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Effect of Levosimendan on Low Cardiac Output Syndrome in Patients With Low Ejection Fraction Undergoing Coronary Artery Bypass Grafting With Cardiopulmonary BypassThe LICORN Randomized Clinical Trial

Educational Objective
To learn whether levosimendan, given preoperatively, can prevent postoperative low cardiac output syndrome.
1 Credit CME
Key Points

Question  Does a prophylactic levosimendan infusion reduce the incidence of postoperative low cardiac output syndrome in patients with impaired left ventricular function who are undergoing isolated or combined coronary artery bypass grafting surgery under cardiopulmonary bypass?

Findings  In this randomized clinical trial involving 335 patients, levosimendan compared with placebo did not result in a significant difference in the composite end point of prolonged catecholamine infusion, use of left ventricular mechanical assist device, or renal replacement therapy (52% in the levosimendan group vs 61% in the placebo group).

Meaning  Levosimendan was not effective in reducing the incidence of postoperative low cardiac output syndrome in patients such as these.

Abstract

Importance  Low cardiac output syndrome after cardiac surgery is associated with high morbidity and mortality in patients with impaired left ventricular function.

Objective  To assess the ability of preoperative levosimendan to prevent postoperative low cardiac output syndrome.

Design, Setting, and Participants  Randomized, double-blind, placebo-controlled trial conducted in 13 French cardiac surgical centers. Patients with a left ventricular ejection fraction less than or equal to 40% and scheduled for isolated or combined coronary artery bypass grafting with cardiopulmonary bypass were enrolled from June 2013 until May 2015 and followed during 6 months (last follow-up, November 30, 2015).

Interventions  Patients were assigned to a 24-hour infusion of levosimendan 0.1 µg/kg/min (n = 167) or placebo (n = 168) initiated after anesthetic induction.

Main Outcomes and Measures  Composite end point reflecting low cardiac output syndrome with need for a catecholamine infusion 48 hours after study drug initiation, need for a left ventricular mechanical assist device or failure to wean from it at 96 hours after study drug initiation when the device was inserted preoperatively, or need for renal replacement therapy at any time postoperatively. It was hypothesized that levosimendan would reduce the incidence of this composite end point by 15% in comparison with placebo.

Results  Among 336 randomized patients (mean age, 68 years; 16% women), 333 completed the trial. The primary end point occurred in 87 patients (52%) in the levosimendan group and 101 patients (61%) in the placebo group (absolute risk difference taking into account center effect, −7% [95% CI, −17% to 3%]; P = .15). Predefined subgroup analyses found no interaction with ejection fraction less than 30%, type of surgery, and preoperative use of β-blockers, intra-aortic balloon pump, or catecholamines. The prevalence of hypotension (57% vs 48%), atrial fibrillation (50% vs 40%), and other adverse events did not significantly differ between levosimendan and placebo.

Conclusions and Relevance  Among patients with low ejection fraction who were undergoing coronary artery bypass grafting with cardiopulmonary bypass, levosimendan compared with placebo did not result in a significant difference in the composite end point of prolonged catecholamine infusion, use of left ventricular mechanical assist device, or renal replacement therapy. These findings do not support the use of levosimendan for this indication.

Trial Registration  EudraCT Number: 2012-000232-25; clinicaltrials.gov Identifier: NCT02184819

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Article Information

Corresponding Author: Bernard Cholley, MD, PhD, Department of Anesthesiology and Critical Care Medicine, Hôpital Européen Georges Pompidou, AP-HP, 20 rue Leblanc, 75908 Paris Cedex 15, France (bernard.cholley@aphp.fr).

Accepted for Publication: July 6, 2017.

Author Contributions: Drs Cholley and Caruba had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Cholley, Caruba, Chatellier.

Acquisition, analysis, or interpretation of data: Cholley, Caruba, Grosjean, Villacorta, Lévy, Ait Hamou, Carillion, Boughenou, Rosier, Durand, Guidon, Desebbe, Charles-Nelson, Menasché, Rozec, Fellahi, Pirracchio, Chatellier.

Drafting of the manuscript: Cholley, Caruba, Charles-Nelson, Pirracchio, Chatellier.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Charles-Nelson, Pirracchio, Chatellier.

Obtained funding: Cholley, Caruba.

Administrative, technical, or material support: Caruba, Villacorta, Lévy, Ait Hamou, Boughenou, Rosier, Guidon, Desebbe, Rozec, Fellahi, Chatellier.

Supervision: Cholley, Caruba.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Cholley reports receiving an honorarium for an invited lecture for Orion Pharma. Dr Menasché reports serving on the advisory boards of Edwards Lifesciences and Gecko Biomedical. Dr Rozec reports receiving a grant from Baxter and receiving personal fees from Baxter and Xenios. No other disclosures were reported.

Funding/Support: The LICORN study was funded by the French Ministry of Health (Programme Hospitalier de Recherche Clinique national 2011, MIN02-07) and sponsored by Assistance Publique-Hôpitaux de Paris. Orion Pharma provided study drugs free of charge.

Role of the Funder/Sponsor: Orion Pharma and the other funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

LICORN Collaborators: Hôpital Européen Georges Pompidou, AP-HP, and Université Paris Descartes-Sorbonne Paris Cité, Paris, France: Christian Latrémouille, MD, PhD; Paul Achouh, MD, PhD; Jérôme Jouan, MD; Alain Bel, MD; Jean-Noël Fabiani, MD, PhD; Delphine Hourton, PhD; Centre Hospitalo-Universitaire de Dijon-Bourgogne: Olivier Bouchot, MD, PhD; Hôpital de La Pitié Salpêtrière, AP-HP, and Université Pierre et Marie Curie: Adrien Bouglé, MD; Astrid Quessard, MD; Marwan Nader, MD; Pascal Leprince, MD, PhD; CHU de Bordeaux: Delphine Hirtz, MD; Alain Coiffic, MD; Nathalie Noël; Cécile Poisvert; Alain Rémy, MD; Cédric Zaouter, MD; Louis Labrousse MD, PhD; Laurent Barandon, MD, PhD; CHU La Timone, Marseille: Françoise Gaillat, MD; Catherine-Charlotte Joseph, MD; Frédéric Collart, MD, PhD; Hôpital Laënnec, Nantes: Nicolas Cotron, MD; Laurent Delille, MD; Jean-Christian Roussel, MD, PhD; Hubert-François Carton, MD; Hôpital Pontchaillou, Rennes: Laurent Daviet, MD; Erwan Flecher, MD, PhD; Nouvel Hôpital Civil, Strasbourg: Minh Tam Hoang, MD; Clinique Ambroise Paré, Neuilly: Alain Brusset, MD; Philippe Estagnaisie, MD; Hôpital Bichat, AP-HP, Paris: Dan Longrois, MD, PhD; Hôpital Lariboisière, AP-HP, Paris: Alexandre Mebazaa, MD, PhD; Hôpital Claude Huriez, Lille: Olivier Joulin, MD; Grenoble: Sylvaine Robin, MD, Géraldine Dessertaine, MD; Myriam Cassez Brasseur, MD; Olivier Chavanon, MD, PhD; CHU Côte de Nacre, Caen: Fabien Dechanet, MD; Clément Boisselier, MD; Hôpital Cardiologique Louis Pradel, Lyon: Pierre Joseph, MD; Olivier Bastien, MD, PhD; Jean-François Obadia, MD, PhD.

Data and Safety Monitoring Board: Hôpital Henri Mondor, AP-HP, Créteil: Pascal Gueret, MD, PhD; Hôpital Marie Lannelongue, Le Plessis-Robinsson: François Stéphan, MD, PhD; Hôtel-Dieu, AP-HP, Paris, INSERM 1153: Raphaël Porcher, MD, PhD.

Meeting Presentations: Presented at: Meeting of the French Society of Anesthesiologists, September 24, 2016, Paris, France; the International Symposium on Intensive Care and Emergency Medicine, March 23, 2017, Brussels, Belgium; and the European Association of Cardiothoracic Anaesthesiology meeting; April 20, 2017; Berlin, Germany.

Additional Contributions: We thank the team of the Clinical Research Department of Hôpital Européen Georges Pompidou, AP-HP, for expert study management and the Association des Anesthésistes-Réanimateurs en Chirurgie Cardio-Thoracique & Vasculaire (ARCOTHOVA) for facilitating the organization of this study by connecting several French cardiac surgical centers.

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