LEVOSIMENDAN to Facilitate Weaning From ECMO in Severe Cardiogenic Shock Patients

Cardiogenic Shock Clinical Trial

— LEVOECMO  

Official title:

LEVOSIMENDAN to Facilitate Weaning From ECMO in Severe Cardiogenic Shock Patients

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04728932
• Other study ID #: P170914J
• Secondary ID: 2019-004319-29
• Status: Recruiting
• Phase: Phase 3
• Start date: August 27, 2021
• Est. completion date: November 2024

Study information

• Verified date: November 2023
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Alain COMBES, MD
• Phone: +33142163818
• Email: alain.combes[@]aphp.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 206
• Est. completion date: November 2024
• Est. primary completion date: August 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Cardiogenic Shock
• Extracorporeal Membrane Oxygenation Complication
• Shock
• Shock, Cardiogenic

Intervention

Drug:
• Levosimendan
A continuous infusion of Levosimendan over 24h
• Placebo of Levosimendan
A continuous infusion of Placebo of Levosimendan over 24h

Locations

Country	Name	City	State
France	Hôpital Européen Georges Pompidou	Paris
France	Hôpital Pitié Salpêtrière	Paris
France	Hôpital du Haut-Lévêque	Pessac	Bordeaux

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to successful ECMO weaning within the 30 days following randomization		Day 30
Secondary	Mortality		Day 30, Day 60
Secondary	Total duration of ECMO support		Between inclusion and Day 30/Day 60
Secondary	Number of ECMO-free days		Between inclusion and Day 30/Day 60
Secondary	Duration of ICU stay		Between inclusion and Day 60
Secondary	Duration of hospitalization stay		Between inclusion and Day 60
Secondary	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
Secondary	Time to improvement in hemodynamic parameters		Between inclusion and Day 60
Secondary	Time to hemodynamic stabilization		Between inclusion and Day 60
Secondary	Days with organ failure asessed by sequential organ failure assessment		Between inclusion and Day 30
Secondary	Duration of hemodynamic support with catecholamines		Between inclusion and Day 30/Day 60
Secondary	Number of days alive without hemodynamic support		Between inclusion and Day 30/Day 60
Secondary	Duration of mechanical ventilation		Between inclusion and Day 30/Day 60
Secondary	Number of days alive without mechanical ventilation		Between inclusion and Day 30/Day 60
Secondary	Left ventricular function assessed with echocardiography		Day 30
Secondary	Incidence of adverse drug reactions		Between inclusion and Day 60