A randomized controlled trial of levosimendan to reduce mortality in high-risk cardiac surgery patients (CHEETAH): Rationale and design

Zangrillo A 1 , Alvaro G 2 , Pisano A 3 , Guarracino F 4 , Lobreglio R 5 , Bradic N 6 Show all authors , Lembo R 7 , Gianni S 7 , Calabrò MG 7 , Likhvantsev V 8 , Grigoryev E 9 , Buscaglia G 10 , Pala G 11 , Auci E 12 , Amantea B 2 , Monaco F 7 , De Vuono G 2 , Corcione A 13 , Galdieri N 3 , Cariello C 4 , Bove T 7 , Fominskiy E 7 , Auriemma S 12 , Baiocchi M 14 , Bianchi A 15 , Frontini M 16 , Paternoster G 17 , Sangalli F 18 , Wang CY 19 , Zucchetti MC 20 , Biondi-Zoccai G 21 , Gemma M 7 , Lipinski MJ 22 , Lomivorotov VV 23 , Landoni G 24

Affiliations 

  • 1 Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy; Anesthesia and Intensive Care, Policlinico Universitario "Magna Grecia," Catanzaro, Italy
  • 2 Cardiac Anesthesia and Intensive Care Unit, Monaldi Hospital A.O.R.N. "Dei Colli", Naples, Italy
  • 3 Department of Anaesthesia and Critical Care Medicine, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
  • 4 Department of Anaesthesia and Critical Care Medicine, Città della Salute e della Scienza, Torino, Italy
  • 5 Clinic of Anesthesiology and Intensive Care Medicine, University Hospital Dubrava, Zagreb, Croatia
  • 6 Anesthesiology & Intensive Care Department Moscow Regional Clinical & Research Institute, Moscow, Russia
  • 7 Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
  • 8 Department of Intensive Care, Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo, Russia
  • 9 Anesthesia and Intensive Care, A.O.U. IRCSS IST San Martino, Genova, Italy
  • 10 Cardiac Anesthesia and Intensive Care, Ospedale Civile SS. Annunziata, Sassari, Italy
  • 11 Anesthesia and Intensive Care, Azienda Ospedaliera Universitaria Santa Maria della Misericordia, Udine, Italy
  • 12 Department of Cardiac Surgery, Ospedale S.Bortolo, Vicenza, Italy
  • 13 Department of Anesthesia and Critical Care, AORN "Dei Colli", Naples, Italy
  • 14 Anesthesia and Intensive Care, S.Orsola-Malpighi University Hospital, Bologna, Italy
  • 15 Anesthesia and Intensive Care, Azienda Ospedaliera Ordine Mauriziano, Torino, Italy
  • 16 Anesthesia and Intensive Care, Azienda Ospedaliera Spedali Civili, Brescia, Italy
  • 17 Departement of Cardiovascular Anaesthesia and Intensive Care, Azienda Ospedaliera S. Carlo, Potenza, Italy
  • 18 Anesthesia and Intensive Care, Ospedale S. Gerardo, Monza, Italy
  • 19 Department of Anaesthesiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 20 Anesthesia and Intensive Care, Azienda Ospedaliera Papardo-Piemonte, Messina, Italy
  • 21 Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy; Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli, Italy
  • 22 Division of Cardiology, Medstar Washington Hospital Center, Washington DC
  • 23 Department of Anesthesiology and Intensive Care, State Research Institute of Circulation Pathology, Novosibirsk, Russia
  • 24 Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy. Electronic address: landoni.giovanni@hsr.it
Am Heart J, 2016 Jul;177:66-73.
PMID: 27297851 DOI: 10.1016/j.ahj.2016.03.021

Abstract

OBJECTIVE: Patients undergoing cardiac surgery are at risk of perioperative low cardiac output syndrome due to postoperative myocardial dysfunction. Myocardial dysfunction in patients undergoing cardiac surgery is a potential indication for the use of levosimendan, a calcium sensitizer with 3 beneficial cardiovascular effects (inotropic, vasodilatory, and anti-inflammatory), which appears effective in improving clinically relevant outcomes.

DESIGN: Double-blind, placebo-controlled, multicenter randomized trial.

SETTING: Tertiary care hospitals.

INTERVENTIONS: Cardiac surgery patients (n = 1,000) with postoperative myocardial dysfunction (defined as patients with intraaortic balloon pump and/or high-dose standard inotropic support) will be randomized to receive a continuous infusion of either levosimendan (0.05-0.2 μg/[kg min]) or placebo for 24-48 hours.

MEASUREMENTS AND MAIN RESULTS: The primary end point will be 30-day mortality. Secondary end points will be mortality at 1 year, time on mechanical ventilation, acute kidney injury, decision to stop the study drug due to adverse events or to start open-label levosimendan, and length of intensive care unit and hospital stay. We will test the hypothesis that levosimendan reduces 30-day mortality in cardiac surgery patients with postoperative myocardial dysfunction.

CONCLUSIONS: This trial is planned to determine whether levosimendan could improve survival in patients with postoperative low cardiac output syndrome. The results of this double-blind, placebo-controlled randomized trial may provide important insights into the management of low cardiac output in cardiac surgery.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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