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
- Cardiogenic Shock
- Interventions
- Drug: Placebo
- Registration Number
- NCT04020263
- Lead Sponsor
- Central Hospital, Nancy, France
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 610
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 and at dose ≥ 5 microgram/kg/min at inclusion.
- Tissue hypoperfusion: at least 1 sign (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);
- 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;
- Cardiogenic choc post cardiac surgery under cardiopulmonary bypass (CPBP) weaned for less or equal of 6 hours.
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Levosimendan Levosimendan 2.5 MG/ML Injectable Solution Experimental group: patients with cardiogenic shock treated with levosimendan in addition to the conventional strategy. Placebo Placebo Control group: Patients with cardiogenic shock treated with placebo (Cernevit/Soluvit) in addition to the conventional strategy.
- Primary Outcome Measures
Name Time Method Proportion of All-cause mortality Day 30 following randomization Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis)
Proportion of Extra Corporel Life Support implantation Day 30 following randomization Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis)
Proportion of Dialysis Day 30 following randomization Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis)
- Secondary Outcome Measures
Name Time Method Proportion of death. Day 90 Proportion of urgent coronary revascularization Day 90 number of cardiovascular events Day 90 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).
Time to death Day 90 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).
Time to escalation to permanent left ventricular assist device or cardiac transplantation Day 90 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).
Time to dialysis Day 90 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).
Time to ECLS requirement Day 90 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).
Proportion of All-cause mortality days 7, 60, and 180 days and 12 months Composite endpoint of all-cause mortality and/or ECLS requirement and/or dialysis
Proportion of Dialysis Day 90 Composite endpoint of all-cause mortality and/or ECLS requirement and/or dialysis on day 90.
Number of dobutamine free days From randomization to day 30 proportion of escalation to permanent left ventricular assist device days 180 and at 12 months Number of vasopressors free days From randomization to day 30 Number of ventilatory free days From randomization to day 30 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 Day 90 Proportion of escalation to permanent Left Ventricular Assist Device Day 90 Proportion of stroke days 180 and at 12 months Proportion of recurrent myocardial infarction days 180 and at 12 months Proportion of re-hospitalization for heart failure Day 90 Number of renal replacement free days D 30, 60, 180 and at 12 months Lactate clearance from randomization to day 7 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) Proportion of death days 180 and at 12 months proportion of cardiac transplantation 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 from randomization to intensive care unit discharge. Occurrence of arrhythmias requiring therapy with anti-arrhythmic drugs or electric cardioversion (including atrial fibrillation, ventricular tachycardia, ventricular fibrillation, torsade de pointe)
the changes in biomarkers from randomization to intensive care unit discharge. 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
All-cause mortality and/or ECLS and/or dialysis At intensive care unit discharge 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
Trial Locations
- Locations (31)
CHRU Strasbourg -Nouvel Hôpital Civil
🇫🇷Strasbourg, Bas-Rhin, France
CHU Besançon Jean Minjoz Hospital
🇫🇷Besançon, Doubs, France
CHU Grenoble, Michallon Hospital
🇫🇷La Tronche, Isère, France
CHU Nantes
🇫🇷Nantes, Loire-Atlantique, France
CHU de Toulouse
🇫🇷Toulouse, Haute-Garonne, France
CHR Metz-Thionville, Mercy Hospital
🇫🇷Ars-Laquenexy, Moselle, France
CHRU Lille, Cœur Poumon Institute
🇫🇷Lille, Nord, France
Hospices Civils de Lyon - Louis Pradel Hospital
🇫🇷Bron, Rhône, France
APHP, Lariboisière Hospital (intensive care unit and toxicology)
🇫🇷Paris, France
CH Henri Duffaut, Avignon
🇫🇷Avignon, Vaucluse, France
APHP- HEGP Paris
🇫🇷Paris, France
AP-HM CHU la Timone
🇫🇷Marseille, France
CHU Grenoble -USIC
🇫🇷La Tronche, France
CHU Montpellier -hôpital Arnaud de Villeneuve
🇫🇷Montpellier, France
APHP, La Pitié Salpêtrière (medical intensive care unit)
🇫🇷Paris, France
Chu Dijon
🇫🇷Dijon, France
CHU Bordeaux
🇫🇷Bordeaux, France
CHU Limoges, Dupuytren Hospital
🇫🇷Limoges, Haute-Vienne, France
CHU Dijon
🇫🇷Dijon, Côte d'Or, France
AP-HM, Nord Hospital, Marseille
🇫🇷Marseille, Bouches Du Rhône, France
AP-HM, la Timone Hospital, Marseille
🇫🇷Marseille, Bouches Du Rhône, France
CHU Caen
🇫🇷Caen, Calvados, France
CHU Bordeaux - Hopital haut-leveque
🇫🇷Bordeaux, Gironde, France
CHU Montpellier, site Lapeyronie
🇫🇷Montpellier, Hérault, France
CHU Nîmes, Carémeau Hospital
🇫🇷Nîmes, Gard, France
CHU Montpellier, Arnaud de Villeneuve Hospital
🇫🇷Montpellier, Hérault, France
CHU Rennes, Pontchaillou Hospital
🇫🇷Rennes, Ille Et Vilaine, France
CHU Rouen, Charles Nicolle Hospital
🇫🇷Rouen, Seine Maritime, France
APHP, Henri Mondor Hospital
🇫🇷Créteil, Val De Marne, France
Chu Rouen
🇫🇷Rouen, France
CHRU Nancy
🇫🇷Vandoeuvre les Nancy, France