Levosimendan Tx Fails to Boost Successful ECMO Weaning

Early administration of levosimendan to patients experiencing acute cardiogenic shock did not reduce time to successful weaning of venoarterial extracorporeal membrane oxygenation (VA-ECMO), compared to placebo, according to the multicenter, randomized, double-blind, placebo-controlled LEVOECMO trial.

"Levosimendan is an inodilator that enhances cardiac contractility by sensitizing myocardial contractile proteins to calcium without increasing intracellular calcium concentrations," Alain Combes, MD, PhD, at Sorbonne Université, INSERM, UMRS_1166-ICAN, Institute of Cardiometabolism and Nutrition and Service de Médecine Intensive-Réanimation, and the Assistance Publique-Hôpitaux de Paris, Sorbonne Université Hôpital Pitié-Salpêtrière, Paris, France, and colleagues wrote in their findings, published in JAMA.

The authors randomized 205 patients (median age, 58 [IQR, 50-67] years; 149 [72.7%] male) "with acute cardiogenic shock who had started VA-ECMO in the preceding 48 hours" 1:1 for either levosimendan, 0.15 μg/kg per minute, increased to 0.20 μg/kg per minute after 2 hours, or placebo. Weaning took place through the first 30 days after randomization, with a maximum follow-up of 60 days total to verify qualification of outcomes. The trial was conducted at 11 centers in France from 2021 to 2024.

"[The] main cardiogenic shock etiologies were postcardiotomy (79 [38.5%]), acute myocardial infarction (56 [27.3%]), and myocarditis (28 [13.7%])," the authors reported.

"The primary outcome was time to successful ECMO weaning within 30 days following randomization. ECMO weaning (ie, ECMO separation) was considered successful only if a patient was alive without ECMO, use of another mechanical circulatory support device, or heart transplant 30 days after ECMO removal," Combs and colleagues wrote.

Competing events were weaning failure (additional ECMO runs or mechanical circulatory devices, transplant or death within 30 days), and death while receiving ECMO, the authors noted.

Secondary outcomes included all-cause mortality at day 30 and 60, SOFA score (days alive without organ failure), duration of ECMO and mechanical ventilation, ventilation-free days at 30 and 60 days, left ventricular ejection fraction (LVEF) at day 30, and mean blood pressure evolution up to day 30, and serious adverse events.

The authors reported the following results:

• "Within 30 days, 69 of 101 patients (68.3%) had a successful ECMO weaning in the levosimendan group compared with 71 of 104 (68.3%) in the placebo group (risk difference, 0.0% [95% CI, −12.8% to 12.7%]; subdistribution hazard ratio, 1.02 [95% CI, 0.74-1.39]; P = 0.92).
• "In the levosimendan and placebo groups, respectively, median ECMO duration (5 [IQR, 4-7] days versus 6 [IQR, 4-11] days; P = 0.53), mean ICU length of stay (18 [SD, 15] days versus 19 [SD, 15] days; P = 0.42), and 60-day mortality (27.7% versus 25.0%; risk difference, 2.7% [95% CI, −9.0% to 15.3%]; P = 0.78) did not differ significantly.
• "Ventricular arrhythmias occurred more frequently with levosimendan (18 [17.8%] versus 9 [8.7%]; absolute risk difference, 9.2% [95% CI, 0.4%-18.1%])," wrote Combes et al.

In an invited commentary, Mark H. Drazner, MD, MSc, University of Texas Southwestern Medical Center, Dallas, Texas, explored the validity of the findings from the LEVOECMO trial, and pointed out that the sample size combined with lower than expected ECMO failure rate indicated the trial was underpowered.

"Nevertheless, the absence of any signal of benefit for the primary outcome and the consistency of the results for numerous secondary outcomes suggest a valid result," Drazner wrote.

He continued, and suggested that within countries where approval for clinical use of levosimendan is already established, weaning of VA-ECMO with the therapy should wane or stop entirely, and that clinicians should re-assess the evidence for using levosimendan for other conditions.

"There remain ongoing efforts to identify a potential role for levosimendan. Furthest along in development is a phase III RCT being conducted in the U.S. and Canada of an oral preparation of levosimendan as a therapy for pulmonary hypertension in the setting of heart failure with preserved ejection fraction," he wrote.

Additional limitations of the LEVOECMO included unknown pharmacokinetic efficacy alterations of levosimendan in adults, and unblinding of nurses during treatment reconstitution.

"These findings do not support the routine use of levosimendan to improve outcomes in this patient population," Combes and colleagues concluded.

The trial was financed by a grant from the French Ministry of Health (PHRC APHP-P170914J) and was sponsored by the Direction de la Recherche Clinique et du Développement, Assistance Publique–Hôpitaux de Paris. Orion Pharmaceuticals provided levosimendan and placebo free of charge.

Combes reported receipt of personal fees from Getinge and Baxter and grants from Getinge.

Drazner reported no conflicts of interest, and was supported by the James M. Wooten Chair in Cardiology at the University of Texas Southwestern Medical Center.

Combes A, Saura O, et al "Levosimendan to facilitate weaning from ECMO in patients with severe cardiogenic shock: The LEVOECMO randomized clinical trial" JAMA 2025; DOI: 10.1001/jama.2025.19843.

Drazner MH "Levosimendan and weaning from VA-ECMO" JAMA 2025; DOI: 10.1001/jama.2025.20299.