Effect of Early Use of Levosimendan Versus Placebo on Top of a Conventional Strategy of Inotrope Use on a Combined Morbidity-mortality Endpoint in Patients With Cardiogenic Shock (LevoHeartShock)

Cardiogenic shock (CS) mortality remains high (40%). Despite their frequent use, few clinical outcome data are available to guide the initial selection of vasoactive drug therapies in patients with CS. Based on experts' opinions, the combination of norepinephrine-dobutamine is generally recommended as a first line strategy. Inotropic agents increase myocardial contractility, thereby increasing cardiac output. Dobutamine is commonly recommended to be the inotropic agent of choice and levosimendan is generally used following dobutamine failure. It may represent an ideal agent in cardiogenic shock, since it improves myocardial contractility without increasing cAMP or calcium concentration. At present, there are no convincing data to support a specific inotropic agent in patients with cardiogenic shock. Our hypothesis is that the early use of levosimendan, by enabling the discontinuation of dobutamine, would accelerate the resolution of signs of low cardiac output and facilitate myocardial recovery.

Study Overview

• Status: Recruiting
• Conditions: Cardiogenic Shock
• Intervention / Treatment: Drug: Levosimendan 2.5 MG/ML Injectable Solution; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 610
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Bruno LEVY, Pr; Phone Number: +33 3 83 15 40 84; Email: b.levy@chru-nancy.fr

Study Locations

• France
  • Bordeaux, France
    • Recruiting
    • CHU Bordeaux
    • Contact: Alexandre OUTARRA, MD-PhD
    • Principal Investigator: Alexandre OUTARRA, Md-PhD
  • Creteil, France
    • Not yet recruiting
    • HENRI MONDOR -réanimation
    • Contact: Armand MEKONTSO DESSAP, MD-Phd; Phone Number: +33 1 49 81 21 11; Email: armand.dessap@aphp.fr
    • Principal Investigator: Armand MEKONTSO DESSAP, MD-PhD
  • Dijon, France
    • Recruiting
    • CHU Dijon
    • Contact: Pierre Grégoire GUINOT, MD-PhD
    • Principal Investigator: Pierre Grégoire GUINOT, MD-PhD
  • La Tronche, France, 38700
    • Recruiting
    • CHU Grenoble -USIC
    • Contact: Nicolas PILIERO, MD
    • Principal Investigator: Nicolas PILIERO, MD
  • Marseille, France, 13385
    • Recruiting
    • AP-HM CHU La Timone
    • Contact: Florent ARREGLE, MD
    • Principal Investigator: Florent ARREGLE, MD
  • Montpellier, France, 34295
    • Recruiting
    • CHU Montpellier -hôpital Arnaud de Villeneuve
    • Contact: Philippe GAUDARD, MD-PhD
    • Principal Investigator: Philippe GAUDARD, MD-PhD
  • Paris, France, 75013
    • Recruiting
    • APHP, La Pitié Salpêtrière (medical intensive care unit)
    • Contact: Alain Combes, MD
    • Principal Investigator: Alain Combes, MD
  • Rouen, France
    • Recruiting
    • CHU Rouen
    • Contact: Emmanuel BESNIER, MD-PhD
    • Principal Investigator: Emmanuel BESNIER, MD-PhD
  • Strasbourg, France
    • Not yet recruiting
    • HU Strasbourg USIC
    • Contact: Olivier MOREL, MD PhD; Phone Number: +33 3 88 11 67 68; Email: olivier.morel@chru-strasbourg.fr
    • Principal Investigator: Olivier MOREL, MD-pHD
  • Vandoeuvre les Nancy, France
    • Recruiting
    • CHRU Nancy
    • Contact: Bruno Lévy, Prof
    • Principal Investigator: Bruno LEVY, Prof
  • Bas-Rhin
    • Strasbourg, Bas-Rhin, France, 67091
      • Recruiting
      • CHRU Strasbourg -Nouvel Hôpital Civil
      • Contact: Ferhat MEZIANI, MD-PhD
      • Principal Investigator: Ferhat MEZIANI, MD-PhD
  • Bouches du Rhône
    • Marseille, Bouches du Rhône, France, 13015
      • Recruiting
      • AP-HM, Nord Hospital, Marseille
      • Contact: Laurent Bonello, MD
      • Principal Investigator: Laurent Bonello, MD
  • Calvados
    • Caen, Calvados, France, 14000
      • Not yet recruiting
      • CHU Caen
      • Contact: Katrien Blanchart, MD
      • Principal Investigator: Katrien Blanchart, MD
  • Côte d'Or
    • Dijon, Côte d'Or, France, 21000
      • Recruiting
      • CHU Dijon
      • Contact: Jean-Pierre Quenot, MD-PhD
      • Principal Investigator: Jean-Pierre Quenot, MD-PhD
  • Doubs
    • Besançon, Doubs, France, 25000
      • Recruiting
      • CHU Besançon Jean Minjoz Hospital
      • Contact: Hadrien WINISZEWSKI, MD
      • Principal Investigator: Hadrien WINISZEWSKI, MD
  • Gard
    • Nîmes, Gard, France, 30029
      • Recruiting
      • CHU Nîmes, Carémeau Hospital
      • Contact: Benoît Lattuca, MD
      • Principal Investigator: Benoît Lattuca, MD
  • Gironde
    • Bordeaux, Gironde, France, 33600
      • Recruiting
      • Chu Bordeaux - Hôpital Haut-Lévêque
      • Contact: Edouard Gerbaud, MD
      • Principal Investigator: Edouard Gerbaud, MD
  • Haute-Garonne
    • Toulouse, Haute-Garonne, France, 31059
      • Recruiting
      • CHU de Toulouse
      • Contact: Clément DELMAS, MD
      • Principal Investigator: Clément Delmas, MD
  • Haute-Vienne
    • Limoges, Haute-Vienne, France, 87000
      • Recruiting
      • CHU Limoges, Dupuytren Hospital
      • Contact: Philippe Vignon, MD
      • Principal Investigator: Philippe Vignon, MD
  • Hérault
    • Montpellier, Hérault, France, 34090
      • Recruiting
      • CHU Montpellier, Arnaud de Villeneuve Hospital
      • Contact: François Roubille, MD
      • Principal Investigator: François Roubille, MD
  • Ille et Vilaine
    • Rennes, Ille et Vilaine, France, 35000
      • Recruiting
      • CHU Rennes, Pontchaillou Hospital
      • Contact: Abdelkader BAKHTI, MD
      • Principal Investigator: Abdelkader BAKHTI, MD
  • Isère
    • La Tronche, Isère, France, 38043
      • Recruiting
      • CHU Grenoble, Michallon Hospital
      • Contact: Joanna Bougnaud, MD
      • Principal Investigator: Joanna Bougnaud, MD
  • Loire-Atlantique
    • Nantes, Loire-Atlantique, France, 44000
      • Recruiting
      • Chu Nantes
      • Contact: Julien Plessis, MD
      • Principal Investigator: Julien Plessis, MD
  • Moselle
    • Ars-Laquenexy, Moselle, France, 57245
      • Recruiting
      • CHR Metz-Thionville, Mercy Hospital
      • Contact: Guillaume Louis, MD
      • Principal Investigator: Guillaume LOUIS, MD
  • Nord
    • Lille, Nord, France, 59000
      • Recruiting
      • CHRU Lille, Cœur Poumon Institute
      • Contact: Gilles LEMESLE, MD-PhD
      • Principal Investigator: Gilles LEMESLE, MD-PhD
  • Rhône
    • Bron, Rhône, France, 69500
      • Recruiting
      • Hospices Civils de Lyon - Louis Pradel Hospital
      • Contact: Bertrand SCHEPPLER, MD; Phone Number: +33 4 72 11 80 88; Email: bertrand.scheppler01@chu-lyon.fr
      • Principal Investigator: Bertrand SCHEPPLER, MD
  • Val de Marne
    • Créteil, Val de Marne, France, 94010
      • Recruiting
      • APHP, Henri Mondor Hospital
      • Contact: Raphaëlle HUGUET, MD; Phone Number: +33 1 49 81 21 11; Email: raphaelle.huguet@aphp.fr
      • Principal Investigator: Raphaelle HUGUET, MD
  • Vaucluse
    • Avignon, Vaucluse, France, 84000
      • Not yet recruiting
      • CH Henri Duffaut, Avignon
      • Contact: Stéphane Andrieu, MD
      • Principal Investigator: Stéphane Andrieu, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Adult patient ≥ 18 years with cardiogenic shock defined by:

• Adequate intravascular volume
• Norepinephrine to maintain MAP at least at 65 mmHg for at least 3 hours and less than 24h. At inclusion the dose must be <1 microgram/kg/min under norepinephrine base or <2 microgram/kg/min under norepinephrine tartrate, OR/AND Dobutamine since at least 3h and less than 24h at inclusion.
• Tissue hypoperfusion: at least 1 sign within 24h prior to inclusion (lactate ≥ 2 mmol/l; mottling, capillary refeel time > 3 seconds, oliguria <500ml/24h or ≤ 20 ml/h during the last 2 hours, ScVO2 ≤ 60% or veno-arterial PCO2 gap ≥ 5 mmHg);

Exclusion Criteria:

• Myocardial sideration after cardiac arrest of non-cardiac etiology
• Immediate or anticipated (within 6 hours) indication of Extra Corporel Life Support
• Use of VA-ECMO or IMPELLA or LVAD;
• Chronic renal failure requiring hemodialysis
• Cardiotoxic poisoning
• Septic cardiomyopathy
• Previous levosimendan administration within 15 days
• Cardiac arrest with non-shockable rhythm;
• No flow time higher > 3 minutes;
• Cardiac arrest with unknown no flow duration;
• Total duration of cardiac arrest (no flow plus low flow) > 45 minutes;
• Cerebral deficit with fixed dilated pupils
• Patient moribund on the day of enrollment
• Irreversible neurological pathology
• Known hypersensitivity to levosimendan or placebo, or one of its excipients
• Pregnant woman, birthing or breastfeeding mother
• Minor (not emancipated)
• Person deprived of liberty for judicial or administrative decision;
• Adult subject to a legal protection measure (such as guardianship, conservatorship)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Levosimendan; Experimental group: patients with cardiogenic shock treated with levosimendan in addition to the conventional strategy.	Drug: Levosimendan 2.5 MG/ML Injectable Solution; Levosimendan will be diluted with Glucose G5%. The reconstitution of levosimendan will be performed, as close as possible to the start of the infusion. A continuous infusion of levosimendan will be administered over 24 h without bolus, started at a rate of 0.1 μg per kilogram of body weight per minute and, in both the persistence of hypoperfusion signs and in the absence of rate-limiting side effects, will be increased after 2 to 4 hours to a maximum of 0.2 μg per kilogram per minute for a further 20 to 22 hours.
Placebo Comparator: Placebo; Control group: Patients with cardiogenic shock treated with placebo (Cernevit/Soluvit) in addition to the conventional strategy.	Drug: Placebo; Placebo will be diluted with Glucose G5%. The reconstitution of Placebo will be performed, as close as possible to the start of the infusion. A continuous infusion of Placebo will be administered over 24 h without bolus, started at a rate of 0.1 μg per kilogram of body weight per minute and, in both the persistence of hypoperfusion signs and in the absence of rate-limiting side effects, will be increased after 2 to 4 hours to a maximum of 0.2 μg per kilogram per minute for a further 20 to 22 hours.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of All-cause mortality	Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis)	Day 30 following randomization
Proportion of Extra Corporel Life Support implantation	Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis)	Day 30 following randomization
Proportion of Dialysis	Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis)	Day 30 following randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of intensive care unit stay		Up to Intensive Care Unit discharge (assessed up to 1 month)
Duration of hospitalization		Up to hospitalization discharge (assessed up to 1 month)
Time to death	Prioritized composite endpoint with the following priority order: 1/ time to death, 2/ escalation to permanent left ventricular assist device or cardiac transplantation, 3/ dialysis, 4/ ECLS requirement, 5/ number of cardiovascular events (stroke, recurrent myocardial infarction, urgent coronary revascularization, re-hospitalization for heart failure).	Day 90
Time to escalation to permanent left ventricular assist device or cardiac transplantation	Prioritized composite endpoint with the following priority order: 1/ time to death, 2/ escalation to permanent left ventricular assist device or cardiac transplantation, 3/ dialysis, 4/ ECLS requirement, 5/ number of cardiovascular events (stroke, recurrent myocardial infarction, urgent coronary revascularization, re-hospitalization for heart failure).	Day 90
Time to dialysis	Prioritized composite endpoint with the following priority order: 1/ time to death, 2/ escalation to permanent left ventricular assist device or cardiac transplantation, 3/ dialysis, 4/ ECLS requirement, 5/ number of cardiovascular events (stroke, recurrent myocardial infarction, urgent coronary revascularization, re-hospitalization for heart failure).	Day 90
Time to ECLS requirement	Prioritized composite endpoint with the following priority order: 1/ time to death, 2/ escalation to permanent left ventricular assist device or cardiac transplantation, 3/ dialysis, 4/ ECLS requirement, 5/ number of cardiovascular events (stroke, recurrent myocardial infarction, urgent coronary revascularization, re-hospitalization for heart failure).	Day 90
number of cardiovascular events	Prioritized composite endpoint with the following priority order: 1/ time to death, 2/ escalation to permanent left ventricular assist device or cardiac transplantation, 3/ dialysis, 4/ ECLS requirement, 5/ number of cardiovascular events (stroke, recurrent myocardial infarction, urgent coronary revascularization, re-hospitalization for heart failure).	Day 90
Proportion of death.		Day 90
Proportion of Extra Corporel Life Support implantation		Day 90
Proportion of dialysis		Day 90
Proportion of cardiac transplantation		Day 90
Proportion of escalation to permanent Left Ventricular Assist Device		Day 90
Proportion of stroke		Day 90
Proportion of recurrent myocardial infarction		Day 90
Proportion of urgent coronary revascularization		Day 90
Proportion of re-hospitalization for heart failure		Day 90
Proportion of All-cause mortality	Composite endpoint of all-cause mortality and/or ECLS requirement and/or dialysis on day 90.	Day 90
Proportion of Extra Corporel Life Support implantation	Composite endpoint of all-cause mortality and/or ECLS requirement and/or dialysis on day 90.	Day 90
Proportion of Dialysis	Composite endpoint of all-cause mortality and/or ECLS requirement and/or dialysis on day 90.	Day 90
Number of dobutamine free days		From randomization to day 30
Number of vasopressors free days		From randomization to day 30
Number of ventilatory free days		From randomization to day 30
Number of renal replacement free days		From randomization to day 90
Lactate clearance		from randomization to day 7
Proportion of All-cause mortality	Composite endpoint of all-cause mortality and/or ECLS requirement and/or dialysis	days 7, 60, and 180 days and 12 months
Proportion of Extra Corporel Life Support implantation	Composite endpoint of all-cause mortality and/or ECLS requirement and/or dialysis	days 7, 60, and 180 days and 12 months
Proportion of dialysis	Composite endpoint of all-cause mortality and/or ECLS requirement and/or dialysis	days 7, 60, and 180 days and 12 months
Number of renal replacement free days		D 30, 60, 180 and at 12 months
Proportion of death		days 180 and at 12 months
Proportion of Extra Corporel Life Support implantation		days 180 and at 12 months
Proportion of dialysis		days 180 and at 12 months
proportion of cardiac transplantation		days 180 and at 12 months
proportion of escalation to permanent left ventricular assist device		days 180 and at 12 months
Proportion of stroke		days 180 and at 12 months
Proportion of recurrent myocardial infarction		days 180 and at 12 months
Proportion urgent coronary revascularization		days 180 and at 12 months
proportion of re-hospitalization for heart failure		days 180 and at 12 months
Occurrence of arrhythmias requiring therapy	Occurrence of arrhythmias requiring therapy with anti-arrhythmic drugs or electric cardioversion (including atrial fibrillation, ventricular tachycardia, ventricular fibrillation, torsade de pointe)	from randomization to intensive care unit discharge.
the changes in biomarkers	From a dedicated biological collection on which we will measure existing and future biological parameters, we will evaluate the effect of Levosimendan on the changes in biomarkers between randomization and ICU/CCU discharge	from randomization to intensive care unit discharge.
All-cause mortality and/or ECLS and/or dialysis	From a dedicated biological collection on which we will measure existing and future biological parameters, we will evaluate the ability of clinical and biological measure to predict levosimendan effect for the primary endpoint.	Day 30
All-cause mortality and/or ECLS and/or dialysis	From a dedicated biological collection on which we will measure existing and future biological parameters, we will evaluate the ability of biological measure to predict subsequent outcome	At intensive care unit discharge

Collaborators and Investigators

• Sponsor: Pr Bruno LEVY
• Investigators: Study Chair: Clément DELMAS, Dr, Chu Toulouse; Study Chair: Nicolas GIRERD, Pr, CHRU Nancy; Study Chair: Patrick ROSSIGNOL, Pr, CHRU Nancy

Study record dates

Study Major Dates

• Study Start (Actual): July 3, 2023
• Primary Completion (Estimated): February 3, 2027
• Study Completion (Estimated): January 3, 2028

Study Registration Dates

• First Submitted: June 28, 2019
• First Submitted That Met QC Criteria: July 11, 2019
• First Posted (Actual): July 16, 2019

Study Record Updates

• Last Update Posted (Actual): August 5, 2025
• Last Update Submitted That Met QC Criteria: July 31, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: heart failure; levosimendan
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Infarction; Necrosis; Myocardial Ischemia; Myocardial Infarction; Ischemia; Shock, Cardiogenic; Shock; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protective Agents; Cardiotonic Agents; Vasodilator Agents; Phosphodiesterase Inhibitors; Phosphodiesterase 3 Inhibitors; Simendan
• Other Study ID Numbers: 2024-513811-29-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No