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

Julia Schumann; Eva C Henrich; Hellen Strobl; Roland Prondzinsky; Sophie Weiche; Holger Thiele; Karl Werdan; Stefan Frantz; Susanne Unverzagt

doi:10.1002/14651858.CD009669.pub3

Cochrane Database of Systematic Reviews

Agentes inotrópicos y estrategias vasodilatadoras para el tratamiento del shock cardiogénico o síndrome de gasto cardíaco bajo

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DOI:

https://doi.org/10.1002/14651858.CD009669.pub3 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

29 enero 2018see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Corazón

Copyright:

Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Autores

Julia Schumann

Correspondencia a: Department of Anaesthesiology and Surgical Intensive Care, Martin‐Luther‐University Halle‐Wittenberg, Halle/Saale, Germany

[email protected]
Eva C Henrich

Institute of Medical Epidemiology, Biostatistics and Informatics, Martin‐Luther‐University Halle‐Wittenberg, Halle/Saale, Germany
Hellen Strobl

Institute of Medical Epidemiology, Biostatistics and Informatics, Martin‐Luther‐University Halle‐Wittenberg, Halle/Saale, Germany
Roland Prondzinsky

Cardiology/Intensive Care Medicine, Carl von Basedow Klinikum Merseburg, Merseburg, Germany
Sophie Weiche

Department of Internal Medicine III, Martin‐Luther‐University Halle‐Wittenberg, Halle/Saale, Germany
Holger Thiele

Medical Clinic II (Kardiology, Angiology, Intensive Care Medicine), University Clinic Schleswig‐Holstein, Campus Lübeck, Lubeck, Germany
Karl Werdan

Department of Internal Medicine III, Martin‐Luther‐University Halle‐Wittenberg, Halle/Saale, Germany
Stefan Frantz

Department of Internal Medicine III, Martin‐Luther‐University Halle‐Wittenberg, Halle/Saale, Germany
Susanne Unverzagt

Institute of Medical Epidemiology, Biostatistics and Informatics, Martin‐Luther‐University Halle‐Wittenberg, Halle/Saale, Germany

Contributions of authors

Julia Schumann (contact author): co‐ordination of the review, data collection for the review (screening, appraisal of inclusion criteria and quality of papers, extracting data from papers, screening data on unpublished studies), writing the review

Eva Henrich: data collection for the review (screening, appraisal of inclusion criteria and quality of papers, extracting data from papers, screening data on unpublished studies)

Hellen Strobl: data collection for the review (screening, appraisal of inclusion criteria and quality of papers, extracting data from papers, screening data on unpublished studies)

Roland Prondzinsky: writing the protocol and conclusions, appraisal of inclusion criteria and quality of papers, interpretation of data from a clinical and consumer perspective

Sophie Weiche: data collection for the review (screening, appraisal of inclusion criteria and quality of papers, extracting data from papers, screening data on unpublished studies), providing general advice from a clinical perspective

Holger Thiele: screening data on unpublished studies, contacting authors, providing general advice from a clinical perspective

Karl Werdan: providing general advice from a clinical and a policy perspective

Stefan Frantz: appraisal of inclusion criteria and quality of papers, screening data on unpublished studies, writing the introductory part of the review, providing general advice from a clinical perspective

Susanne Unverzagt: design and co‐ordination of the review, design and organisation of the search strategy, data collection for the review (screening, appraisal of inclusion criteria and quality of papers, extracting data from papers, contacting authors, data management, methodological interpretation of data), analysis of data, writing the review

Sources of support

Internal sources

No sources of support supplied

External sources

The Cochrane Heart US Satellite is supported by intramural support from the Northwestern University Feinberg School of Medicine and the Northwestern University Clinical and Translational Science (NUCATS) Institute (UL1TR000150), USA.
This project was supported by the National Institute for Health Research, via Cochrane Infrastructure to Cochrane Heart. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health, UK.

Declarations of interest

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.

Acknowledgements

The excellent support from Cochrane Heart was very much appreciated.

We are grateful to authors of individual studies who provided information and answered our questions concerning their studies: James Baldassare and Trygve Husebye.

Version history

Published

Title

Stage

Authors

Version

2020 Nov 05

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

Review

Konstantin Uhlig, Ljupcho Efremov, Jörn Tongers, Stefan Frantz, Rafael Mikolajczyk, Daniel Sedding, Julia Schumann

https://doi.org/10.1002/14651858.CD009669.pub4

2018 Jan 29

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

Review

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

https://doi.org/10.1002/14651858.CD009669.pub3

2014 Jan 02

Inotropic agents and vasodilator strategies for acute myocardial infarction complicated by cardiogenic shock or low cardiac output syndrome

Review

Susanne Unverzagt, Lisa Wachsmuth, Katharina Hirsch, Holger Thiele, Michael Buerke, Johannes Haerting, Karl Werdan, Roland Prondzinsky

https://doi.org/10.1002/14651858.CD009669.pub2

2012 Feb 15

Inotropic agents and vasodilator strategies for acute myocardial infarction complicated by cardiogenic shock or low cardiac output syndrome

Protocol

Susanne Unverzagt, Katharina Hirsch, Michael Buerke, Holger Thiele, Johannes Haerting, Karl Werdan, Roland Prondzinsky

https://doi.org/10.1002/14651858.CD009669

Differences between protocol and review

Handsearching in the annual conference proceedings was planned from 1960 to the present but proceedings were not available in Germany for this period. Due to the first publication of eligible trials in 2003 we restricted our search to the available proceedings in Halle, Leipzig and Munich.

In the update, we expanded the review to all people with CS or LCOS. We included trials with a subgroup of eligible participants. We used the risk ratio to measure treatment effects on mortality, major adverse cardiac events (MACE) and adverse events instead of hazard ratios and odds ratios.

We searched for conference proceedings in ISI Web of Science (Conference Proceedings Citation Index‐Science, Thomson Reuters 1990 to 22 June 2017) and did no separately handsearch in the annual conference proceedings of the American Heart Association (AHA), American College of Cardiology (ACC), European Society of Cardiology (ESC), European Society of Intensive Care (ESICM) and Deutsche Gesellschaft für Kardiologie (DGK) for the years 2013 to 2016.

We excluded trials on children.

We excluded trials not reporting on the acute setting, that is, prevention trials and long‐term studies (treatment lasting one month or more).

We excluded studies that did not report on our primary outcome (all‐cause mortality). We plan to change this in future updates of this review.

We added 'Summary of findings' tables with GRADE rating.

We added adverse events as a secondary outcome.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Aged; Humans; Middle Aged;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Figure 1

Study flow diagram

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

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Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

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Analysis 1.1

Comparison 1 Levosimendan versus control, Outcome 1 All‐cause short‐term mortality.

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Analysis 1.2

Comparison 1 Levosimendan versus control, Outcome 2 All‐cause short‐term mortality: subgroup analysis.

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Analysis 1.3

Comparison 1 Levosimendan versus control, Outcome 3 All‐cause long‐term mortality.

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Analysis 1.4

Comparison 1 Levosimendan versus control, Outcome 4 All‐cause long‐term mortality:subgroup analysis.

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Analysis 1.5

Comparison 1 Levosimendan versus control, Outcome 5 Cardiac index.

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Analysis 1.6

Comparison 1 Levosimendan versus control, Outcome 6 Pulmonary capillary wedge pressure.

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Analysis 1.7

Comparison 1 Levosimendan versus control, Outcome 7 Mean arterial pressure.

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Analysis 2.1

Comparison 2 Levosimendan versus control: sensitivity analyses, Outcome 1 All‐cause short‐term mortality: fixed‐effect model.

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Analysis 2.2

Comparison 2 Levosimendan versus control: sensitivity analyses, Outcome 2 All‐cause short‐term mortality: low risk of bias.

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Summary of findings for the main comparison. Levosimendan compared to dobutamine for cardiogenic shock or low cardiac output syndrome

Levosimendan compared to dobutamine for cardiogenic shock or low cardiac output syndrome
Patient or population: people with cardiogenic shock or low cardiac output syndrome Settings: hospital Intervention: levosimendan Comparison: dobutamine
Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	No of participants (studies)	Quality	Comments
	Risk with dobutamine	Risk with levosimendan
All‐cause, short‐term mortality: range 15 days to 12 months	Moderate¹		RR 0.60 (0.37 to 0.95)	1776 (6 studies)	⊕⊕⊝⊝ low^3,4	Studies included participants with LCOS or CS due to cardiac surgery, HF or AMI
	154 per 1000	92 per 1000 (57 to 146)
	High²
	500 per 1000	300 per 1000 (185 to 475)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AMI: acute myocardial infarction; CI: confidence interval; CS: cardiogenic shock; HF: heart failure; LCOS: low cardiac output syndrome; RR: risk ratio
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Very low quality: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
¹Control group risk estimate comes from the median risk among the control group risk in included studies with participants with low cardiac output, low cardiac output or cardiogenic shock, or cardiogenic shock. ²Control group risk estimate comes from a large observational study, due to the small size of included studies in this population (Singh 2007). ³Downgraded one step due to study limitations because of lack of blinding of participants and physicians in four studies, high risk of bias due to loss to follow‐up in one study, and baseline imbalances on prognostic relevance in one study. ⁴Downgraded one step for imprecision due to few events.

Summary of findings for the main comparison. Levosimendan compared to dobutamine for cardiogenic shock or low cardiac output syndrome

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Summary of findings 2. Levosimendan compared to placebo for cardiogenic shock or low cardiac output syndrome

Levosimendan compared with placebo for cardiogenic shock or low cardiac output syndrome
Patient or population: adults with cardiogenic shock or low cardiac output syndrome Settings: hospital Intervention: levosimendan Comparison: placebo
Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	No of participants (studies)	Quality	Comments
	Risk with placebo	Risk with levosimendan
All‐cause short‐term mortality: range 4 to 6 months	Moderate¹		RR 0.48 (0.12 to 1.94)	55 (2)	⊕⊕⊝⊝ very low^3,4	Studies included participants with LCOS or CS due to HF or AMI
	187 per 1000	90 per 1000 (22 to 363)
	High²
	500 per 1000	240 per 1000 (60 to 970)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AMI: acute myocardial infarction; CI: confidence interval; CS: cardiogenic shock; HF: heart failure; LCOS: low cardiac output syndrome; RR: risk ratio
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Very low quality: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
¹Control group risk estimate comes from median risk among the control group risk in included studies with low cardiac output or cardiogenic shock. ²Control group risk estimate comes from a large observational study, due to the small size of included studies in this population (Singh 2007). ³Downgraded one step due to study limitation because of lack of blinding of participants and physicians, and missing information on randomisation in the larger study. ⁴Downgraded two steps for imprecision due to few events and the confidence interval crosses the line of no difference and includes possible benefit from both approaches.

Summary of findings 2. Levosimendan compared to placebo for cardiogenic shock or low cardiac output syndrome

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Summary of findings 3. Levosimendan compared to enoximone for cardiogenic shock

Levosimendan compared with enoximone for cardiogenic shock
Patient or population: adults with cardiogenic shock Settings: hospital Intervention: levosimendan Comparison: enoximone
Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	No of participants (studies)	Quality	Comments
	Risk with enoximone	Risk with levosimendan
All‐cause short‐term mortality: 30 days	625 per 1000¹	313 per 1000 (138 to 712)	RR 0.50 (0.22 to 1.14)	32 (1)	⊕⊝⊝⊝ very low^2,3	Study included participants with CS due to AMI
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AMI: acute myocardial infarction; CI: confidence interval; CS: cardiogenic shock; RR: risk ratio
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Very low quality: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
¹Control group risk estimate comes from the control group risk in a small included study with low cardiac output or cardiogenic shock. ²Downgraded one step for imprecision because the confidence interval crosses the line of no difference and includes possible benefit from both approaches. ³Downgraded two steps due to study limitation with lack of blinding of participants and physicians, baseline differences and stopping for early benefit in one study.

Summary of findings 3. Levosimendan compared to enoximone for cardiogenic shock

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Summary of findings 4. Epinephrine compared to norepinephrine‐dobutamine for low cardiac output syndrome

Epinephrine compared with norepinephrine‐dobutamine for low cardiac output syndrome
Patient or population: adults with low cardiac output syndrome Setting: in‐hospital Intervention: epinephrine Comparison: norepinephrine‐dobutamine
Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	No of participants (studies)	Quality	Comments
	Risk with norepinephrine‐dobutamine	Risk with epinephrine
All‐cause short‐term mortality: 28 days	267 per 1000	333 per 1000 (109 to 1000)	RR 1.25 (0.41 to 3.77)	30 (1)	⊕⊝⊝⊝ very low^1,2	Study included participants with LCOS due to HF
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; LCOS: low cardiac output syndrome; HF: heart failure; RR: risk ratio
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Very low quality: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
¹Downgraded two steps for imprecision due to few events, and the confidence interval crosses the line of no difference and includes possible benefit from both approaches. ²Downgraded one step due to study limitation, with lack of blinding of participants and physicians.

Summary of findings 4. Epinephrine compared to norepinephrine‐dobutamine for low cardiac output syndrome

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Summary of findings 5. Amrinone compared to dobutamine for low cardiac output syndrome

Amrinone compared with dobutamine for low cardiac output syndrome
Patient or population: adults with low cardiac output syndrome Setting: hospital Intervention: amrinone Comparison: dobutamine
Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	No of participants (studies)	Quality	Comments
	Risk with dobutamine	Risk with amrinone
All‐cause short‐term mortality: 30 days	200 per 1000¹	66 per 1000 (8 to 570)	RR 0.33 (0.04 to 2.85)	30 (1)	⊕⊝⊝⊝ very low^2,3	Study included participants with LCOS following cardiac surgery
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; LCOS: low cardiac output syndrome; RR: risk ratio
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Very low quality: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
¹Control group risk estimate comes from the control group risk in participants with low cardiac output and no cardiogenic shock in the included small study. ²Downgraded two steps for serious imprecision due to few events, and the confidence interval crosses the line of no difference and includes possible benefit from both approaches. ³Downgraded one step due to study limitation, with lack of blinding of participants and physicians.

Summary of findings 5. Amrinone compared to dobutamine for low cardiac output syndrome

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Summary of findings 6. Dopexamine compared to dopamine for cardiogenic shock or low cardiac output syndrome

Dopexamine compared with dopamine for cardiogenic shock or low cardiac output syndrome
Patient or population: adults with cardiogenic shock or low cardiac output syndrome Setting: hospital Intervention: dopexamine Comparison: dopamine
Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	No of participants (studies)	Quality	Comments
	Risk with dopexamine	Risk with dopamine
All‐cause short‐term mortality: time in hospital	500 per 1000¹	Not estimable²	RR not estimable²	70 (1)	⊕⊝⊝⊝ very low^3,4	Study included participants with LCOS/CS following elective surgery for CABG
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CABG: coronary artery bypass graft surgery; CI: confidence interval; CS: cardiogenic shock; LCOS: low cardiac output syndrome; RR: risk ratio
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Very low quality: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
¹Control group risk estimate comes from a large observational study, due to the small size of included studies in this population (Singh 2007). ²No in‐hospital deaths were observed in the study. ³Downgraded two steps for imprecision due to no observed events, and not estimable risk ratio and confidence interval, which results in possible benefit from both approaches. ⁴Downgraded one step due to indirectness. Due to the very low mortality and morbidity in the study population, we assume that inclusion of participants with low cardiac output syndrome was based on other definitions, as there were no hospital deaths or major adverse events in this study.

Summary of findings 6. Dopexamine compared to dopamine for cardiogenic shock or low cardiac output syndrome

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Summary of findings 7. Enoximone compared to dobutamine for low cardiac output syndrome

Enoximone compared with dobutamine for low cardiac output syndrome
Patient or population: adults with low cardiac output syndrome Setting: hospital Intervention: enoximone Comparison: dobutamine
Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	No of participants (studies)	Quality	Comments
	Risk with dobutamine	Risk with enoximone
All‐cause short‐term mortality: 1 month	500 per 1000¹	Not estimable²	RR not estimable²	40 (1)	⊕⊝⊝⊝ very low^3,4	Study included participants with LCOS after mitral valve surgery
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; LCOS: low cardiac output syndrome; RR: risk ratio
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Very low quality: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
¹Control group risk estimate comes from a large observational study, due to the small size of included studies in this population (Singh 2007). ²No in‐hospital deaths were observed in the study. ³Downgraded two steps for imprecision due to few events, and risk ratio and confidence interval were not estimable, which results in possible benefit from both approaches. ⁴Downgraded one step due to indirectness. Due to the very low mortality in the study population, we assume that inclusion of participants with low cardiac output syndrome was based on other definitions.

Summary of findings 7. Enoximone compared to dobutamine for low cardiac output syndrome

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Summary of findings 8. Nitric oxide compared to placebo for cardiogenic shock

Nitric oxide compared with placebo for cardiogenic shock
Patient or population: adults with cardiogenic shock Setting: in‐hospital Intervention: nitric oxide Comparison: placebo
Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	No of participants (studies)	Quality	Comments
	Risk with nitric oxide	Risk with placebo
All‐cause short‐term mortality: 1 month	500 per 1000¹	Not estimable²	RR not estimable²	3 (1)	⊕⊝⊝⊝ very low^3,4	Study included participants with CS due to AMI
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AMI: acute myocardial infarction; CI: confidence interval; CS: cardiogenic shock; RR: risk ratio
GRADE Working Group grades of evidence High quality: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Very low quality: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
¹Control group risk estimate comes from a large observational study, due to the small size of included studies in this population (Singh 2007). ²One death out of one participant with placebo and no deaths in two participants with nitric oxide, risk ratio was not estimable due to the small number of participants. ³Downgraded two steps for imprecision because the risk ratio and confidence interval were not estimated due to few events and participants, which results in possible benefit from both approaches ⁴Downgraded one step due to study limitation, with early stop due to lack of enrolment.

Summary of findings 8. Nitric oxide compared to placebo for cardiogenic shock

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Table 1. Major adverse cardiac events (MACE) (no deaths) in hospital

Comparison	Primary studies	MACE	Intervention		Control		RR (95% CI)
			events	total	events	total
Levosimendan vs dobutamine	Levin 2008	Perioperative infarction	1 (1.4%)	69	8 (11.8%)	68	0.12 (0.02 to 0.96)
	Garcίa‐González 2006	Re‐infarction	0 (0%)	11	0 (0%)	11	Not estimable
	Levin 2008	Cerebrovascular accidents	2 (2.9%)	69	6 (8.8%)	68	0.33 (0.07 to 1.57)
	Garcίa‐González 2006	Cerebrovascular accidents	0 (0%)	11	0 (0%)	11	Not estimable
Levosimendan vs placebo	Husebye 2013	MACE (death, non‐fatal myocardial infarction, revascularisation of the infarct‐related artery)	2 (50.0%)	4	2 (40.0%)	5	1.25 (0.29 to 5.35)
Levosimendan vs placebo	Husebye 2013	Repeat PCI	1 (25.0%)	4	0 (0%)	5	3.60 (0.18 to 70.34)
Amrinone vs dobutamine	Dupuis 1992	Re‐infarction (2 h)	0 (0%)	15	6 (40.0%)	15	0.08 (0.00 to 1.25)
Dopexamine vs dopamine	Rosseel 1997	Perioperative infarction	3 (8.6%)	35	2 (5.7%)	35	1.50 (0.27 to 8.43)
Nitric oxide vs placebo	Baldassarre 2008	Myocardial infarction	1 (50.0%)	2	1 (100%)	1	0.67 (0.17 to 2.67)
CI: confidence interval; PCI: percutaneous coronary intervention; RR: risk ratio

Table 1. Major adverse cardiac events (MACE) (no deaths) in hospital

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Table 2. Length of hospital stay

Comparison	Primary studies	Reported information	Intervention		Control
			Events/time	Total	Events/time	Total
Levosimendan vs dobutamine	Levin 2008	Stay in ICU (hours, median with IQR)	66 (58‐74)	69	158 (106‐182)	68
Levosimendan vs enoximone	Fuhrmann 2008	Stay in ICU (days, median with IQR)	10 (5‐23)	16	13 (7‐19)	16
Enoximone vs dobutamine	Atallah 1990	Stay in ICU (hours, mean)	92 ± 37	18	155 ± 129	19
ICU: intensive care unit; IQR: intra‐quartile‐range

Table 2. Length of hospital stay

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Table 3. Haemodynamics

Comparison	Primary studies	Haemodynamics	Intervention		Control		MD (95% CI)
Intervention vs control		last measurements	mean ± SD or median (IQR)	total	mean ± SD or median (IQR)	total
Levosimendan vs dobutamine	Adamopoulos 2006	Cardiac index (after 72 h, L/min/m²)	1.9 ± 0.1	23	1.8 ± 0.04	23	0.10 (0.06 to 0.14)
	Alvarez 2006	Cardiac index (after 48 h, L/min/m²)	2.8 ± 0.3	21	2.3 ± 0.2	20	0.50 (0.34 to 0.66)
	Garcίa‐González 2006	Cardiac index (after 30 h, L/min/m²)	2.9 ± 0.4	11	2.4 ± 0.2	11	0.50 (0.24 to 0.76)
	Levin 2008	Cardiac index (after 48 hrs, L/min/m²)	3.4 ± 0.2	69	2.7 ± 0.1	68	0.70 (0.65 to 0.75)
	Adamopoulos 2006	PCWP (after 72 h, mmHg)	19.0 ± 1	23	23.0 ± 1.0	23	‐4.00 (‐4.60 to ‐3.40)
	Alvarez 2006	MAP (after 48 h, mmHg)	77.0 ± 5	21	81.0 ± 7.0	20	‐4.00 (‐7.70 to ‐0.30)
	Levin 2008	MAP (after 48 h, mmHg)	78.8 ± 7	69	80.1 ± 4	68	‐1.30 (‐3.20 to 0.60)
Levosimendan vs placebo	Adamopoulos 2006	Cardiac index (after 72 h, (L/min/m²)	1.9 ± 0.1	23	1.8 ± 0.1	23	0.10 (0.04 to 0.16)
Levosimendan vs placebo	Adamopoulos 2006	PCWP (after 72 h, mmHg)	19.0 ± 1	23	23.0 ± 1.0	23	‐4.00 (‐4.60 to ‐3.40)
Levosimendan vs enoximone	Fuhrmann 2008	Cardiac index (after 48 h, L/min/m²)	3.1 (2.5‐3.5)	16	3.1 (2.8‐3.3)	16	Not estimable
Levosimendan vs enoximone	Fuhrmann 2008	MAP (after 48 h (mmHg)	75.0 (58.0‐79.0)	16	70.0 (63.0‐83.0)	16	Not estimable
Epinephrine vs norepinephrine‐dobutamine	Levy 2011	Cardiac index (after 24 h, L/min/m²)	2.9 ± 0.5	15	2.8 ± 0.4	15	0.10 (‐0.22 to 0.42)
Epinephrine vs norepinephrine‐dobutamine	Levy 2011	MAP (after 24 h, mmHg)	64 ± 9	15	65.0 ± 11.0	15	‐1.00 (‐8.20 to 6.20)
Dopexamine vs dopamine	Rosseel 1997	Cardiac index (after 6 h, L/min/m²)	3.1 ± 0.7	29	2.8 ± 0.5	30	0.30 (‐0.01 to 0.61)
	Rosseel 1997	PCWP (after 6 h, mmHg)	9.3 ± 3.2	29	10.8 ± 2.9	30	‐1.50 (‐3.10 to 0.10)
	Rosseel 1997	MAP (after 6 h, mmHg)	76.3 ± 11.5	29	78.2 ± 12.8	30	‐1.90 (‐8.10 to 4.30)
CI: confidence interval; IQR: intra‐quartile‐range; MAP: mean arterial pressure; MD: mean difference; PCWP: pulmonary capillary wedge pressure; SD: standard deviation

Table 3. Haemodynamics

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Table 4. Adverse events

Comparison	Primary studies	Adverse events (no MACE)	Intervention		Control
			events	total	events	total
Levosimendan vsdobutamine	Alvarez 2006, Levin 2008, Mebazaa (SURVIVE) 2007	Atrial fibrillation	78 (10.4%)	750	71 (9.5%)	748
	Mebazaa (SURVIVE) 2007	Ventricular fibrillation	15 (2.3%)	660	19 (2.9%)	660
	Alvarez 2006, Follath(LIDO) 2002, Levin 2008	Ventricular arrhythmias	7 (3.6%)	193	25 (13.3%)	188
	Mebazaa (SURVIVE) 2007	Ventricular tachycardia	52 (7.9%)	660	48 (7.3%)	660
		Ventricular extrasystoles	40 (6.1%)	660	24 (3.6%)	660
		Tachycardia	33 (5.0%)	660	33 (5.0%)	660
		Bradycardia	8 (1.2%)	660	17 (2.6%)	660
	Follath(LIDO) 2002, Mebazaa (SURVIVE) 2007	Headache	69 (9.0%)	763	36 (4.7%)	760
	Follath(LIDO) 2002, Mebazaa (SURVIVE) 2007	Cardiac failure	91 (11.9%)	763	127 (16.7%)	760
	Mebazaa (SURVIVE) 2007	Congestive cardiac failure	26 (3.9%)	660	22 (3.3%)	660
	Mebazaa (SURVIVE) 2007	Cardiac arrest	20 (3.0%)	660	26 (3.9%)	660
	Follath(LIDO) 2002, Mebazaa (SURVIVE) 2007	Disorder aggravated	17 (2,2%)	763	27 (3.6%)	760
	Follath(LIDO) 2002, Mebazaa (SURVIVE) 2007	Gastrointestinal disorders	54 (7.1%)	763	52 (6.8%)	760
	Levin 2008, Mebazaa (SURVIVE) 2007	Acute kidney failure	29 (4.0%)	729	43 (5.9%)	728
	Levin 2008	Need for dialysis	2 (2.9%)	69	8 (11.9%)	68
	Levin 2008, Mebazaa (SURVIVE) 2007	Pneumonia	34 (4.7%)	729	34 (4.7%)	728
	Garcίa‐González 2006	Multiple organ failure	0 (0%)	11	0 (0%)	11
	Garcίa‐González 2006	Stroke	0 (0%)	11	0 (0%)	11
	Levin 2008	Vasoplegia	1 (1.4 %)	69	9 (13.2%)	68
		Dyspnoea	1 (1.4%)	69	4 (5.8%)	68
		Inflammatory response syndrome	4 (5.8%)	69	15 (22.1%)	68
		Sepsis	1 (1.4%)	69	9 (13.2%)	68
		Prolonged ventilatory assistance	6 (8.7%)	69	22 (32.3%)	68
	Mebazaa (SURVIVE) 2007	Hypokalaemia	62 (9.4%)	660	39 (5.9%)	660
		Hyperkalaemia	15 (2.3%)	660	16 (2.4%)	660
		Hypotension	102 (15.5%)	660	92 (13.9%)	660
		Nausea	45 (6.8%)	660	49 (7.4%)	660
		Insomnia	37 (5.6%)	660	29 (4.4%)	660
		Chest pain	32 (4.8%)	660	47 (7.1%)	660
		Constipation	26 (3.9%)	660	28 (4.2%)	660
		Pyrexia	22 (3.3%)	660	19 (2.9%)	660
		Urinary tract infection	21 (3.2%)	660	30 (4.5%)	660
		Anexiety	20 (3.0%)	660	19 (2.9%)	660
		Pulmonary oedema	20 (3.0%)	660	18 (2.7%)	660
		Dizziness	19 (2.9%)	660	16 (2.4%)	660
		Cough	19 (2.9%)	660	21 (3.2%)	660
		Pain in extremity	18 (2.7%)	660	10 (1.5%)	660
		Pruritus	16 (2.4%)	660	7 (1.1%)	660
		Anaemia	15 (2.3%)	660	17 (2.6%)	660
		Epistaxis	14 (2.1%)	660	7 (1.1%)	660
		Back pain	13 (2.0%)	660	18 (2.7%)	660
		Angina pectoris	12 (1.8%)	660	18 (2.7%)	660
		Muscle spasms	12 (1.8%)	660	13 (2.0%)	660
		Dyspnoea	9 (1.4%)	660	17 (2.6%)	660
		Hypertension	9 (1.4%)	660	15 (2.3%)	660
		Cataract	7 (1.1%)	660	14 (2.1%)	660
		Agitation	7 (1.1%)	660	0 (0%)	660
Levosimendan vsplacebo	Husebye 2013	Non‐sustained ventricular tachycardia	1 (25.0%)	4	3 (60.0%)	5
		Atrial fibrillation	1 (25.0%)	4	0 (0%)	5
		Episodes of hypotension during drug infusion (MAP fall > 10 mmHg)	2 (50.0%)	4	1 (20.0%)	5
Levosimendan vsenoximone	Fuhrmann 2008	Need of mechanical ventilation	13 (81.3%)	16	15 (93.8%)	16
		Acute renal failure	5 (31.3%)	16	8 (50.0%)	16
		Need of continuous renal replacement therapy	5 (31.5%)	16	8 (50.0%)	16
		New onset atrial fibrillation	7 (43.8%)	16	9 (56.3%)	16
		Ventricular tachycardia or fibrillation	8 (50.0%)	16	11 (68.8%)	16
		Development of systemic inflammatory response	8 (50.0%)	16	13 (81.3%)	16
		Pneumonia	7 (43.8%)	16	7 (43.8%)	16
		Urinary infections	0 (0%)	16	2 (12.5%)	16
		Sepsis	3 (18.8%)	16	2 (12.5%)	16
Epinephrine vs. norepinephrine‐dobutamine	Levy 2011	Supraventricular arrhythmia	2 (13.3%)	15	0 (0%)	15
Epinephrine vs. norepinephrine‐dobutamine	Levy 2011	Sustained ventricular tachycardia	1 (6.7%)	15	0 (0%)	15
Amrinone vs. dobutamine	Dupuis 1992	Cardiac arrhythmias during treatment	0 (0%)	15	4 (26.7%)	15
Amrinone vs. dobutamine	Dupuis 1992	Myocardial ischemias (within 16 to 20 hrs)	4 (26.7%)	15	4 (26.7%)	15
Dopexamine vs. dopamine	Rosseel 1997	Cardiac events	19 (54.3%)	35	22 (62.9%)	35
		Abnormal blood loss	2 (5.7%)	35	1 (2.9%)	35
		Kidney failure	1 (2.9%)	35	1 (2.9%)	35
		Other adverse events	5 (14.3%)	35	1 (2.9%)	35
		Major adverse events	0 (0%)	35	0 (0%)	35
MACE: major adverse cardiac events; MAP: mean arterial pressure

Table 4. Adverse events

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Comparison 1. Levosimendan versus control

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause short‐term mortality Show forest plot	8		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Levosimendan versus dobutamine	6	1776	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.37, 0.95]
1.2 Levosimendan versus placebo	2	55	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.12, 1.94]
1.3 Levosimendan versus enoximone	1	32	Risk Ratio (M‐H, Random, 95% CI)	0.5 [0.22, 1.14]
2 All‐cause short‐term mortality: subgroup analysis Show forest plot	6		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 Levosimendan versus dobutamine: males	1	956	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.65, 1.27]
2.2 Levosimendan versus dobutamine: females	1	371	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.46, 1.32]
2.3 Levosimendan versus dobutamine: age < 65 years	1	501	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.57, 1.81]
2.4 Levosimendan versus dobutamine: age ≥ 65 years	1	826	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.58, 1.10]
2.5 Levosimendan versus dobutamine: LCOS due to HF	3	1576	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.42, 1.11]
2.6 Levosimendan versus dobutamine: LCOS due to cardiac surgery	2	178	Risk Ratio (M‐H, Random, 95% CI)	0.38 [0.17, 0.87]
2.7 Levosimendan versus placebo: LCOS due to HF	1	46	Risk Ratio (M‐H, Random, 95% CI)	0.5 [0.10, 2.47]
2.8 Levosimendan versus placebo: CS due to AMI	1	9	Risk Ratio (M‐H, Random, 95% CI)	0.4 [0.02, 7.82]
2.9 Levosimendan versus dobutamine: LCOS with no history of CHF	1	156	Risk Ratio (M‐H, Random, 95% CI)	1.54 [0.82, 2.87]
2.10 Levosimendan versus dobutamine: LCOS with history of CHF	1	1171	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.55, 1.04]
3 All‐cause long‐term mortality Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Levosimendan versus dobutamine	3	1552	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.65, 1.12]
3.2 Levosimendane versus dobutamine	1	22	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.37, 24.58]
3.3 Levosimendan versus placebo	1	9	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.08, 4.66]
4 All‐cause long‐term mortality:subgroup analysis Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4.1 Levosimendan versus dobutamine: males	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Levosimendan versus dobutamine: females	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 Levosimendan versus dobutamine: age < 65 years	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.4 Levosimendan versus dobutamine: age ≥ 65 years	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Cardiac index Show forest plot	6		Mean Difference (IV, Random, 95% CI)	Totals not selected

5.1 Levosimendan versus dobutamine	4		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
5.2 Levosimendan versus placebo	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
5.3 Epinephrine versus norepinephrine‐dobutamine	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
5.4 Dopexamine versus dopamine	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
6 Pulmonary capillary wedge pressure Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Totals not selected

6.1 Levosimendan versus dobutamine	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
6.2 Levosimendan versus placebo	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
6.3 Dopexamine versus dopamine	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
7 Mean arterial pressure Show forest plot	4		Mean Difference (IV, Random, 95% CI)	Subtotals only

7.1 Levosimendan versus dobutamine	2	178	Mean Difference (IV, Random, 95% CI)	‐2.15 [‐4.61, 0.31]
7.2 Epinephrine versus norepinephrine‐dobutamine	1	30	Mean Difference (IV, Random, 95% CI)	‐1.0 [‐8.19, 6.19]
7.3 Dopexamine versus dopamine	1	59	Mean Difference (IV, Random, 95% CI)	‐1.90 [‐8.10, 4.30]

Comparison 1. Levosimendan versus control

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Comparison 2. Levosimendan versus control: sensitivity analyses

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause short‐term mortality: fixed‐effect model Show forest plot	7		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Levosimendan versus dobutamine	6	1776	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.57, 0.93]
1.2 Levosimendan versus placebo	2	55	Risk Ratio (M‐H, Fixed, 95% CI)	0.47 [0.12, 1.93]
2 All‐cause short‐term mortality: low risk of bias Show forest plot	2	1530	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.39, 1.27]

Comparison 2. Levosimendan versus control: sensitivity analyses

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