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Meta-Analysis
. 2018 Jan 29;1(1):CD009669.
doi: 10.1002/14651858.CD009669.pub3.

Inotropic agents and vasodilator strategies for the treatment of cardiogenic shock or low cardiac output syndrome

Julia Schumann  1 , Eva C Henrich, Hellen Strobl, Roland Prondzinsky, Sophie Weiche, Holger Thiele, Karl Werdan, Stefan Frantz, Susanne Unverzagt
Affiliations
Meta-Analysis

Inotropic agents and vasodilator strategies for the treatment of cardiogenic shock or low cardiac output syndrome

Julia Schumann et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: Cardiogenic shock (CS) and low cardiac output syndrome (LCOS) as complications of acute myocardial infarction (AMI), heart failure (HF) or cardiac surgery are life-threatening conditions. While there is a broad body of evidence for the treatment of people with acute coronary syndrome under stable haemodynamic conditions, the treatment strategies for people who become haemodynamically unstable or develop CS remain less clear. We have therefore summarised here the evidence on the treatment of people with CS or LCOS with different inotropic agents and vasodilative drugs. This is the first update of a Cochrane review originally published in 2014.

Objectives: To assess efficacy and safety of cardiac care with positive inotropic agents and vasodilator strategies in people with CS or LCOS due to AMI, HF or cardiac surgery.

Search methods: We searched CENTRAL, MEDLINE, Embase and CPCI-S Web of Science in June 2017. We also searched four registers of ongoing trials and scanned reference lists and contacted experts in the field to obtain further information. No language restrictions were applied.

Selection criteria: Randomised controlled trials in people with myocardial infarction, heart failure or cardiac surgery complicated by cardiogenic shock or LCOS.

Data collection and analysis: We used standard methodological procedures expected by Cochrane.

Main results: We identified 13 eligible studies with 2001 participants (mean or median age range 58 to 73 years) and two ongoing studies. We categorised studies into eight comparisons, all against cardiac care and additional other active drugs or placebo. These comparisons investigated the efficacy of levosimendan versus dobutamine, enoximone or placebo, epinephrine versus norepinephrine-dobutamine, amrinone versus dobutamine, dopexamine versus dopamine, enoximone versus dopamine and nitric oxide versus placebo.All trials were published in peer-reviewed journals, and analysis was done by the intention-to-treat (ITT) principle. Twelve of 13 trials were small with few included participants. Acknowledgement of funding by the pharmaceutical industry or missing conflict of interest statements emerged in five of 13 trials. In general, confidence in the results of analysed studies was reduced due to serious study limitations, very serious imprecision or indirectness. Domains of concern, which show a high risk of more than 50%, include performance bias (blinding of participants and personnel) and bias affecting the quality of evidence on adverse events.Levosimendan may reduce short-term mortality compared to a therapy with dobutamine (RR 0.60, 95% CI 0.37 to 0.95; 6 studies; 1776 participants; low-quality evidence; NNT: 16 (patients with moderate risk), NNT: 5 (patients with CS)). This initial short-term survival benefit with levosimendan vs. dobutamine is not confirmed on long-term follow up. There is uncertainty (due to lack of statistical power) as to the effect of levosimendan compared to therapy with placebo (RR 0.48, 95% CI 0.12 to 1.94; 2 studies; 55 participants, very low-quality evidence) or enoximone (RR 0.50, 95% CI 0.22 to 1.14; 1 study; 32 participants, very low-quality evidence).All comparisons comparing other positive inotropic, inodilative or vasodilative drugs presented uncertainty on their effect on short-term mortality with very low-quality evidence and based on only one RCT. These single studies compared epinephrine with norepinephrine-dobutamine (RR 1.25, 95% CI 0.41 to 3.77; 30 participants), amrinone with dobutamine (RR 0.33, 95% CI 0.04 to 2.85; 30 participants), dopexamine with dopamine (no in-hospital deaths from 70 participants), enoximone with dobutamine (two deaths from 40 participants) and nitric oxide with placebo (one death from three participants).

Authors' conclusions: Apart from low quality of evidence data suggesting a short-term mortality benefit of levosimendan compared with dobutamine, at present there are no robust and convincing data to support a distinct inotropic or vasodilator drug-based therapy as a superior solution to reduce mortality in haemodynamically unstable people with cardiogenic shock or LCOS.Considering the limited evidence derived from the present data due to a generally high risk of bias and imprecision, it should be emphasised that there remains a great need for large, well-designed randomised trials on this topic to close the gap between daily practice in critical care medicine and the available evidence. It seems to be useful to apply the concept of 'early goal-directed therapy' in cardiogenic shock and LCOS with early haemodynamic stabilisation within predefined timelines. Future clinical trials should therefore investigate whether such a therapeutic concept would influence survival rates much more than looking for the 'best' drug for haemodynamic support.

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Conflict of interest statement

Julia Schumann: no relevant conflicts of interests Eva Henrich: no relevant conflicts of interests Hellen Strobl: no relevant conflicts of interests Roland Prondzinsky: no relevant conflicts of interests Sophie Weiche: no relevant conflicts of interests Holger Thiele has received research funding (Maquet Cardiovascular, Teleflex Medical, Terumo, Lilly Germany, The Medicines Company), honoraria for advisory board activities (Lilly, Maquet Cardiovascular), honoraria for lectures (AstraZeneca, Lilly, Daiichi Sankyo, The Medicines Company, Terumo, Maquet Cardiovascular, Bayer, Boehringer Ingelheim). Karl Werdan has received honoraria for lectures (Abbott, Biogen, Biotest, Boston scientific, Brahms, Datascope, Maquet, Novartis, Roche, Servier), honoraria for advisory board activities (Abbott, Baxter, Biotest, Datascope, Servier), took part in clinical trials (Arrows, Datascope, MSD, Novartis, Servier) and has received research funding from Biotest, Bayer, Datascope, Novartis Roche, Servier. Stefan Frantz has received research funding (Charite Berlin, Covance Inc 210 Carnegie Center Princeton, Janssen‐Cilag GmbH, Mapi Life Sciences (Germany) GmbH, Medtronic Bakken Research Center, NOVARTIS PHARMA GMBH, Bayer, Boehringer, BMS, Astra), received honoraria for lectures (AMGEN Europe, AstraZeneca, Assistenz, Bayer Vital, Boehringer Ingelheim, Bristol‐Meyers Squibb GmbH, Daiichi Sankyo, Messe Düsseldorf, MSD, Novartis, ORGASYMPOSIA, Pfizer, Servier) and honoraria for advisory board activities (Bayer, Boehringer, MSD, Pfizer). Susanne Unverzagt: no relevant conflicts of interests.

Figures

1
1
Study flow diagram
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
1.1
1.1. Analysis
Comparison 1 Levosimendan versus control, Outcome 1 All‐cause short‐term mortality.
1.2
1.2. Analysis
Comparison 1 Levosimendan versus control, Outcome 2 All‐cause short‐term mortality: subgroup analysis.
1.3
1.3. Analysis
Comparison 1 Levosimendan versus control, Outcome 3 All‐cause long‐term mortality.
1.4
1.4. Analysis
Comparison 1 Levosimendan versus control, Outcome 4 All‐cause long‐term mortality:subgroup analysis.
1.5
1.5. Analysis
Comparison 1 Levosimendan versus control, Outcome 5 Cardiac index.
1.6
1.6. Analysis
Comparison 1 Levosimendan versus control, Outcome 6 Pulmonary capillary wedge pressure.
1.7
1.7. Analysis
Comparison 1 Levosimendan versus control, Outcome 7 Mean arterial pressure.
2.1
2.1. Analysis
Comparison 2 Levosimendan versus control: sensitivity analyses, Outcome 1 All‐cause short‐term mortality: fixed‐effect model.
2.2
2.2. Analysis
Comparison 2 Levosimendan versus control: sensitivity analyses, Outcome 2 All‐cause short‐term mortality: low risk of bias.
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Update of

Comment in

References

References to studies included in this review

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References to ongoing studies

NCT02767024 {published data only}
    1. NCT02767024. Effect of levosimendan on the short‐term clinical course of patients with acutely decompensated heart failure. clinicaltrials.gov/ct2/show/NCT02767024 (first received 28 July 2017).
NCT03207165 {published data only}
    1. NCT03207165. Milrinone versus dobutamine in critically Ill patients. clinicaltrials.gov/ct2/show/NCT03207165 (first received 28 July 2017).

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References to other published versions of this review

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