Clinical trial NCT04020263: 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
Official title: 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 type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Cardiogenic Shock
Keywords: heart failure
levosimendan
Lead sponsor: Central Hospital, Nancy, France
Sponsor class: OTHER
First posted: 2019-07-16
Enrollment: 610
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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).
Primary purpose: TREATMENT

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.


Eligibility criteria: 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 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);

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;
* 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)

Primary outcomes:
measure: Proportion of All-cause mortality
timeFrame: Day 30 following randomization
measure: Proportion of Extra Corporel Life Support implantation
timeFrame: Day 30 following randomization
measure: Proportion of Dialysis
timeFrame: Day 30 following randomization
Secondary outcomes:
measure: Time to death
timeFrame: Day 90
measure: Time to escalation to permanent left ventricular assist device or cardiac transplantation
timeFrame: Day 90
measure: Time to dialysis
timeFrame: Day 90
measure: Time to ECLS requirement
timeFrame: Day 90
measure: number of cardiovascular events
timeFrame: Day 90
measure: Proportion of death.
timeFrame: Day 90
measure: Proportion of Extra Corporel Life Support implantation
timeFrame: Day 90
measure: Proportion of dialysis
timeFrame: Day 90
measure: Proportion of cardiac transplantation
timeFrame: Day 90
measure: Proportion of escalation to permanent Left Ventricular Assist Device
timeFrame: Day 90
measure: Proportion of stroke
timeFrame: Day 90
measure: Proportion of recurrent myocardial infarction
timeFrame: Day 90
measure: Proportion of urgent coronary revascularization
timeFrame: Day 90
measure: Proportion of re-hospitalization for heart failure
timeFrame: Day 90
measure: Proportion of All-cause mortality
timeFrame: Day 90
measure: Proportion of Extra Corporel Life Support implantation
timeFrame: Day 90
measure: Proportion of Dialysis
timeFrame: Day 90
measure: Number of dobutamine free days
timeFrame: From randomization to day 30
measure: Number of vasopressors free days
timeFrame: From randomization to day 30
measure: Number of ventilatory free days
timeFrame: From randomization to day 30
measure: Number of renal replacement free days
timeFrame: From randomization to day 90
measure: Lactate clearance
timeFrame: from randomization to day 7
measure: Duration of intensive care unit stay
timeFrame: Up to Intensive Care Unit discharge (assessed up to 1 month)
measure: Duration of hospitalization
timeFrame: Up to hospitalization discharge (assessed up to 1 month)
measure: Proportion of All-cause mortality
timeFrame: days 7, 60, and 180 days and 12 months
measure: Proportion of Extra Corporel Life Support implantation
timeFrame: days 7, 60, and 180 days and 12 months
measure: Proportion of dialysis
timeFrame: days 7, 60, and 180 days and 12 months
measure: Number of renal replacement free days
timeFrame: D 30, 60, 180 and at 12 months
measure: Proportion of death
timeFrame: days 180 and at 12 months
measure: Proportion of Extra Corporel Life Support implantation
timeFrame: days 180 and at 12 months
measure: Proportion of dialysis
timeFrame: days 180 and at 12 months
measure: proportion of cardiac transplantation
timeFrame: days 180 and at 12 months
measure: proportion of escalation to permanent left ventricular assist device
timeFrame: days 180 and at 12 months
measure: Proportion of stroke
timeFrame: days 180 and at 12 months
measure: Proportion of recurrent myocardial infarction
timeFrame: days 180 and at 12 months
measure: Proportion urgent coronary revascularization
timeFrame: days 180 and at 12 months
measure: proportion of re-hospitalization for heart failure
timeFrame: days 180 and at 12 months
measure: Occurrence of arrhythmias requiring therapy
timeFrame: from randomization to intensive care unit discharge.
measure: the changes in biomarkers
timeFrame: from randomization to intensive care unit discharge.
measure: All-cause mortality and/or ECLS and/or dialysis
timeFrame: Day 30
measure: All-cause mortality and/or ECLS and/or dialysis
timeFrame: At intensive care unit discharge
Other outcomes:
Locations:
city: Strasbourg
country: France
facility: CHRU Strasbourg -Nouvel Hôpital Civil
state: Bas-Rhin
city: Marseille
country: France
facility: AP-HM, la Timone Hospital, Marseille
state: Bouches Du Rhône
city: Marseille
country: France
facility: AP-HM, Nord Hospital, Marseille
state: Bouches Du Rhône
city: Caen
country: France
facility: CHU Caen
state: Calvados
city: Dijon
country: France
facility: CHU Dijon
state: Côte d'Or
city: Besançon
country: France
facility: CHU Besançon Jean Minjoz Hospital
state: Doubs
city: Nîmes
country: France
facility: CHU Nîmes, Carémeau Hospital
state: Gard
city: Bordeaux
country: France
facility: CHU Bordeaux - Hopital haut-leveque
state: Gironde
city: Toulouse
country: France
facility: CHU de Toulouse
state: Haute-Garonne
city: Limoges
country: France
facility: CHU Limoges, Dupuytren Hospital
state: Haute-Vienne
city: Montpellier
country: France
facility: CHU Montpellier, Arnaud de Villeneuve Hospital
state: Hérault
city: Montpellier
country: France
facility: CHU Montpellier, site Lapeyronie
state: Hérault
city: Rennes
country: France
facility: CHU Rennes, Pontchaillou Hospital
state: Ille Et Vilaine
city: La Tronche
country: France
facility: CHU Grenoble, Michallon Hospital
state: Isère
city: Nantes
country: France
facility: CHU Nantes
state: Loire-Atlantique
city: Ars-Laquenexy
country: France
facility: CHR Metz-Thionville, Mercy Hospital
state: Moselle
city: Lille
country: France
facility: CHRU Lille, Cœur Poumon Institute
state: Nord
city: Bron
country: France
facility: Hospices Civils de Lyon - Louis Pradel Hospital
state: Rhône
city: Rouen
country: France
facility: CHU Rouen, Charles Nicolle Hospital
state: Seine Maritime
city: Créteil
country: France
facility: APHP, Henri Mondor Hospital
state: Val De Marne
city: Avignon
country: France
facility: CH Henri Duffaut, Avignon
state: Vaucluse
city: Bordeaux
country: France
facility: CHU Bordeaux
city: Dijon
country: France
facility: Chu Dijon
city: La Tronche
country: France
facility: CHU Grenoble -USIC
city: Marseille
country: France
facility: AP-HM CHU la Timone
city: Montpellier
country: France
facility: CHU Montpellier -hôpital Arnaud de Villeneuve
city: Paris
country: France
facility: APHP, Lariboisière Hospital (intensive care unit and toxicology)
city: Paris
country: France
facility: APHP, La Pitié Salpêtrière (medical intensive care unit)
city: Paris
country: France
facility: APHP- HEGP Paris
city: Rouen
country: France
facility: Chu Rouen
city: Vandoeuvre les Nancy
country: France
facility: CHRU Nancy
Study officials:
affiliation: CHU Toulouse
name: Clément DELMAS, Dr
role: STUDY_CHAIR
affiliation: CHRU Nancy
name: Nicolas GIRERD, Pr
role: STUDY_CHAIR
affiliation: CHRU Nancy
name: Patrick ROSSIGNOL, Pr
role: STUDY_CHAIR
References: