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

Phase 3RecruitingNCT04020263

Pr Bruno LEVY610 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

610

Conditions

Cardiogenic Shock

Interventions

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.

PlaceboDRUG

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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)

Locations (28)

CHRU Strasbourg -Nouvel Hôpital Civil

Strasbourg, Bas-Rhin, France

RECRUITING

AP-HM, Nord Hospital, Marseille

Marseille, Bouches du Rhône, France

RECRUITING

CHU Caen

Caen, Calvados, France

NOT_YET_RECRUITING

CHU Dijon

Dijon, Côte d'Or, France

Outcomes

Primary Outcomes

Proportion of All-cause mortality

Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis)

Time frame: 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)

Time frame: Day 30 following randomization

Proportion of Dialysis

Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis)

Time frame: Day 30 following randomization

Secondary Outcomes

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).

Time frame: Day 90

Time to escalation to permanent left ventricular assist device or cardiac transplantation

Time frame: Day 90

Time to dialysis

Time frame: Day 90

Time to ECLS requirement

Time frame: Day 90

number of cardiovascular events

Time frame: Day 90

Proportion of death.

Time frame: Day 90

Proportion of Extra Corporel Life Support implantation

Time frame: Day 90

Proportion of dialysis

Time frame: Day 90

Proportion of cardiac transplantation

Time frame: Day 90

Proportion of escalation to permanent Left Ventricular Assist Device

Time frame: Day 90

Proportion of stroke

Time frame: Day 90

Proportion of recurrent myocardial infarction

Time frame: Day 90

Proportion of urgent coronary revascularization

Time frame: Day 90

Proportion of re-hospitalization for heart failure

Time frame: Day 90

Proportion of All-cause mortality

Composite endpoint of all-cause mortality and/or ECLS requirement and/or dialysis on day 90.

Time frame: 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.

Time frame: Day 90

Proportion of Dialysis

Composite endpoint of all-cause mortality and/or ECLS requirement and/or dialysis on day 90.

Time frame: Day 90

Number of dobutamine free days

Time frame: From randomization to day 30

Number of vasopressors free days

Time frame: From randomization to day 30

Number of ventilatory free days

Time frame: From randomization to day 30

Number of renal replacement free days

Time frame: From randomization to day 90

Lactate clearance

Time frame: from randomization to day 7

Duration of intensive care unit stay

Time frame: Up to Intensive Care Unit discharge (assessed up to 1 month)

Duration of hospitalization

Time frame: Up to hospitalization discharge (assessed up to 1 month)

Proportion of All-cause mortality

Composite endpoint of all-cause mortality and/or ECLS requirement and/or dialysis

Time frame: 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

Time frame: 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

Time frame: days 7, 60, and 180 days and 12 months

Number of renal replacement free days

Time frame: D 30, 60, 180 and at 12 months

Proportion of death