Effect of levosimendan treatment in cardiac surgery: a network meta-analysis of randomized controlled trials

Background: The prophylactic administration of levosimendan in patients undergoing cardiac surgery remains clinically contentious, particularly regarding its efficacy and safety in improving key postoperative outcomes, such as cardiac function, renal protection, and mortality in high-risk surgical populations. Existing randomized controlled trials (RCTs) are heterogeneous in sample size, timing, and dosing of levosimendan and comparator inotropes and have yielded neutral or conflicting results for these endpoints. Moreover, prior meta-analyses have predominantly used pairwise comparisons and have not systematically compared levosimendan with all major inotropic alternatives (e.g., dobutamine, milrinone, and standard therapy) across multiple clinically relevant outcomes. As a result, the relative benefits and harms of levosimendan vs. other perioperative inotropic strategies in cardiac surgery remain unclear. To evaluate the potential benefits and risks of perioperative levosimendan therapy, we conducted a systematic network meta-analysis of available evidence. Methods: A comprehensive literature search was conducted in PubMed, Embase, the Cochrane Library, and other databases for RCTs evaluating perioperative levosimendan vs. placebo or alternative inotropic therapies, published up to 31 December 2024. Primary outcomes included cardiac index, central venous pressure (CVP), mean arterial pressure (MAP), intensive care unit (ICU) length of stay, and creatinine levels. The frequentist surface under the cumulative ranking curve (SUCRA) was calculated for each outcome to rank competing interventions. Results: A total of 29 RCTs encompassing 4,509 patients were included. Levosimendan was associated with higher postoperative CI [standardized mean difference (SMD) 1.16, 95% CI 0.04-2.29] compared with placebo and lower postoperative MAP (SMD -0.93, 95% CI -1.62 to -0.23) compared with dobutamine. Milrinone had lower CVP compared with dobutamine (SMD -0.66, 95% CI -1.22 to -0.10) and placebo (SMD -0.46, 95% CI -0.83 to -0.09), and levosimendan (SMD 0.40, 95% CI 0.05-0.75) had higher CVP compared with milrinone. Both levosimendan (SMD -0.68, 95% CI -1.13 to -0.24) and milrinone (SMD -0.71, 95% CI -1.25 to -0.17) significantly shortened ICU stays compared with dobutamine. No significant differences in creatinine levels were identified across interventions in the network meta-analysis. Conclusion: Levosimendan improved postoperative hemodynamic parameters, showing a higher cardiac index than placebo and shorter ICU stays than dobutamine, but it did not provide significant renal protection as assessed by creatinine levels. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/recorddashboard, identifier CRD42024612151.