Preoperative Levosimendan in CABG Patients With Poor LV Function (LICORN)

Effects of Levosimendan Pretreatment in Patients With Low Ejection Fraction (40 % or Less) Undergoing CABG: a Randomised, Double Blind, Multicenter Trial

The investigators want to test the hypothesis that an infusion of levosimendan started prior to CABG surgery can reduce incidence and severity of low cardiac output syndrome in patients with poor LV function (EF 40% or less).

Study Overview

• Status: Completed
• Conditions: Coronary Artery Bypass Grafting; Left Ventricular Dysfonction
• Intervention / Treatment: Drug: levosimendan; Drug: Placebo

Detailed Description

Background: Patients with an ejection fraction of less than 40% are at high risk of developing postoperative low cardiac output syndrome (LCOS). Despite the use of potent inotropic agents or even ventricular mechanical assist devices, the mortality rate of such patients remains very high (from 17 to 38%). Their hospital stay is also prolonged and the cost of care for this population is increased. Two studies have suggested that post-operative administration of levosimendan could reduce hospital length of stay and long term (Day180) mortality in patients with LCOS. In addition a few studies have also suggested that pre-operative infusion of levosimendan (pre-conditioning) could reduce the use of other inotropes and mechanical assist devices in patients at high risk of developing LCOS. Unfortunately, the data supporting the beneficial effects of levosimendan in high risk cardiac surgery patients is very limited. Main goal: To evaluate the efficacy of a pre-operative infusion of levosimendan in high risk patients (EF less than 40%) undergoing cardiac surgery (CABG or combined surgery: CABG and valve replacement) to improve outcome. Secondary goals: To evaluate: 1) the clinical safety of a pre-operative infusion of levosimendan, 2) the costs of care in the levosimendan and control groups. Experimental setup: Prospective, multicenter, randomized versus placebo, double-blind trial. Treatment modalities: levosimendan will be administered by the intravenous route, according to a continuous infusion of 0.1mcg/kg/min over 24 hours. Levosimendan infusion (0.1mcg/kg/min) will be started immediately after induction of anaesthesia. The delay between infusion start and skin incision can be estimated between 30 to 60 min. The investigators decided to skip the bolus infusion that is frequently associated with systemic hypotension, which may result in serious adverse events and protocol exclusion. Study duration and patient follow-up: Patients will be recruited over 23 months. Individual follow-up will last 6 months. Overall duration of study will be 29 months.

• Study Type: Interventional
• Enrollment (Actual): 335
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Paris, France, 75015
    • Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, France

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 18 Years and older
• scheduled for CABG with CPB
• with or without asociated cardiac repair
• ejection fraction less than 40%
• signed informed consent

Exclusion Criteria:

• preoperative renal failure (creatinine clearance less than 30 ml/min)
• liver failure (prothrombine time less than 50% in the absence of vitamin K antagonist)
• cardiac surgery without CABG
• pregnancy
• emergency surgery
• known allergy to levosimendan
• severe hypotension prior to surgery
• severe tachycardia
• prior history of torsade de pointe
• dynamic obstruction od left ventricular outflow tract
• lack of signed informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: placebo; placebo group	Drug: Placebo; 24 hour infusion at a rate of 0,1 µg/kg/min assuming that it contains study drug; Other Names: riboflavine
Active Comparator: levosimendan; study drug	Drug: levosimendan; 24 hour continuous infusion at the rate of 0,1 µg/kg/min; Other Names: Simdax

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Confirmed low cardiac output syndrome	Composite of the three following items:the need for inotropic agents beyond 24 hours following the end of levosimendan/placebo infusion; the need for post-operative mechanical assist devices (intra-aortic balloon pump: IABP, extra-corporeal life support: ECLS) or failure to wean from these techniques if they were inserted pre-operatively; the need for renal replacement therapy during ICU stay	within the 28 days after ICU admission

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
mortality at Day 28 and Day 180		180 postoperative days
The need for inotropic agents beyond 24 hours following the end of levosimendan/placebo infusion		1 time during 24h beyond operative
The description of renal replacement therapy during ICU stay	renal failure requiring renal replacement therapy may occur anytime within 12 hours following surgery and may last 1-2 weeks on average.	within the 28 days after ICU admission
number of ventilator-free days and out-of-ICU days at Day 28.		28 postoperative days

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Ministry of Health, France
• Investigators: Principal Investigator: Bernard Cholley, MD, PhD, Anesthesiology and Intensive Care, Hopital Européen Georges Pompidou, Paris, France; Principal Investigator: Thibaut Caruba, PharmD, Pharmacy department, Hopital Européen Georges Pompidou, Paris, France

Publications and helpful links

General Publications

• De Hert SG, Lorsomradee S, Cromheecke S, Van der Linden PJ. The effects of levosimendan in cardiac surgery patients with poor left ventricular function. Anesth Analg. 2007 Apr;104(4):766-73. doi: 10.1213/01.ane.0000256863.92050.d3. Erratum In: Anesth Analg. 2007 Jun;104(6):1544. Dosage error in article text.
• Levin R, Degrange M, Del Mazo C, Tanus E, Porcile R. Preoperative levosimendan decreases mortality and the development of low cardiac output in high-risk patients with severe left ventricular dysfunction undergoing coronary artery bypass grafting with cardiopulmonary bypass. Exp Clin Cardiol. 2012 Sep;17(3):125-30.
• Tritapepe L, De Santis V, Vitale D, Santulli M, Morelli A, Nofroni I, Puddu PE, Singer M, Pietropaoli P. Preconditioning effects of levosimendan in coronary artery bypass grafting--a pilot study. Br J Anaesth. 2006 Jun;96(6):694-700. doi: 10.1093/bja/ael082. Epub 2006 Apr 4.
• Cholley B, Caruba T, Grosjean S, Amour J, Ouattara A, Villacorta J, Miguet B, Guinet P, Levy F, Squara P, Ait Hamou N, Carillion A, Boyer J, Boughenou MF, Rosier S, Robin E, Radutoiu M, Durand M, Guidon C, Desebbe O, Charles-Nelson A, Menasche P, Rozec B, Girard C, Fellahi JL, Pirracchio R, Chatellier G; -. Effect of Levosimendan on Low Cardiac Output Syndrome in Patients With Low Ejection Fraction Undergoing Coronary Artery Bypass Grafting With Cardiopulmonary Bypass: The LICORN Randomized Clinical Trial. JAMA. 2017 Aug 8;318(6):548-556. doi: 10.1001/jama.2017.9973.
• Caruba T, Hourton D, Sabatier B, Rousseau D, Tibi A, Hoffart-Jourdain C, Souag A, Freitas N, Yjjou M, Almeida C, Gomes N, Aucouturier P, Djadi-Prat J, Menasche P, Chatellier G, Cholley B. Rationale and design of the multicenter randomized trial investigating the effects of levosimendan pretreatment in patients with low ejection fraction (</=40 %) undergoing CABG with cardiopulmonary bypass (LICORN study). J Cardiothorac Surg. 2016 Aug 5;11(1):127. doi: 10.1186/s13019-016-0530-z.

Study record dates

Study Major Dates

• Study Start: June 1, 2013
• Primary Completion (Actual): June 1, 2015
• Study Completion (Actual): November 1, 2015

Study Registration Dates

• First Submitted: October 23, 2013
• First Submitted That Met QC Criteria: July 3, 2014
• First Posted (Estimate): July 9, 2014

Study Record Updates

• Last Update Posted (Estimate): February 25, 2016
• Last Update Submitted That Met QC Criteria: February 24, 2016
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Keywords: mortality; coronary artery bypass graft; levosimendan; ICU stay; left ventricular dysfunction; low cardiac output syndrome; renal replacement therapy; inotropic agents; cardiac mechanical assist devices; mechanical ventilation duration
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Protective Agents; Cardiotonic Agents; Photosensitizing Agents; Dermatologic Agents; Micronutrients; Vitamins; Vitamin B Complex; Phosphodiesterase Inhibitors; Phosphodiesterase 3 Inhibitors; Riboflavin; Simendan
• Other Study ID Numbers: P110138