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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Cardiogenic Shock

Intervention / Treatment
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* Drug: Levosimendan 2.5 MG/ML Injectable Solution
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patient with cardiogenic shock defined by: Adequate intravascular volume Norepinephrine infusion <1 microgram/kg/min to maintain MAP at least at 65 mmHg for at least 3 hours and less than 12h or dobutamine ≥ 5 microgram/kg/min since at least 3h and less than 12h Tissue hypoperfusion: at least 2 signs (lactate ≥ 2 mmol/l, mottling, oliguria, ScVO2 ≤ 60% or veno-arterial PCO2 gap ≥ 5 mmHg) Clinical pulmonary congestion or elevated natriuretic peptides or echocardiographic sign of elevated left ventricular pressure or elevated right atrial pressure. Exclusion Criteria: Myocardial sideration after cardiac arrest of non-cardiac etiology Immediate or anticipated (within 6 hours) indication of Extra Corporel Life Support Extra Corporel Life Support (Extracorporeal Membrane Oxygenation (ECMO) or Impella) Chronic renal failure requiring hemodialysis Cardiotoxic poisoning Septic cardiomyopathy Previous levosimendan administration within 15 days Cardiac arrest resuscitation >30 minutes Cerebral deficit with fixed dilated pupils Patient moribund on the day of randomization Irreversible neurological pathology Known hypersensitivity to levosimendan or placebo, or one of its excipients Woman of childbearing age without effective contraception Persons referred in articles L.1121-5 to L.1121-8 and L.1122-2 of the Public Health Code: Pregnant, parturient or breastfeeding woman Person deprived of liberty for judicial or administrative decision Person under psychiatric care Minor person (non-emancipated) Adult person under legal protection (any form of public guardianship)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The LevoHeartShock trial is a prospective, double-blind, multicenter, randomized controlled trial comparing the early initiation of levosimendan versus placebo in patients with cardiogenic shock treated with vasopressor therapy according to a conventional strategy of inotrope use (dobutamine as first line agent).
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Levosimendan<br>Experimental group: patients with cardiogenic shock treated with levosimendan in addition to the conventional strategy. | Drug: Levosimendan 2.5 MG/ML Injectable Solution<br>* 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.<br>|
| Placebo Comparator: Placebo<br>Control group: Patients with cardiogenic shock treated with placebo for levosimendan in addition to the conventional strategy. | Drug: Placebo<br>* 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.<br>|

What is the study measuring?
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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 |
| --- | --- | --- |
| Proportion of All-cause mortality | Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis) | Days 7, 30, 60, 90, 180 | 
| Proportion of Extra Corporel Life Support implantation | Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis) | Days 7, 30, 60, 90, 180 | 
| Proportion of dialysis | Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis) | Days 7, 30, 60, 90, 180 | 
| Proportion of death | Composite endpoint of major adverse cardiovascular events defined as death, cardiac transplantation, escalation to permanent left ventricular assist device, stroke, recurrent myocardial infarction, urgent coronary revascularization, dialysis, re-hospitalization for heart failure | Days 30, 60, 90, 180 and 12 months | 
| Proportion of cardiac transplantation | Composite endpoint of major adverse cardiovascular events defined as death, cardiac transplantation, escalation to permanent left ventricular assist device, stroke, recurrent myocardial infarction, urgent coronary revascularization, dialysis, re-hospitalization for heart failure | Days 30, 60, 90, 180 and 12 months | 
| Proportion of escalation to permanent Left Ventricular Assist Device | Composite endpoint of major adverse cardiovascular events defined as death, cardiac transplantation, escalation to permanent left ventricular assist device, stroke, recurrent myocardial infarction, urgent coronary revascularization, dialysis, re-hospitalization for heart failure | Days 30, 60, 90, 180 and 12 months | 
| Proportion of stroke | Composite endpoint of major adverse cardiovascular events defined as death, cardiac transplantation, escalation to permanent left ventricular assist device, stroke, recurrent myocardial infarction, urgent coronary revascularization, dialysis, re-hospitalization for heart failure | Days 30, 60, 90, 180 and 12 months | 
| Proportion of recurrent myocardial infarction | Composite endpoint of major adverse cardiovascular events defined as death, cardiac transplantation, escalation to permanent left ventricular assist device, stroke, recurrent myocardial infarction, urgent coronary revascularization, dialysis, re-hospitalization for heart failure | Days 30, 60, 90, 180 and 12 months | 
| Proportion of urgent coronary revascularization | Composite endpoint of major adverse cardiovascular events defined as death, cardiac transplantation, escalation to permanent left ventricular assist device, stroke, recurrent myocardial infarction, urgent coronary revascularization, dialysis, re-hospitalization for heart failure | Days 30, 60, 90, 180 and 12 months | 
| Proportion of dialysis | Composite endpoint of major adverse cardiovascular events defined as death, cardiac transplantation, escalation to permanent left ventricular assist device, stroke, recurrent myocardial infarction, urgent coronary revascularization, dialysis, re-hospitalization for heart failure | Days 30, 60, 90, 180 and 12 months | 
| Proportion of re-hospitalization for heart failure | Composite endpoint of major adverse cardiovascular events defined as death, cardiac transplantation, escalation to permanent left ventricular assist device, stroke, recurrent myocardial infarction, urgent coronary revascularization, dialysis, re-hospitalization for heart failure | Days 30, 60, 90, 180 and 12 months | 
| Amount of administered dobutamine |  | From baseline to Intensive Care Unit discharge (assessed up to 1 month) | 
| Duration of administered dobutamine |  | From baseline to Intensive Care Unit discharge (assessed up to 1 month) | 
| Duration with abnormal lactate value | Lactate Clearance | From baseline to Intensive Care Unit discharge (assessed up to 1 month) | 
| Number of days with organ failure(s) | Defined with the SOFA score | From baseline to Intensive Care Unit discharge (assessed up to 1 month) | 
| The number of days between inclusion and D30, without organ failure | Defined with the SOFA score | From baseline to day 30 | 
| Duration of catecholamine hemodynamic support |  | From baseline to Intensive Care Unit discharge (assessed up to 1 month) | 
| The number of days between inclusion and D30 without hemodynamic support |  | From baseline to day 30 | 
| Duration of mechanical ventilation |  | From baseline to Intensive Care Unit discharge (assessed up to 1 month) | 
| The number of days alive without mechanical ventilation |  | From baseline to day 30 | 
| 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) | 
| Occurrence of arrhythmias | Including atrial fibrillation and other arrhythmias, ventricular tachycardia, ventricular fibrillation, torsade de pointe | From baseline to Intensive Care Unit discharge (assessed up to 1 month) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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heart failure, levosimendan