Effect of levosimendan on prognosis in adult patients undergoing cardiac surgery: a meta-analysis of randomized controlled trials

Abstract

Background: Small trials suggest that levosimendan is associated with a favorable outcome in patients undergoing cardiac surgery. However, recently published larger-scale trials did not provide evidence for a similar benefit from levosimendan. We performed a meta-analysis to assess the survival benefits of levosimendan in patients undergoing cardiac surgery and to investigate its effects in subgroups of patients with preoperative low-ejection fraction (EF).

Methods: We identified randomized clinical trials through 20 April 2017 that investigated levosimendan therapy versus control in patients undergoing cardiac surgery. Individual patient data from each study were compiled. Meta-analyses were performed for primary outcomes, secondary outcomes and serious adverse events, and subgroup analyses according to the preoperative EF of enrolled patients were also conducted. The risk of bias was assessed using the Cochrane risk-of-bias tool.

Results: Seventeen studies involving a total of 2756 patients were included. Levosimendan therapy was associated with a significant reduction in 30-day mortality (RR 0.67; 95% CI, 0.49 to 0.93; p = 0.02) and reduced the risk of death in single-center trials (RR 0.49; 95% CI, 0.30 to 0.79; p = 0.004) and in subgroup trials of inferior quality (RR 0.39; 95% CI, 0.17 to 0.92; p = 0.02); however, in multicenter and in high-quality subgroup-analysis trials, no significant difference in mortality was observed between patients who received levosimendan therapy and controls (p > 0.05). However, in high-quality subgroup trials, levosimendan therapy was associated with reduced mortality in patients in a preoperative low-EF subgroup (RR 0.58; 95% CI, 0.38 to 0.88; p = 0.01). Similarly, only patients in the preoperative low-EF subgroup benefited in terms of reduced risk of renal replacement therapy (RR 0.54; 95% CI, 0.34 to 0.85; p = 0.007). Furthermore, levosimendan therapy was associated with a significant reduction in intensive care unit (ICU) length of stay (MDR -17.19; 95% CI, -34.43 to -2.94; p = 0.02).

Conclusions: In patients undergoing cardiac surgery, the benefit of levosimendan in terms of survival was not shown in multicenter or in high-quality trials; however, levosimendan therapy was associated with reduced mortality in patients with preoperative ventricular systolic dysfunction.

Keywords: Cardiac surgery; Levosimendan; Meta-analyses; Mortality.

Fig. 1

Flow diagram of the identified trials

Fig. 2

Risk of bias summary. Review of authors’ judgments about each risk-of-bias item for each included study. Red, high risk; green, low risk; blank, unclear

Fig. 3

Trial sequential analysis (TSA) for mortality in randomized controlled trials: one-sided boundary, incidence of 8.59% in the control arm, incidence of 5.99% in the treatment arm, low-bias estimated relative-risk reduction of 80%, α of 5%, and power of 80% were set. There is an estimated required information sample size of 2739 randomized patients, which was not achieved. The boundaries for futility are crossed

Fig. 4

The funnel plot for mortality demonstrates there is no publication bias

Fig. 5

The effect of levosimendan therapy on postoperative mortality in patients undergoing cardiac surgery. M-H, Mantel-Haenszel

Fig. 6

A subgroup meta-analysis of the effect of levosimendan therapy on postoperative mortality according to the single-center or multicenter nature of the trials. M-H, Mantel-Haenszel

Fig. 7

A subgroup meta-analysis of the effect of levosimendan therapy on postoperative mortality according to trial quality. M-H, Mantel-Haenszel

Fig. 8

A subgroup meta-analysis of the effect of levosimendan therapy on postoperative mortality according to preoperative ejection fraction (EF). M-H, Mantel-Haenszel