The Efficacy and Safety of Levosimendan in Patients with Advanced Heart Failure: An Updated Meta-Analysis of Randomized Controlled Trials

Abstract

Background: Intermittent ambulatory levosimendan administration has been shown in several small randomized controlled trials to benefit patients with advanced heart failure, preventing heart failure rehospitalization and mortality. We aim to investigate the totality of high-quality evidence regarding the efficacy and safety of intermittent levosimendan in advanced heart failure patients.

Methods: Up to September 2023, we systematically reviewed the randomized controlled trials indexed in PubMed, Embase Cochrane, SCOPUS, and Web of Science. We used mean difference (MD) to estimate the continuous outcomes, and risk ratio (RR) for the dichotomous outcomes with a 95% confidence interval (CI), using the random-effects model. Ultimately, a trial sequential analysis was employed to enhance the reliability of our findings and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework for certainty leveling.

Results: Fifteen randomized controlled trials with 1181 patients were included. Intermittent levosimendan was significantly associated with an improved left ventricular ejection fraction compared with placebo (MD 6.39 [95% CI 3.04-9.73], P = 0.002; I² = 75, P = 0.0005), with cumulative z-score of change after ≤ 1 week passing the monitoring boundaries, favoring the levosimendan, but did not cross the required information size. Additionally, levosimendan reduced the all-cause mortality rate (RR 0.60 [95% CI 0.40-0.90], P = 0.01; I² = 9, P = 0.36). However, we found no difference between levosimendan and placebo in all-cause rehospitalization rate (RR 0.75 [95% CI 0.46-1.22], P = 0.25; I² = 70, P = 0.04), event-free survival rate (RR 0.97 [95% CI 0.72-1.30], P = 0.84; I² = 63, P = 0.03), or any adverse event (RR 1 [95% CI 0.73-1.37], P = 1.00, I² = 0%, P = 0.70).

Conclusion: In patients with advanced heart failure, intermittent levosimendan significantly improved left ventricular ejection fraction, brain natriuretic peptide values, and all-cause mortality rate. Levosimendan use is not associated with a change in rehospitalization or event-free survival.

Registration: PROSPERO identifier number (CRD42023487838).

Fig. 1

PRISMA flow chart of the screening process. PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analysis

Fig. 2

Quality assessment of risk of bias in the included trials. The upper panel presents a schematic representation of risks (low = green, unclear = yellow, and high = red) for specific types of biases of each study in the review. The lower panel presents risks (low = green, unclear = yellow, and high = red) for the subtypes of biases of the combination of studies included in this review

Fig. 3

Forest plot and TSA of LVEF change: A forest plot; B TSA LVEF change ≤ 1 week. CI confidence interval, LVEF left ventricular ejection fraction, TSA trial sequential analysis

Fig. 4

Forest plot of all-cause mortality. CI confidence interval

Fig. 5

Forest plot of secondary efficacy outcomes: A change in BNP; B event-free survival; C all-cause rehospitalization. BNP brain natriuretic peptide, CI confidence interval, Std. standardized

Fig. 6

Forest plot of safety outcomes: A any adverse events; B hypotension; C tachycardia. CI confidence interval