Elsevier

Journal of Clinical Anesthesia

Volume 52, February 2019, Pages 37-47
Journal of Clinical Anesthesia

Levosimendan use in patients with preoperative low ejection fraction undergoing cardiac surgery: A systematic review with meta-analysis and trial sequential analysis

https://doi.org/10.1016/j.jclinane.2018.08.019Get rights and content

Highlights

  • This meta-analysis neither support nor oppose the use of levosimendan in cardiac patients with low preoperative LVEF≤50%.

  • The level of evidence was assessed as low and the trial sequential analysis was inconclusive.

  • Therefore, multi-centre, adequately powered, randomised controlled trials are warranted.

Abstract

Objectives

Patients with preoperative low left ventricular ejection fraction (LVEF) are known to be associated with high morbidities and mortality in cardiac surgery. The primary aim of this review was to examine the clinical outcomes of levosimendan versus placebo in patients with preoperative low LVEF ≤ 50% undergoing cardiac surgery.

Data sources

MEDLINE, EMBASE, PubMed and CENTRAL were searched systematically from their inception until June 2018.

Review methods

All the randomised clinical trials (RCTs) were included.

Results

Twelve trials were eligible (n = 1867) for inclusion in the data synthesis. In comparison to the placebo cohort, the levosimendan cohort showed a significant reduction in mortality (TSA = inconclusive; ρ = 0.002; I2 = 0%; FEM: OR 0.56; 95% CI 0.39, 0.80), especially in the subgroups of preoperative severe low LVEF ≤ 30% (ρ = 0.003; OR 0.33; 95% CI 0.16, 0.69), preoperative administering of levosimendan (ρ = 0.001; OR 0.46; 95% CI 0.29, 0.74) and patients who had bolus followed by infusion of levosimendan (ρ = 0.005; OR 0.50; 95% CI 0.30, 0.81). However, the effect on mortality was not significant in the subgroup analysis of high quality trials (ρ = 0.14; OR 0.73; 95% CI 0.47, 1.12). The levosimendan cohort showed a significantly lower incidence of low-cardiac-output-syndrome (ρ < 0.001; OR 0.58; 95% CI 0.46, 0.74) and lesser need for mechanical support of cardiac assist devices (ρ = 0.02; OR 0.39; 95% CI 0.18, 0.86).

Conclusions

Given the low level of evidence and inconclusive TSA, the results of this meta-analysis neither support nor oppose the use of levosimendan in cardiac patients with preoperative low LVEF ≤ 50%. Therefore, multi-centre, adequately powered, randomised controlled trials are warranted.

PROSPERO registration

CRD42017067572.

Introduction

Preoperative low left ventricular ejection fraction (LVEF) among cardiac surgery patients was associated with higher risk of postoperative complications, namely low-cardiac-output-syndrome (LCOS), new-onset of atrial fibrillation and acute renal failure [[1], [2], [3], [4], [5], [6]]. All these complications caused longer duration of ventilation and hospitalisation, and subsequently significant costs to the healthcare system [3,4].

In a Bayesian network meta-analysis, levosimendan (Simdax, Orion) is ranked as the most likely inotrope to reduce mortality among cardiac surgery patients [7]. Unlike other inotropes, levosimendan (Simdax, Orion) is a non-catecholamine calcium sensitizer that stabilises troponin C to improve cardiac contractility without an increase in myocardial oxygen consumption [[7], [8], [9]]. It also has the properties of cardioprotection and vasodilatation that promote the haemodynamic stability of myocardium during cardiac surgery [[9], [10], [11]]. All these beneficial effects of levosimendan were well-supported by multiple systematic reviews based on the meta-analytic data from small studies [[12], [13], [14], [15], [16], [17], [18]]. However, three recent major randomised controlled trials (RCTs)-CHEETAH [19], LEVO-CTS [20], LICORN [21] reported no significant difference in mortality among adult patients undergoing cardiac surgery.

To date, after the publication of three major RCTs, eleven meta-analyses [[22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32]] with different inclusion criteria were synthesised to investigate the role of levosimendan in cardiac surgery. Most of them used a non-standardized threshold to define low LVEF (<35% [31], ≤40% [22,23,28,30] or <50% [25,32]). Thus, some of the studies that had the inclusion criteria of preoperative LVEF <50% were excluded from those reviews [[33], [34], [35], [36], [37]]. All the reviews were updated before December 2017 and some meta-analyses did not include the LICORN trial [25,30,31]. Thus, the efficacy and safety profile of levosimendan in improving the outcomes of cardiac surgery among patients with low preoperative LVEF (≤50%) remained unclear.

The primary aim of this review was to examine whether levosimendan affects the mortality among adult cardiac patients with low preoperative LVEF (≤50%). Secondary aims were to investigate the role of levosimendan in minimising the postoperative complications, namely author-defined LCOS, new-onset atrial fibrillation and acute renal failure.

Section snippets

Methods

This meta-analysis was conducted and reported in accordance with the ‘Preferred Reporting Items for Systematic Review and Meta-analysis’ (PRISMA) statement 2015 [38]. The review protocol was registered on PROSPERO (www.crd.york.ac.uk; PROSPERO ID-CRD42017067572). The research questions were formulated using a population (preoperative low LEVF ≤ 50% patients undergoing cardiac surgery), intervention (levosimendan), placebo and outcomes approach.

Results

The results of the literature search and study selection process are outlined in the PRISMA flow chart (Fig. 1). The titles and abstracts of 1477 non-duplicate articles were screened. Of these, 41 articles were retrieved. After applying the inclusion and exclusion criteria, twelve RCTs with a total of 1867 subjects were included in this review. Details of the excluded studies are outlined in eTable 2.

Discussion

This meta-analysis suggested that levosimendan was associated with a significant reduction in mortality (overall), especially in the subgroups of patients with severe low preoperative LVEF ≤30%, who were administered levosimendan preoperatively, and among patients who received bolus followed by infusion of levosimendan. Our TSA showed that it was still premature to draw firm conclusion from this meta-analysis as it was based on inadequate data.

Our findings corresponded with the other four

Conflict of interest and source of funding

All authors have declared that they do not have any conflicts of interest in this review. No funding was received in support of this project.

Authors' contributions

  • KN: Protocol/project management, data collection or management, data analysis, manuscript writing/editing

  • XC: Protocol/project management, manuscript writing/editing

  • WT: Protocol/project management, manuscript writing/editing

  • CW: Data collection or management, manuscript writing/editing.

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    This project was presented in part as an oral presentation at the 5th SG-ANZICS Asia Pacific Intensive Care Forum 2018 on 19th May 2018 (Suntec Convention Centre, Singapore).

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