LEVOSIMENDAN to Facilitate Weaning From ECMO in Severe Cardiogenic Shock Patients

NCT ID: NCT04728932

Last Updated: 2025-03-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 206 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-08-27
• Study Completion Date: 2024-11-09

Brief 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.

Conditions

Cardiogenic Shock; Extracorporeal Membrane Oxygenation Complication

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

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

Group Type: EXPERIMENTAL

Levosimendan

Intervention Type: DRUG

A continuous infusion of Levosimendan over 24h

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

Group Type: PLACEBO_COMPARATOR

Placebo of Levosimendan

Intervention Type: DRUG

A continuous infusion of Placebo of Levosimendan over 24h

Interventions

Levosimendan

A continuous infusion of Levosimendan over 24h

Intervention Type: DRUG

Placebo of Levosimendan

A continuous infusion of Placebo of Levosimendan over 24h

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

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

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 women

3. Initiation of VA-ECMO >48 h

4. Resuscitation >30 minutes in the 48 hours before ECMO (cumulative low-flow time). If a low-flow episode occurs before the 48 hours window prior to ECMO, patients must fully recover consciousness to be randomized.

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. 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. History of torsades de pointes in the 30 days prior to inclusion

18. History of epilepsy

19. Individuals under guardianship, or permanently legally incompetent adults

20. Participation to another interventional study

21. Patient with a weight over 180 kg

22. Known hypersensitivity to polyvitamin CERNEVIT®

23. In case of hypervitaminosis to any vitamin contained in this formulation,

24. In case of severe hypercalcemia, hypercalciuria, treatment, pathology and/or disorders leading to severe hypercalcemia and/or hypercalciuria

25. In combination with vitamin A or retinoids

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Hôpital du Haut-Lévêque

Pessac, Bordeaux, France

Hôpital Pitié Salpêtrière

Paris, , France

Hôpital Européen Georges Pompidou

Paris, , France

Countries

France

Other Identifiers

2019-004319-29

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

P170914J

Identifier Type: -

Identifier Source: org_study_id