.
abstract: OBJECTIVE
  The goal of this study was to assess the safety and tolerability of omecamtiv mecarbil treatment during symptom-limited exercise in patients with ischemic cardiomyopathy and angina. These patients may have increased vulnerability to prolongation of the systolic ejection time.
  
  
  BACKGROUND
  Omecamtiv mecarbil is a selective cardiac myosin activator that augments cardiac contractility in patients with systolic heart failure through a dose-dependent increase in systolic ejection time.
  
  
  METHODS
  In this double-blind, placebo-controlled study, patients with chronic heart failure were randomized 2:1 to receive omecamtiv mecarbil or placebo in 2 sequential cohorts of escalating doses designed to achieve plasma concentrations previously shown to increase systolic function. Patients underwent 2 symptom-limited exercise treadmill tests (ETTs) at baseline (ETT1 and ETT2) and again before the end of a 20-h infusion of omecamtiv mecarbil (ETT3).
  
  
  RESULTS
  The primary pre-defined safety endpoint (i.e., the proportion of patients who stopped ETT3 because of angina at a stage earlier than baseline) was observed in 1 patient receiving placebo and none receiving omecamtiv mecarbil. No dose-dependent differences emerged in the proportion of patients stopping ETT3 for any reason or in the pattern of adverse events.
  
  
  CONCLUSIONS
  Doses of omecamtiv mecarbil producing plasma concentrations previously shown to increase systolic function were well tolerated during exercise in these study patients with ischemic cardiomyopathy and angina. There was no indication that treatment increased the likelihood of myocardial ischemia in this high-risk population. (Pharmacokinetics [PK] and Tolerability of Intravenous [IV] and Oral CK-1827452 in Patients With Ischemic Cardiomyopathy and Angina; NCT00682565).
authors.affiliation: University of California at San Diego, San Diego, California. Electronic address: bgreenberg@ucsd.edu.
authors.forename: Barry H
authors.initials: BH
authors.lastname: Greenberg
authors.affiliation: Cytokinetics, Inc., South San Francisco, California.
authors.forename: Willis
authors.initials: W
authors.lastname: Chou
authors.affiliation: Cytokinetics, Inc., South San Francisco, California.
authors.forename: Khalil G
authors.initials: KG
authors.lastname: Saikali
authors.affiliation: Cytokinetics, Inc., South San Francisco, California.
authors.forename: Rafael
authors.initials: R
authors.lastname: Escandón
authors.affiliation: Cytokinetics, Inc., South San Francisco, California.
authors.forename: Jacqueline H
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Cytokinetics, Inc., South San Francisco, California.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Chen
authors.affiliation: Almazov Federal Heart Blood and Endocrinology Centre, St. Petersburg, Russia.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Treshkur
authors.affiliation: Cardiology Clinic, Tbilisi, Georgia.
authors.forename: Irakli
authors.initials: I
authors.lastname: Megreladze
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Wasserman
authors.affiliation: Amgen Inc., Thousand Oaks, California.
authors.forename: Paul
authors.initials: P
authors.lastname: Eisenberg
authors.affiliation: Cytokinetics, Inc., South San Francisco, California.
authors.forename: Fady I
authors.initials: FI
authors.lastname: Malik
authors.affiliation: Cytokinetics, Inc., South San Francisco, California.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Wolff
authors.affiliation: Diagnostic Services Clinic, Tbilisi, Georgia.
authors.forename: Tamaz
authors.initials: T
authors.lastname: Shaburishvili
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000787:Angina Pectoris / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004361:Drug Tolerance; D015444:Exercise / Q000502:physiology*; D005080:Exercise Test; D005260:Female; D005500:Follow-Up Studies; D005846:Georgia (Republic); D006801:Humans; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D012189:Retrospective Studies; D012426:Russia; D016896:Treatment Outcome; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: C547293:omecamtiv mecarbil; D014508:Urea
keywords: exercise tolerance; heart failure; ischemic cardiomyopathy; omecamtiv mecarbil