LEVOSIMENDAN to Facilitate Weaning From ECMO in Severe Cardiogenic Shock Patients (LEVOECMO)

In the last decade, venoarterial extracorporeal membrane oxygenation (VA-ECMO) has become the first-line therapy in patients with refractory cardiogenic shock. VA-ECMO provides both respiratory and cardiac support, is easy to insert, even at the bedside, provides stable flow rates, and is associated with less organ failure after implantation compared to large biventricular assist-devices that require open-heart surgery. In patients with potentially reversible cardiac failure (e.g. myocarditis, myocardial stunning post-myocardial infarction, post-cardiotomy or post-cardiac arrest), VA-ECMO might be weaned after a few days of support and used as a bridge to recovery.

Although considered as the ultimate life-saving technology for refractory cardiac failure, veno-arterial ECMO is still associated with severe complications. Specifically, excessive LV afterload and lack of LV unloading under VA-ECMO might induce LV stasis with thrombus formation, pulmonary edema, myocardial ischemia caused by ventricular distension and ultimately increase mortality. ECMO support also exposes to many complications such as infections, hemorrhage or peripheral vascular embolism. These complications are more frequent with prolonged support and are responsible for significant morbidity and mortality, prolonged ICU and hospital stays and higher costs.

Levosimendan, which acts to sensitize myocardial contractile proteins to calcium, improves cardiac contractility without increasing the intracellular calcium concentration. Unlike traditional inotropes such as dobutamine, levosimendan neither increases myocardial oxygen consumption nor impairs diastolic function or possess proarrhythmic effects. It also influences the opening of ATP-dependent potassium channels, including those in vascular smooth muscle cells, leading to coronary, pulmonary, and peripheral vasodilation and antiinflammatory, antioxidative, antiapoptotic, anti-stunning and cardioprotective effects. Additionally, Levosimendan which has a long lasting action (up to 7-9 d), resulting from the formation of active metabolite, may be used as a single 24h perfusion.

In recent preliminary studies, the drug was associated with accelerated weaning from VA-ECMO and even improved survival. Therefore, a multicenter randomized trial with sufficient statistical power is needed in refractory cardiogenic shock patients supported by VA-ECMO to test if the early administration of Levosimendan can facilitate and accelerate VA-ECMO weaning, and ultimately translate in significantly less morbidity, reduced ICU and hospital length of stays and associated costs.

Study Overview

• Status: Recruiting
• Conditions: Cardiogenic Shock; Extracorporeal Membrane Oxygenation Complication
• Intervention / Treatment: Drug: Levosimendan; Drug: Placebo of Levosimendan

• Study Type: Interventional
• Enrollment (Estimated): 206
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Alain COMBES, MD; Phone Number: +33142163818; Email: alain.combes@aphp.fr

Study Locations

• France
  • Paris, France, 75013
    • Recruiting
    • Hopital Pitie Salpetriere
    • Contact: Alain COMBES, MD
  • Paris, France
    • Recruiting
    • Hopital Europeen Georges Pompidou
    • Contact: Bernard Cholley, MD
  • Bordeaux
    • Pessac, Bordeaux, France
      • Recruiting
      • Hopital Du Haut-Leveque
      • Contact: Alexandre OUATTARA

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Acute cardiogenic shock patient refractory to conventional therapy placed on VA-ECMO support in the preceding 48h.

   (The rationale for the early use of levosimendan after VA-ECMO initiation appears strong in patients with refractory cardiogenic shock related to conditions such as acute myocardial infarction, myocarditis, post-cardiac surgery or post-cardiac arrest. Myocardial injuries in these situations share many common pathophysiological features, including ischemia, inflammation and increased oxidative stress leading to extensive myocardial stunning and dysfunction [26-28]. Besides its inotropic properties that might quickly improve myocardial contractility, levosimendan might also exert beneficial antiinflammatory, antioxidative, antiapoptotic, cardioprotective and anti-stunning effects [29-35] that might accelerate cardiac recovery allowing earlier weaning from the support).

2. Obtain informed consent from a close relative or surrogate. According to the specifications of emergency consent, randomization without the close relative or surrogate consent could be performed.

Close relative/surrogate/family consent will be asked as soon as possible. The patient will be asked to give his/her consent for the continuation of the trial when his/her condition will allow.

Exclusion Criteria:

1. Age <18
2. Pregnant or lactating womency
3. Initiation of ECMO >48 h
4. Resuscitation >30 minutes before ECMO
5. Irreversible neurological pathology
6. End-stage cardiomyopathy with no hope of LV function recovery
7. Mechanical complication of myocardial infarction
8. Aortic regurgitation > II
9. VA-ECMO for pulmonary embolism
10. VA-ECMO for cardiotoxic drug intoxication
11. VA-ECMO after left-ventricle assist device implantation
12. VA-ECMO in heart transplant patients
13. Patient moribund on the day of randomization, SAPS II >90
14. Liver cirrhosis (Child B or C) and other severe hepatic insufficiency
15. Chronic renal failure requiring hemodialysis
16. Known hypersensitivity to levosimendan
17. Prior history of "torsades de pointes"
18. History of epilepsy
19. Individuals under guardianship, or permanently legally incompetent adults
20. Participation to another interventional study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Levosimendan; A continuous infusion of Levosimendan will be administered over 24 h, with no initial bolus. The starting infusion rate will be 0.15 µg/kg/min and will be increased to 0.20 µg/kg/min after 2 hours in the absence of rate-limiting side effects	Drug: Levosimendan; A continuous infusion of Levosimendan over 24h
Placebo Comparator: Placebo; A continuous infusion of Placebo will be administered over 24 h, with no initial bolus. The starting infusion rate will be 0.15 µg/kg/min and will be increased to 0.20 µg/kg/min after 2 hours in the absence of rate-limiting side effects	Drug: Placebo of Levosimendan; A continuous infusion of Placebo of Levosimendan over 24h

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Time to successful ECMO weaning within the 30 days following randomization	Day 30

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality		Day 30, Day 60
Total duration of ECMO support		Between inclusion and Day 30/Day 60
Number of ECMO-free days		Between inclusion and Day 30/Day 60
Duration of ICU stay		Between inclusion and Day 60
Duration of hospitalization stay		Between inclusion and Day 60
Major adverse cardiovascular events	defined as death, cardiac transplant, escalation to permanent left ventricular assist device, stroke, dialysis, re-hospitalization for heart failure	Day 30, Day 60
Time to improvement in hemodynamic parameters		Between inclusion and Day 60
Time to hemodynamic stabilization		Between inclusion and Day 60
Days with organ failure asessed by sequential organ failure assessment		Between inclusion and Day 30
Duration of hemodynamic support with catecholamines		Between inclusion and Day 30/Day 60
Number of days alive without hemodynamic support		Between inclusion and Day 30/Day 60
Duration of mechanical ventilation		Between inclusion and Day 30/Day 60
Number of days alive without mechanical ventilation		Between inclusion and Day 30/Day 60
Left ventricular function assessed with echocardiography		Day 30
Incidence of adverse drug reactions		Between inclusion and Day 60

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): August 27, 2021
• Primary Completion (Estimated): August 1, 2024
• Study Completion (Estimated): November 1, 2024

Study Registration Dates

• First Submitted: January 12, 2021
• First Submitted That Met QC Criteria: January 24, 2021
• First Posted (Actual): January 28, 2021

Study Record Updates

• Last Update Posted (Actual): November 27, 2023
• Last Update Submitted That Met QC Criteria: November 23, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: LEVOSIMENDAN
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Myocardial Infarction; Infarction; Shock; Shock, Cardiogenic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Protective Agents; Cardiotonic Agents; Phosphodiesterase Inhibitors; Phosphodiesterase 3 Inhibitors; Simendan
• Other Study ID Numbers: P170914J; 2019-004319-29 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No