title: Levosimendan in patients with left ventricular systolic dysfunction undergoing cardiac surgery on cardiopulmonary bypass: Rationale and study design of the Levosimendan in Patients with Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery Requiring Cardiopulmonary Bypass (LEVO-CTS) trial.
abstract: BACKGROUND
  Low cardiac output syndrome is associated with increased mortality and occurs in 3% to 14% of patients undergoing cardiac surgery on cardiopulmonary bypass (CPB). Levosimendan, a novel calcium sensitizer and KATPchannel activator with inotropic, vasodilatory, and cardioprotective properties, has shown significant promise in reducing the incidence of low cardiac output syndrome and related adverse outcomes in patients undergoing cardiac surgery on CPB.
  
  
  METHODS
  LEVO-CTS is a phase 3 randomized, controlled, multicenter study evaluating the efficacy, safety, and cost-effectiveness of levosimendan in reducing morbidity and mortality in high-risk patients with reduced left ventricular ejection fraction (≤35%) undergoing cardiac surgery on CPB. Patients will be randomly assigned to receive either intravenous levosimendan (0.2 μg kg-1min-1for the first hour followed by 0.1 μg/kg for 23hours) or matching placebo initiated within 8hours of surgery. The co-primary end points are (1) the composite of death or renal replacement therapy through day 30 or perioperative myocardial infarction, or mechanical assist device use through day 5 (quad end point tested at α<.01), and (2) the composite of death through postoperative day 30 or mechanical assist device use through day 5 (dual end point tested at α<.04). Safety end points include new atrial fibrillation and death through 90days. In addition, an economic analysis will address the cost-effectiveness of levosimendan compared with placebo in high-risk patients undergoing cardiac surgery on CPB. Approximately 880 patients will be enrolled at approximately 60 sites in the United States and Canada between July 2014 and September 2016, with results anticipated in January 2017.
  
  
  CONCLUSIONS
  LEVO-CTS, a large randomized multicenter clinical trial, will evaluate the efficacy, safety, and cost-effectiveness of levosimendan in reducing adverse outcomes in high-risk patients undergoing cardiac surgery on CPB.
  
  
  BACKGROUND
  ClinicalTrials.gov (NCT02025621).
authors.affiliation: Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC. Electronic address: raj.mehta@dm.duke.edu.
authors.forename: Rajendra H
authors.initials: RH
authors.lastname: Mehta
authors.affiliation: Canadian VIGOUR Centre, University of Alberta, Alberta, Edmonton, Canada.
authors.forename: Sean
authors.initials: S
authors.lastname: Van Diepen
authors.affiliation: Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC.
authors.forename: James
authors.initials: J
authors.lastname: Meza
authors.affiliation: Tenax Therapeutics, Morrisville, NC.
authors.forename: Paula
authors.initials: P
authors.lastname: Bokesch
authors.affiliation: Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Leimberger
authors.affiliation: Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC.
authors.forename: Sandra
authors.initials: S
authors.lastname: Tourt-Uhlig
authors.affiliation: Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC.
authors.forename: Merri
authors.initials: M
authors.lastname: Swartz
authors.affiliation: Canadian VIGOUR Centre, University of Alberta, Alberta, Edmonton, Canada.
authors.forename: Jodi
authors.initials: J
authors.lastname: Parrotta
authors.affiliation: Tenax Therapeutics, Morrisville, NC.
authors.forename: Rachael
authors.initials: R
authors.lastname: Jankowich
authors.affiliation: Tenax Therapeutics, Morrisville, NC.
authors.forename: Douglas
authors.initials: D
authors.lastname: Hay
authors.affiliation: Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Harrison
authors.affiliation: Canadian VIGOUR Centre, University of Alberta, Alberta, Edmonton, Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Fremes
authors.affiliation: Canadian VIGOUR Centre, University of Alberta, Alberta, Edmonton, Canada.
authors.forename: Shaun G
authors.initials: SG
authors.lastname: Goodman
authors.affiliation: Franciscan Health System, Tacoma, WA.
authors.forename: John
authors.initials: J
authors.lastname: Luber
authors.affiliation: University of Graz, Graz, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Toller
authors.affiliation: University of Lübeck, Lübeck, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Heringlake
authors.affiliation: Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Anstrom
authors.affiliation: Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC.
authors.forename: Jerrold H
authors.initials: JH
authors.lastname: Levy
authors.affiliation: Stanford University School of Medicine, Stanford, CA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harrington
authors.affiliation: Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC.
authors.forename: John H
authors.initials: JH
authors.lastname: Alexander
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D006348:Cardiac Surgical Procedures / Q000009:adverse effects / Q000379:methods; D002315:Cardiopulmonary Bypass / Q000379:methods; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006801:Humans; D006835:Hydrazones / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications / Q000401:mortality / Q000517:prevention & control; D011724:Pyridazines / Q000008:administration & dosage / Q000009:adverse effects; D000077464:Simendan; D013318:Stroke Volume; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000175:diagnosis / Q000503:physiopathology / Q000628:therapy*
chemical_list: D002317:Cardiovascular Agents; D006835:Hydrazones; D011724:Pyridazines; D000077464:Simendan