Highlight
– The LEVOECMO randomized, double‑blind trial (n=205) found no reduction in time to successful VA‑ECMO weaning with early levosimendan versus placebo.
– Successful weaning at 30 days occurred in 68.3% of patients in both groups; subdistribution hazard ratio 1.02 (95% CI, 0.74–1.39; P = .92).
– Secondary outcomes including ECMO duration, ICU length of stay, and 60‑day mortality were similar; ventricular arrhythmias were more frequent with levosimendan.
Background
Cardiogenic shock remains a leading cause of mortality in patients with acute myocardial injury, high‑risk postcardiotomy states, and fulminant myocarditis. Venoarterial extracorporeal membrane oxygenation (VA‑ECMO) provides short‑term circulatory and respiratory support for patients with potentially reversible causes of circulatory collapse, serving as a bridge to recovery, decision, or definitive therapy. Timely weaning from VA‑ECMO is important to mitigate complications of extracorporeal support (bleeding, thrombosis, infection, limb ischemia) and to shorten ICU length of stay.
Levosimendan is a calcium‑sensitizing inodilator that increases myocardial contractility without substantially increasing intracellular calcium, and it also has vasodilatory effects via opening ATP‑sensitive potassium channels. It has a long‑acting active metabolite, which has prompted interest in its use to facilitate recovery of cardiac function and reduce dependence on mechanical circulatory support. Observational studies and small randomized trials in various settings have suggested potential benefits of levosimendan on haemodynamics and weaning from mechanical circulatory support, but robust randomized evidence in patients on VA‑ECMO has been lacking.
Study design
The LEVOECMO trial was a randomized, double‑blind, placebo‑controlled study conducted across 11 intensive care units in France between August 27, 2021 and September 10, 2024. The trial enrolled 205 adult patients with acute cardiogenic shock who had received VA‑ECMO within the preceding 48 hours and whose condition was judged potentially reversible. Participants were randomized 1:1 to receive either continuous infusion of levosimendan (starting at 0.15 μg/kg/min and increased to 0.20 μg/kg/min after 2 hours) or matching placebo. The infusion protocol was followed in the vast majority of patients: dosing was increased to ~0.20 μg/kg/min in 93% of the levosimendan arm and 96% of the placebo arm (blinding preserved).
The primary endpoint was time to successful ECMO weaning within 30 days after randomization. Successful weaning was defined per trial protocol (sustained removal of extracorporeal support without ongoing need for ECMO). Key secondary endpoints 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. Final follow‑up was completed on November 10, 2024. The trial was prospectively registered (ClinicalTrials.gov NCT04728932).
Key findings
Baseline characteristics: Among 205 randomized patients (median age 58 years, interquartile range [IQR] 50–67; 72.7% male), leading causes of cardiogenic shock were postcardiotomy (38.5%), acute myocardial infarction (27.3%), and myocarditis (13.7%). The population reflects a heterogeneous mix of etiologies commonly encountered in tertiary ECMO centers.
Primary outcome
Within 30 days, successful ECMO weaning occurred in 69 of 101 patients (68.3%) assigned to levosimendan and 71 of 104 patients (68.3%) assigned to placebo. The absolute risk difference was 0.0% (95% CI, −12.8% to 12.7%). The subdistribution hazard ratio for time to successful weaning was 1.02 (95% CI, 0.74–1.39; P = .92), indicating no evidence of a treatment effect on the primary endpoint.
Secondary and other clinical outcomes
ECMO duration: Median ECMO duration was similar between groups—levosimendan 5 days (IQR 4–7) versus placebo 6 days (IQR 4–11); P = .53.
ICU length of stay: Mean ICU stay was 18 days (SD 15) for levosimendan versus 19 days (SD 15) for placebo (P = .42).
Mortality: All‑cause 60‑day mortality did not differ significantly—27.7% in the levosimendan group versus 25.0% in placebo (risk difference 2.7%; 95% CI, −9.0% to 15.3%; P = .78).
Safety and adverse events
Overall serious adverse events were reported, but a notable safety signal was an increased incidence of ventricular arrhythmias with levosimendan: 18 events (17.8%) versus 9 events (8.7%) in the placebo group, for an absolute risk difference of 9.2% (95% CI, 0.4%–18.1%). This imbalance warrants attention given the proarrhythmic potential in a population already at high arrhythmic risk (ischemia, myocarditis, postcardiotomy electrical instability).
Interpretation
The LEVOECMO trial provides high‑quality randomized evidence that routine early administration of levosimendan in patients with severe but potentially reversible cardiogenic shock supported with VA‑ECMO does not shorten time to successful weaning within 30 days compared with placebo. The magnitude and precision of the trial estimates indicate that any clinically meaningful benefit on ECMO weaning is unlikely in an unselected population similar to the trial cohort.
Secondary outcomes and mortality data aligned with the primary finding, with no demonstrable benefit on ICU length of stay or 60‑day survival. The observed increase in ventricular arrhythmias with levosimendan raises safety concerns that counterbalance any theoretical advantage from inotropic support, particularly since levosimendan was intended as an agent that could augment contractility without increasing intracellular calcium and catecholamine exposure.
Expert commentary and context
Strengths of LEVOECMO include randomized, double‑blind design, multicenter conduct across high‑volume ICU settings, early intervention timing (within 48 hours of ECMO initiation), and high protocol adherence. These design elements reduce bias and increase confidence in the negative result.
Important limitations and considerations for interpretation: the enrolled population was heterogeneous with multiple etiologies (postcardiotomy, acute MI, myocarditis). It is plausible that subgroups with distinct pathophysiology (for example, fulminant myocarditis with reversible myocyte dysfunction) may respond differently to inodilators, but the trial was not powered for reliable subgroup inference. The dosing regimen chosen (continuous infusion without bolus and titration to 0.20 μg/kg/min) reflects common clinical practice but may differ from protocols used in smaller prior reports.
Prior observational studies and nonrandomized data suggested potential benefits of levosimendan for ECMO weaning, but these were subject to confounding by indication and selection bias. LEVOECMO, as a large randomized trial, therefore provides the most robust evidence to date. Given the neutral primary outcome and the arrhythmia signal, routine use of levosimendan for all patients on VA‑ECMO aiming to facilitate early weaning is not supported.
Clinical implications
For clinicians managing patients on VA‑ECMO, LEVOECMO suggests that levosimendan should not be used routinely as a strategy to accelerate ECMO liberation in an unselected population. Individualized use may still be reasonable in specific clinical contexts where potential benefits might outweigh risks (for example, selected myocarditis cases or where other inotropic strategies are contraindicated), but such approaches should be considered experimental and used with careful monitoring for arrhythmias.
Management of ECMO weaning should continue to rely on meticulous clinical assessment, serial echocardiography and hemodynamic evaluation, optimized preload and afterload management, and targeted use of standard inotropes and vasopressors as guided by physiology and patient‑specific factors. Adjunctive measures and protocols to reduce ECMO complications and to standardize weaning may deliver more impact than routine addition of levosimendan.
Research implications and unanswered questions
Key future research directions include: identifying biologically plausible subgroups who might derive net benefit (for example, patients with isolated contractile depression without ischemia), exploring timing and dosing strategies (including bolus strategies or earlier pre‑ECMO administration), and mechanistic studies linking levosimendan pharmacodynamics to myocardial recovery during extracorporeal support. Trials sufficiently powered to detect mortality differences or powered for prespecified subgroups would be needed before changing practice for selected populations.
Conclusion
The LEVOECMO trial demonstrates that early levosimendan infusion does not reduce time to successful VA‑ECMO weaning nor improve short‑term survival in a heterogeneous cohort of patients with severe but potentially reversible cardiogenic shock. The increased incidence of ventricular arrhythmias observed with levosimendan underscores a potential safety concern. Routine use of levosimendan for ECMO weaning is not supported by current randomized evidence; further targeted research may clarify whether specific subgroups could benefit.
Funding and clinical trial registration
Trial registration: ClinicalTrials.gov Identifier NCT04728932. Details of trial funding are provided in the published report.
Reference
Combes A, Saura O, Nesseler N, Lebbah S, Rozec B, Levy B, Fellahi JL, Beurton A, Meslin S, Gaudard P, Bouglé A, Vincentelli A, Sonneville R, Lebreton G, Lévy D, Ouattara A, Tubach F; LEVOECMO Trial Group and the International ECMO Network (ECMONet). Levosimendan to Facilitate Weaning From ECMO in Patients With Severe Cardiogenic Shock: The LEVOECMO Randomized Clinical Trial. JAMA. 2025 Dec 1:e2519843. doi: 10.1001/jama.2025.19843. Epub ahead of print. PMID: 41324946; PMCID: PMC12670262.