Importance  Levosimendan may facilitate weaning from venoarterial extracorporeal membrane oxygenation (VA-ECMO) and improve survival, but supporting evidence remains limited.

Objective  To assess whether early administration of levosimendan reduces the time to successful VA-ECMO weaning in patients with severe but potentially reversible cardiogenic shock.

Design, Setting, and Participants  Randomized, double-blind, placebo-controlled trial conducted across 11 intensive care units (ICUs) in France. Between August 27, 2021, and September 10, 2024, 205 adult patients with acute cardiogenic shock who had started VA-ECMO in the preceding 48 hours were enrolled. Final follow-up was completed on November 10, 2024.

Interventions  Patients were randomized in a 1:1 ratio to receive levosimendan, 0.15 μg/kg per minute, to be increased to 0.20 μg/kg per minute after 2 hours (n = 101), or placebo (n = 104).

Main Outcomes and Measures  The primary outcome was time to successful ECMO weaning within 30 days following randomization. Secondary outcomes included ECMO-, mechanical ventilation–, and organ failure–free days, ICU and hospital lengths of stay, serious adverse events, and all-cause 30- and 60-day mortality.

Results  Among the 205 randomized patients (median age, 58 [IQR, 50-67] years; 149 [72.7%] male), main cardiogenic shock etiologies were postcardiotomy (79 [38.5%]), acute myocardial infarction (56 [27.3%]), and myocarditis (28 [13.7%]). Treatment dose was increased to 0.20 ± 0.01 μg/kg per minute in 93% of patients receiving levosimendan and in 96% of those receiving placebo. 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 = .92). In the levosimendan and placebo groups, respectively, median ECMO duration (5 [IQR, 4-7] days vs 6 [IQR, 4-11] days; P = .53), mean ICU length of stay (18 [SD, 15] days vs 19 [SD, 15] days; P = .42), and 60-day mortality (27.7% vs 25.0%; risk difference, 2.7% [95% CI, −9.0% to 15.3%]; P = .78) did not differ significantly. Ventricular arrhythmias occurred more frequently with levosimendan (18 [17.8%] vs 9 [8.7%]; absolute risk difference, 9.2% [95% CI, 0.4%-18.1%]).

Conclusions and Relevance  Among patients with severe but potentially reversible cardiogenic shock supported by VA-ECMO, early levosimendan administration did not significantly reduce the time to successful weaning of ECMO compared with placebo.