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Effects of levosimendan for low cardiac output syndrome in critically ill patients: systematic review with meta-analysis and trial sequential analysis

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Abstract

Purpose

To assess the benefits and harms of levosimendan for low cardiac output syndrome in critically ill patients.

Methods

We conducted a systematic review with meta-analyses and trial sequential analyses (TSA) of randomised clinical trials comparing levosimendan with any type of control. Two reviewers independently assessed studies for inclusion. The Cochrane Collaboration methodology was used. Random-effects risk ratios (RR) and 95 % confidence intervals (CI) were derived for the principal primary outcome mortality at maximal follow-up.

Results

A total of 88 trials were included in the systematic review and 49 trials (6,688 patients) in the meta-analysis. One trial had low risk of bias and nine trials (2,490 patients) were considered lower risk of bias. Trials compared levosimendan with placebo, control interventions, and other inotropes. Pooling all trials including heterogenous populations was considered inappropriate. Pooled analysis of 30 trials including critically ill patients not having cardiac surgery showed an association between levosimendan and mortality (RR 0.83, TSA-adjusted 95 % CI 0.59–0.97), while trials with lower risk of bias showed no significant difference (RR 0.83, TSA-adjusted 95 % CI 0.48–1.55). Conventional meta-analysis of all 14 trials including cardiac surgery patients showed an association, while lower risk of bias trials showed no association between levosimendan and mortality (RR 0.52, 95 % CI 0.37–0.73 versus RR 1.02, 95 % CI 0.48–2.16).

Conclusions

The available evidence is inconclusive whether or not levosimendan may have a beneficial effect on mortality due to risks of systematic errors and random errors. Further well-designed randomised trials are needed.

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Abbreviations

DIS:

Diversity adjusted required information size

GRADE:

Grading of Recommendations Assessment, Development and Evaluation

ICU:

Intensive care unit

LVEF:

Left ventricular ejection fraction

MI:

Myocardial infarction

SAE:

Serious adverse events

SVT:

Supraventricular tachyarrhythmia

VT:

Ventricular tachyarrhythmia

TSA:

Trial sequential analysis

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Acknowledgment

We thank Sarah Louise Klingenberg, trials search coordinator at the Copenhagen Trial Unit for her assistance with the search strategy.

Conflicts of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Critical Care, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands

    Geert Koster, Jan G. Zijlstra, Iwan C. C. van der Horst & Frederik Keus

  2. The Copenhagen Trial Unit (CTU), Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, 2100, Copenhagen, Denmark

    Jørn Wetterslev & Christian Gluud

  3. Department of Anaesthesiology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands

    Thomas W. L. Scheeren

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  1. Geert Koster
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  2. Jørn Wetterslev
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  3. Christian Gluud
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  4. Jan G. Zijlstra
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  5. Thomas W. L. Scheeren
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  6. Iwan C. C. van der Horst
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  7. Frederik Keus
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Corresponding author

Correspondence to Geert Koster.

Additional information

Take-home message:

The available evidence is inconclusive whether or not levosimendan may have a beneficial effect on mortality in critically ill patients with low cardiac output syndrome.

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Koster, G., Wetterslev, J., Gluud, C. et al. Effects of levosimendan for low cardiac output syndrome in critically ill patients: systematic review with meta-analysis and trial sequential analysis. Intensive Care Med 41, 203–221 (2015). https://doi.org/10.1007/s00134-014-3604-1

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