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

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.

Interventions

• 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 furth
• 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 hou

Primary outcome measures

• Proportion of All-cause mortality [Time frame: Day 30 following randomization]
• Proportion of Extra Corporel Life Support implantation [Time frame: Day 30 following randomization]
• Proportion of Dialysis [Time frame: Day 30 following randomization]

Secondary outcome measures (12)

• Time to death [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]

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 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)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

France · 28 centers

• CHRU Strasbourg -Nouvel Hôpital Civil — Strasbourg
• AP-HM, Nord Hospital, Marseille — Marseille
• CHU Caen — Caen
• CHU Dijon — Dijon
• CHU Besançon Jean Minjoz Hospital — Besançon
• CHU Nîmes, Carémeau Hospital — Nîmes
• CHU Bordeaux - Hopital haut-leveque — Bordeaux
• CHU de Toulouse — Toulouse
• … and 20 more centers

Identifiers

NCT: NCT04020263 · 2024-513811-29-00 · 2024-513811-29-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗