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

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

doi:10.1002/14651858.CD009669.pub4

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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 dobutamine, Outcome 1: All‐cause short‐term mortality

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Analysis 1.2

Comparison 1: Levosimendan versus dobutamine, Outcome 2: All‐cause short‐term mortality: sensitivity analysis

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Analysis 1.3

Comparison 1: Levosimendan versus dobutamine, Outcome 3: All‐cause long‐term mortality

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Analysis 1.4

Comparison 1: Levosimendan versus dobutamine, Outcome 4: All‐cause long‐term mortality: sensitivity analysis

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Analysis 1.5

Comparison 1: Levosimendan versus dobutamine, Outcome 5: MACE (Perioperative infarction)

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Analysis 1.6

Comparison 1: Levosimendan versus dobutamine, Outcome 6: MACE (Cerebrovascular accidents)

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Analysis 1.7

Comparison 1: Levosimendan versus dobutamine, Outcome 7: Haemodynamics (Cardiac index)

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Analysis 1.8

Comparison 1: Levosimendan versus dobutamine, Outcome 8: Haemodynamics (Pulmonary capillary wedge pressure)

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Analysis 1.9

Comparison 1: Levosimendan versus dobutamine, Outcome 9: Haemodynamics (Mean arterial pressure)

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Analysis 2.1

Comparison 2: Levosimendan versus placebo, Outcome 1: All‐cause long‐term mortality

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Analysis 2.2

Comparison 2: Levosimendan versus placebo, Outcome 2: All‐cause long‐term mortality: sensitivity analysis

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Analysis 2.3

Comparison 2: Levosimendan versus placebo, Outcome 3: Haemodynamics (Cardiac index)

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Analysis 2.4

Comparison 2: Levosimendan versus placebo, Outcome 4: Haemodynamics (Pulmonary capillary wedge pressure)

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Analysis 2.5

Comparison 2: Levosimendan versus placebo, Outcome 5: Haemodynamics (Mean arterial pressure)

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Analysis 3.1

Comparison 3: Levosimendan versus enoximone, Outcome 1: All‐cause short‐term mortality

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Analysis 3.2

Comparison 3: Levosimendan versus enoximone, Outcome 2: All‐cause short‐term mortality: sensitivity analysis

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Analysis 3.3

Comparison 3: Levosimendan versus enoximone, Outcome 3: MACE (Cerebrovascular accidents)

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Analysis 4.1

Comparison 4: Epinephrine versus norepinephrine‐dobutamine, Outcome 1: All‐cause short‐term mortality

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Analysis 4.2

Comparison 4: Epinephrine versus norepinephrine‐dobutamine, Outcome 2: All‐cause short‐term mortality: sensitivity analysis

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Analysis 4.3

Comparison 4: Epinephrine versus norepinephrine‐dobutamine, Outcome 3: Haemodynamics (Cardiac index)

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Analysis 4.4

Comparison 4: Epinephrine versus norepinephrine‐dobutamine, Outcome 4: Haemodynamics (Pulmonary capillary wedge pressure)

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Analysis 4.5

Comparison 4: Epinephrine versus norepinephrine‐dobutamine, Outcome 5: Haemodynamics (Mean arterial pressure)

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Analysis 5.1

Comparison 5: Dopexamine versus dopamine, Outcome 1: MACE (Perioperative infarctions)

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Analysis 5.2

Comparison 5: Dopexamine versus dopamine, Outcome 2: Haemodynamics (Cardiac index)

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Analysis 5.3

Comparison 5: Dopexamine versus dopamine, Outcome 3: Hemodynamics (Pulmonary capillary wedge pressure)

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Analysis 5.4

Comparison 5: Dopexamine versus dopamine, Outcome 4: Haemodynamics (Mean arterial pressure)

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Analysis 6.1

Comparison 6: Milrinone versus dobutamine, Outcome 1: Haemodynamics (Cardiac index)

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Analysis 6.2

Comparison 6: Milrinone versus dobutamine, Outcome 2: Haemodynamics (Pulmonary capillary wedge pressure)

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Analysis 6.3

Comparison 6: Milrinone versus dobutamine, Outcome 3: Haemodynamics (Mean arterial pressure)

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Analysis 7.1

Comparison 7: Enoximone versus dobutamine, Outcome 1: All‐cause short‐term mortality

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Analysis 7.2

Comparison 7: Enoximone versus dobutamine, Outcome 2: All‐cause short‐term mortality: sensitivity analysis

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Analysis 7.3

Comparison 7: Enoximone versus dobutamine, Outcome 3: Haemodynamics (Cardiac index)

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Analysis 7.4

Comparison 7: Enoximone versus dobutamine, Outcome 4: Haemodynamics (Pulmonary capillary wedge pressure)

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Analysis 7.5

Comparison 7: Enoximone versus dobutamine, Outcome 5: Haemodynamics (Mean arterial pressure)

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Analysis 8.1

Comparison 8: Epinephrine versus norepinephrine, Outcome 1: All‐cause short‐term mortality

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Analysis 8.2

Comparison 8: Epinephrine versus norepinephrine, Outcome 2: All‐cause short‐term mortality: sensitivity analysis

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Analysis 8.3

Comparison 8: Epinephrine versus norepinephrine, Outcome 3: All‐cause long‐term mortality

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Analysis 8.4

Comparison 8: Epinephrine versus norepinephrine, Outcome 4: All‐cause long‐term mortality: sensitivity analysis

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Analysis 8.5

Comparison 8: Epinephrine versus norepinephrine, Outcome 5: Haemodynamics (Pulmonary capillary wedge pressure)

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Analysis 8.6

Comparison 8: Epinephrine versus norepinephrine, Outcome 6: Haemodynamics (Mean arterial pressure)

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Analysis 9.1

Comparison 9: Dopamine‐milrinone versus dopamine‐dobutamine, Outcome 1: All‐cause short‐term mortality

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Analysis 9.2

Comparison 9: Dopamine‐milrinone versus dopamine‐dobutamine, Outcome 2: All‐cause short‐term mortality: sensitivity analysis

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Analysis 9.3

Comparison 9: Dopamine‐milrinone versus dopamine‐dobutamine, Outcome 3: Haemodynamics (Cardiac index)

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Analysis 9.4

Comparison 9: Dopamine‐milrinone versus dopamine‐dobutamine, Outcome 4: Haemodynamics (Pulmonary capillary wedge pressure)

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Analysis 9.5

Comparison 9: Dopamine‐milrinone versus dopamine‐dobutamine, Outcome 5: Haemodynamics (Mean arterial pressure)

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Analysis 10.1

Comparison 10: Enoximone versus piroximone, Outcome 1: Haemodynamics (Cardiac index)

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Analysis 10.2

Comparison 10: Enoximone versus piroximone, Outcome 2: Haemodynamics (Pulmonary capillary wedge pressure)

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Analysis 10.3

Comparison 10: Enoximone versus piroximone, Outcome 3: Haemodynamics (Mean arterial pressure)

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Summary of findings 1. Levosimendan compared to dobutamine for cardiogenic shock or low cardiac output syndrome

Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
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	Risk with dobutamine	Risk with levosimendan	Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
All‐cause short‐term mortality: range 15 to 31 days	148 per 1000¹	89 per 1000 (53 to 152)	RR 0.60 (0.36 to 1.03)	1701 (4 studies)	⊕⊕⊝⊝ low²	Studies included participants with LCOS or CS due to cardiac surgery or HF.
All‐cause long‐term mortality: range 4 to 12 months	288 per 1000¹	242 per 1000 (181 to 325)	RR 0.84 (0.63 to 1.13)	1591 (4 studies)	⊕⊕⊝⊝ low²	Studies included participants with LCOS or CS due to HF or 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; 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 control group risk in included studies with low cardiac output or cardiogenic shock. ²Downgraded 1 level for imprecision due to optimal information size criterion not being met and 1 level for study limitation due to stopping trial early for benefit and methodological limitations from lack of blinding.

Summary of findings 1. 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

Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
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	Risk with placebo	Risk with levosimendan	Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
All‐cause short‐term mortality: 1 month	Outcome not reported in any of the included studies.
All‐cause long‐term mortality: range 4 to 6 months	214 per 1000¹	118 per 1000 (35 to 407)	RR 0.55 (0.16 to 1.90)	55 (2 studies)	⊕⊝⊝⊝ very low²	Studies included participants with LCOS or CS due to HF or 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; 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 control group risk in included studies with low cardiac output or cardiogenic shock. ²Downgraded 2 levels for imprecision due to optimal information size criterion not being met and confidence interval crossing line of null effect and including appreciable benefit and harm and 1 level for study limitation due to methodological limitations from lack of blinding.

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

Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
Levosimendan compared with enoximone for cardiogenic shock
Patient or population: adults with cardiogenic shock Settings: hospital Intervention: levosimendan Comparison: enoximone
Outcomes	Risk with enoximone	Risk with levosimendan	Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
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 study)	⊕⊝⊝⊝ very low²	Study included participants with CS due to AMI.
All‐cause long‐term mortality	Outcome not reported in any of the included studies.
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 1 level for imprecision due to optimal information size criterion not being met and 2 levels for study limitation due to stopping trial early for benefit and methodological limitations from lack of blinding.

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 cardiogenic shock

Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
Epinephrine compared with norepinephrine‐dobutamine for cardiogenic shock
Patient or population: adults with cardiogenic shock Setting: hospital Intervention: epinephrine Comparison: norepinephrine‐dobutamine
Outcomes	Risk with norepinephrine‐dobutamine	Risk with epinephrine	Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
All‐cause short‐term mortality: 28 days	267 per 1000¹	333 per 1000 (109 to 1003)	RR 1.25 (0.41 to 3.77)	30 (1 study)	⊕⊝⊝⊝ very low²	Study included participants with CS due to HF.
All‐cause long‐term mortality	Outcome not reported in any of the included studies.
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; CS: cardiogenic shock; 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.
¹Control group risk estimate comes from the control group risk in a small included study with low cardiac output or cardiogenic shock. ²Downgraded 2 levels for imprecision due to optimal information size criterion not being met and confidence interval crossing line of null effect and including appreciable benefit and harm, and 1 level for study limitation due to methodological limitations from lack of blinding.

Summary of findings 4. Epinephrine compared to norepinephrine‐dobutamine for cardiogenic shock

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Summary of findings 5. Dopexamine compared to dopamine for low cardiac output syndrome

Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
Dopexamine compared with dopamine for low cardiac output syndrome
Patient or population: adults with low cardiac output syndrome Setting: hospital Intervention: dopexamine Comparison: dopamine
Outcomes	Risk with dopamine	Risk with dopexamine	Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
All‐cause short‐term mortality: time in hospital	Not estimable¹	Not estimable¹	RR not estimable¹	70 (1 study)	⊕⊝⊝⊝ very low²	Study included participants with LCOS following elective surgery for CABG.
All‐cause long‐term mortality	Outcome not reported in any of the included studies.
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; 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.
¹No in‐hospital deaths were observed in the study. ²Downgraded 1 level for imprecision due to optimal information size criterion not being met, 1 level for publication bias due to incomplete outcome data and 1 level for study limitation due to methodological limitations from inappropriate administration of an intervention.

Summary of findings 5. Dopexamine compared to dopamine for low cardiac output syndrome

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Summary of findings 6. Milrinone compared to dobutamine for low cardiac output syndrome

Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Milrinone compared with dobutamine for low cardiac output syndrome
Patient or population: adults with low cardiac output syndrome Settings: hospital Intervention: milrinone Comparison: dobutamine
Outcomes	Risk with dobutamine	Risk with milrinone	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
All‐cause mortality	Outcome not reported in any of the included studies.
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: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Summary of findings 6. Milrinone compared to dobutamine for low cardiac output syndrome

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

Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
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	Risk with dobutamine	Risk with enoximone	Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
All‐cause short‐term mortality: 1 month	500 per 1000¹	Not estimable²	RR 0.21 (0.01 to 4.11)	37 (1 study)	⊕⊕⊝⊝ very low³	Study included participants with LCOS after mitral valve surgery.
All‐cause long‐term mortality	Outcome not reported in any of the included studies.
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 2 levels for imprecision due to optimal information size criterion not being met and confidence interval crossing line of null effect and 1 level for study limitation due to methodological limitations from lack of blinding.

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

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Summary of findings 8. Epinephrine compared to norepinephrine for cardiogenic shock

Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Epinephrine compared with norepinephrine for cardiogenic shock
Patient or population: adults with cardiogenic shock Settings: hospital Intervention: epinephrine Comparison: norepinephrine
Outcomes	Risk with norepinephrine	Risk with epinephrine	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
All‐cause short‐term mortality: 28 days	266 per 1000¹	482 per 1000 (237 to 979)	RR 1.81 (0.89 to 3.68)	57 (1 study)	⊕⊝⊝⊝ very low²	Study included participants with CS due to AMI.
All‐cause long‐term mortality: 60 days	366 per 1000¹	516 per 1000 (285 to 937)	RR 1.41 (0.78 to 2.56)	57 (1 study)	⊕⊝⊝⊝ very low²	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; [other abbreviations, e.g. OR, etc]
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Control group risk estimate comes from the control group risk in a small included study with low cardiac output or cardiogenic shock. ²Downgraded 2 levels for imprecision due to optimal information size criterion not being met and confidence interval crossing line of null effect and including appreciable benefit and harm and 1 level for study limitation due to stopping trial early for benefit.

Summary of findings 8. Epinephrine compared to norepinephrine for cardiogenic shock

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Summary of findings 9. Dopamine‐milrinone compared to dopamine‐dobutamine for cardiogenic shock

Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Dopamine‐milrinone compared with dopamine‐dobutamine for cardiogenic shock
Patient or population: adults with cardiogenic shock Settings: hospital Intervention: dopamine‐milrinone Comparison: dopamine‐dobutamine
Outcomes	Risk with dopamine‐dobutamine	Risk with dopamine‐milrinone	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
All‐cause short‐term mortality: at intensive care unit	400 per 1000¹	400 per 1000 (136 to 1172)	RR 1.0 (0.34 to 2.93)	20 (1 study)	⊕⊝⊝⊝ very low²	Study included participants with CS due to HF.
All‐cause long‐term mortality	Outcome not reported in any of the included studies.
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; CS: cardiogenic shock; HF: heart failure; RR: Risk Ratio; [other abbreviations, e.g. OR, etc]
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Control group risk estimate comes from the control group risk in a small included study with low cardiac output or cardiogenic shock. ²Downgraded 2 levels for imprecision due to optimal information size criterion not being met and confidence interval crossing line of null effect and including appreciable benefit and harm and 1 level for study limitation due to methodological limitations from lack of blinding and inappropriate random sequence generation.

Summary of findings 9. Dopamine‐milrinone compared to dopamine‐dobutamine for cardiogenic shock

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Summary of findings 10. Enoximone compared to piroximone for low cardiac output syndrome

Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Enoximone compared with piroximone for low cardiac output syndrome
Patient or population: adults with low cardiac output syndrome Settings: hospital Intervention: enoximone Comparison: piroximone
Outcomes	Risk with piroximone	Risk with enoximone	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
All‐cause mortality	Outcome not reported in any of the included studies.
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: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Summary of findings 10. Enoximone compared to piroximone for low cardiac output syndrome

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Summary of findings 11. Enoximone compared to epinephrine‐nitroglycerine for low cardiac output syndrome

Outcomes	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Enoximone compared with epinephrine‐nitroglycerine for low cardiac output syndrome
Patient or population: adults with low cardiac output syndrome Settings: hospital Intervention: enoximone Comparison: epinephrine‐nitroglycerine
Outcomes	Risk with epinephrine‐nitroglycerine	Risk with enoximone	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
All‐cause mortality	Outcome not reported in any of the included studies.
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: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Summary of findings 11. Enoximone compared to epinephrine‐nitroglycerine for low cardiac output syndrome

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Table 1. 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 versus dobutamine	Adamopoulos 2006	Cardiac index (72 h after treatment initiation; L/min/m²)	1.9 ± 0.47	23	1.8 ± 0.19	23	0.10 (‐0.11 to 0.31)
	Alvarez 2006	Cardiac index (48 h after treatment initiation; L/min/m²)	2.8 ± 0.3	21	2.3 ± 0.2	20	0.50 (0.34 to 0.66)
	Levin 2008	Cardiac index (48 h after treatment initiation; L/min/m²)	3.4 ± 0.2	69	2.7 ± 0.1	68	0.70 (0.65 to 0.75)
	Adamopoulos 2006	PCWP (72 h after treatment initiation; mmHg)	19.0 ± 4.79	23	23.0 ± 4.79	23	‐4.00 (‐6.77 to ‐1.23)
	Follath (LIDO) 2002	PCWP (24 h after treatment initiation; mmHg)	18.0 ± 8.0	103	24.0 ± 7.0	100	‐6.00 (‐8.07 to ‐3.93)
	Levin 2008	PCWP (48 h after treatment initiation; mmHg)	12.1 ± 1.0	69	15.0 ± 2.0	68	‐2.90 (‐3.43 to ‐2.37)
	Alvarez 2006	MAP (48 h after treatment initiation; mmHg)	77.0 ± 5	21	81.0 ± 7.0	20	‐4.00 (‐7.74 to ‐0.26)
	Levin 2008	MAP (48 h after treatment initiation; mmHg)	78.7 ± 7.0	69	80.1 ± 4.0	68	‐1.30 (‐3.21 to 0.61)
Levosimendan versus placebo	Adamopoulos 2006	Cardiac index (72 h after treatment initiation; L/min/m²)	1.9 ± 0.47	23	1.8 ± 0.47	23	0.10 (‐0.17 to 0.37)
	Slawsky 2000	Cardiac index (6 h after treatment initiation; L/min/m²)	2.5 ± 0.98	98	1.9 ± 0.69	48	0.60 (0.32 to 0.88)
	Adamopoulos 2006	PCWP (72 h after treatment initiation; mmHg)	19.0 ± 4.79	23	23.0 ± 4.79	23	‐4.00 (‐6.77 to ‐1.23)
	Slawsky 2000	PCWP (6 h after treatment initiation; mmHg)	21.0 ± 9.89	98	28.0 ± 6.92	48	‐7.0 (‐9.77 to ‐4.23)
	Slawsky 2000	MAP (6 h after treatment initiation; mmHg)	81.0 ± 19	98	85.0 ± 13.85	48	‐4.0 (‐9.54 to 1.54)
Levosimendan versus enoximone	Fuhrmann 2008	Cardiac index (48 h after treatment initiation; L/min/m²)	3.1 (2.5 ‐ 3.5)	16	3.1 (2.8 ‐ 3.3)	16	not estimable
	Fuhrmann 2008	PCWP (48 h after treatment initiation; mmHg)	17.0 (16.0 ‐ 20.0)	16	21.0 (19.0 ‐ 28.0)	16	not estimable
	Fuhrmann 2008	MAP (48 h after treatment initiation; mmHg)	75.0 (58.0 ‐ 79.0)	16	70.0 (63.0 ‐ 83.0)	16	not estimable
Epinephrine versus norepinephrine‐dobutamine	Levy 2011	Cardiac index (24 h after treatment initiation; L/min/m²)	2.9 ± 0.5	15	2.8 ± 0.4	15	0.10 (‐0.22 to 0.42)
	Levy 2011	PCWP (24 h after treatment initiation; mmHg)	18.0 ± 7.0	15	18.0 ± 7.0	15	0.00 (‐5.01 to 5.01)
	Levy 2011	MAP (24 h after treatment initiation; mmHg)	64.0 ± 9.0	15	65.0 ± 11.0	15	‐1.0 (‐8.19 to 6.19)
Dopexamine versus dopamine	Rosseel 1997	Cardiac index (6 h after treatment initiation; L/min/m²)	3.1 ± 0.7	35	2.8 ± 0.5	35	0.30 (0.02 to 0.58)
	Rosseel 1997	PCWP (6 h after treatment initiation; mmHg)	9.3 ± 3.2	35	10.8 ± 2.9	35	‐1.50 (‐2.93 to ‐0.07)
	Rosseel 1997	MAP (6 h after treatment initiation; mmHg)	76.3 ± 11.5	35	78.2 ± 12.8	35	‐1.90 (‐7.60 to 3.80)
Milrinone versus dobutamine	Feneck 2001	Cardiac index (4 h after treatment initiation; L/min/m²)	2.4 ± 0.77	60	2.7 ± 2.32	60	‐0.30 (‐0.92 to 0.32)
	Feneck 2001	PCWP (4 h after treatment initiation; mmHg)	11.2 ± 3.09	60	12.6 ± 5.42	60	‐1.40 (‐2.98 to 0.18)
	Feneck 2001	MAP (4 h after treatment initiation; mmHg)	68.5 ± 21.68	60	75.5 ± 32.53	60	‐7.0 (‐16.89 to 2.89)
Enoximone versus dobutamine	Galinier 1990	Cardiac index (12 h after treatment initiation; L/min/m²)	2.56 ± 0.74	10	2.8 ± 0.35	10	‐0.74 (‐0.75 to 0.27)
	Lancon 1990	Cardiac index (14 h after treatment initiation; L/min/m²)	2.8 ± 0.6	10	3.1 ± 0.9	10	‐0.30 (‐0.97 to 0.37)
	Galinier 1990	PCWP (12 h after treatment initiation; mmHg)	20.0 ± 5.7	10	23.7 ± 6.6	10	‐3.70 (‐9.11 to 1.71)
	Lancon 1990	PCWP (14 h after treatment initiation; mmHg)	13.1 ± 4.2	10	12.8 ± 4.1	10	0.30 (‐3.34 to 3.94)
	Galinier 1990	MAP (12 h after treatment initiation; mmHg)	78.0 ± 11.0	10	93.0 ± 17.0	10	‐15.0 (‐27.55 to ‐2.45)
Epinephrine versus norepinephrine	Levy 2018	Cardiac index (72 h after treatment initiation; L/min/m²)	2.6 (1.9 ‐ 3.3)	27	2.6 (2.2 ‐ 3.2)	30	not estimable
	Levy 2018	PCWP (72 h after treatment initiation; mmHg)	12.5 ± 4.1	27	15.8 ± 5.7	30	‐3.30 (‐5.86 to ‐0.74)
	Levy 2018	MAP (72 h after treatment initiation; mmHg)	83.7 ± 12.3	27	76.5 ± 8.1	30	7.20 (1.73 to 12.67)
Dopamine‐milrinone versus dopamine‐dobutamine	Meissner 1996	Cardiac index (1 h after treatment initiation; L/min/m²)	2.6 ± 0.31	10	2.9 ± 0.63	10	‐0.30 (‐0.74 to 0.14)
	Meissner 1996	PCWP (1 h after treatment initiation; mmHg)	17.0 ± 4.42	10	19.0 ± 6.32	10	‐2.0 (‐6.78 to 2.78)
	Meissner 1996	MAP (1 h after treatment initiation; mmHg)	65.0 ± 7.9	10	71.0 ± 12.01	10	‐6.0 (‐14.91 to 2.91)
Enoximone versus piroximone	Patel 1993	Cardiac index (3 h after treatment initiation; L/min/m²)	2.4 ± 0.5	10	2.5 ± 0.4	10	‐0.10 (‐0.50 to 0.30)
	Patel 1993	PCWP (3 h after treatment initiation; mmHg)	8.5 ± 2.0	10	9.2 ± 1.9	10	‐0.70 (‐2.41 to 1.01)
	Patel 1993	MAP (3 h after treatment initiation; mmHg)	72.9 ± 8.7	10	69.6 ± 7.0	10	3.30 (‐3.62 to 10.22)
CI: confidence interval IQR: interquartile range MAP: mean arterial pressure MD: mean difference PCWP: pulmonary capillary wedge pressure SD: standard deviation

Table 1. Haemodynamics

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Table 2. Adverse events

Comparison	Primary studies	Adverse events (no MACE)	Intervention		Control
			events	total	events	total
Levosimendan versus dobutamine	Levin 2008	Acute kidney failure	5 (7.2%)	69	21 (30.9%)	68
	Mebazaa (SURVIVE) 2007	Agitation	7 (1.1%)	660	0 (0%)	660
	Mebazaa (SURVIVE) 2007	Anaemia	15 (2.3%)	660	17 (2.6%)	660
	Follath (LIDO) 2002, Mebazaa (SURVIVE) 2007	Angina pectoris	12 (1.8%)	681	25 (3.7%)	680
	Mebazaa (SURVIVE) 2007	Anxiety	20 (3.0%)	660	19 (2.9%)	660
	Alvarez 2006, Follath (LIDO) 2002, Levin 2008, Mebazaa (SURVIVE) 2007	Atrial fibrillation	80 (9.4%)	853	72 (8.5%)	848
	Mebazaa (SURVIVE) 2007	Back pain	13 (2.0%)	660	18 (2.7%)	660
	Follath (LIDO) 2002, Mebazaa (SURVIVE) 2007	Bradycardia	9 (1.2%)	763	18 (2.4%)	760
	Mebazaa (SURVIVE) 2007	Cardiac arrest	20 (3.0%)	660	26 (3.9%)	660
	Mebazaa (SURVIVE) 2007	Cataract	7 (1.1%)	660	14 (2.1%)	660
	Mebazaa (SURVIVE) 2007	Chest pain	32 (4.8%)	660	47 (7.1%)	660
	Mebazaa (SURVIVE) 2007	(Congestive) cardiac failure	107 (16.2%)	660	134 (20.3%)	660
	Mebazaa (SURVIVE) 2007	Constipation	26 (3.9%)	660	28 (4.2%)	660
	Mebazaa (SURVIVE) 2007	Cough	19 (2.9%)	660	21 (3.2%)	660
	Mebazaa (SURVIVE) 2007	Diarrhea	30 (4.5%)	660	21 (3.2%)	660
	Follath (LIDO) 2002	Disorder aggravated	2 (1,9%)	103	4 (4.0%)	100
	Follath (LIDO) 2002, Mebazaa (SURVIVE) 2007	Dizziness	19 (2.5%)	763	17 (2.2%)	760
	Levin 2008, Mebazaa (SURVIVE) 2007	Dyspnoea	10 (1.4%)	729	21 (2.9%)	728
	Mebazaa (SURVIVE) 2007	Epistaxis	14 (2.1%)	660	7 (1.1%)	660
	Follath (LIDO) 2002	Extrasystoles	1 (1.0%)	103	3 (3.0%)	100
	Follath (LIDO) 2002	Flushing	1 (1.0%)	103	3 (3.0%)	100
	Follath (LIDO) 2002	Gastrointestinal disorders	2 (1.9%)	103	7 (7.0%)	100
	Follath (LIDO) 2002, Mebazaa (SURVIVE) 2007	Headache	69 (9.0%)	763	36 (4.7%)	760
	Mebazaa (SURVIVE) 2007	Hyperkalaemia	15 (2.3%)	660	16 (2.4%)	660
	Mebazaa (SURVIVE) 2007	Hypertension	9 (1.4%)	660	15 (2.3%)	660
	Mebazaa (SURVIVE) 2007	Hypokalaemia	62 (9.4%)	660	39 (5.9%)	660
	Follath (LIDO) 2002, Mebazaa (SURVIVE) 2007	Hypotension	111 (14.5%)	763	96 (12.6%)	760
	Mebazaa (SURVIVE) 2007	Insomnia	37 (5.6%)	660	29 (4.4%)	660
	Garcίa‐González 2006	Multiple organ failure	0 (0%)	11	0 (0%)	11
	Mebazaa (SURVIVE) 2007	Muscle spasms	12 (1.8%)	660	13 (2.0%)	660
	Mebazaa (SURVIVE) 2007	Nausea	45 (6.8%)	660	49 (7.4%)	660
	Levin 2008	Need for dialysis	2 (2.9%)	69	8 (11.9%)	68
	Mebazaa (SURVIVE) 2007	Pain in extremity	18 (2.7%)	660	10 (1.5%)	660
	Levin 2008, Mebazaa (SURVIVE) 2007	Pneumonia	34 (4.7%)	729	34 (4.7%)	728
	Levin 2008	Prolonged ventilatory assistance	6 (8.7%)	69	22 (32.3%)	68
	Mebazaa (SURVIVE) 2007	Pruritus	16 (2.4%)	660	7 (1.1%)	660
	Mebazaa (SURVIVE) 2007	Pulmonary oedema	20 (3.0%)	660	18 (2.7%)	660
	Mebazaa (SURVIVE) 2007	Pyrexia	22 (3.3%)	660	19 (2.9%)	660
	Mebazaa (SURVIVE) 2007	Renal failure	24 (3.6%)	660	22 (3.3%)	660
	Levin 2008	Sepsis	1 (1.4%)	69	9 (13.2%)	68
	Levin 2008	Systemic inflammatory response syndrome	4 (5.8%)	69	15 (22.1%)	68
	Follath (LIDO) 2002, Mebazaa (SURVIVE) 2007	Tachycardia	86 (11.3%)	763	88 (11.6%)	760
	Mebazaa (SURVIVE) 2007	Urinary infections	21 (3.2%)	660	30 (4.5%)	660
	Levin 2008	Vasoplegia	1 (1.4%)	69	9 (13.2%)	68
	Alvarez 2006, Levin 2008	Ventricular arrhythmia	3 (3.3%)	90	12 (13.6%)	88
	Mebazaa (SURVIVE) 2007	Ventricular extrasystoles	40 (6.1%)	660	24 (3.6%)	660
	Follath (LIDO) 2002, Mebazaa (SURVIVE) 2007	Ventricular fibrillation	16 (2.1%)	763	20 (2.6%)	760
	Mebazaa (SURVIVE) 2007	Vomiting	22 (3.3%)	660	24 (3.6%)	660
Levosimendan versus placebo	Husebye 2013	Atrial fibrillation	1 (25.0%)	4	0 (0%)	5
Levosimendan versus placebo	Husebye 2013, Slawsky 2000	Ventricular tachycardia	3 (2.9%)	102	3 (5.7%)	53
Levosimendan versus enoximone	Fuhrmann 2008	Acute renal failure	5 (31.3%)	16	8 (50.0%)	16
		Atrial fibrillation	7 (43.8%)	16	9 (56.3%)	16
		Need of mechanical ventilation	13 (81.3%)	16	15 (93.8%)	16
		Pneumonia	7 (43.8%)	16	7 (43.8%)	16
		Sepsis	3 (18.8%)	16	2 (12.5%)	16
		Systemic inflammatory response	8 (50.0%)	16	13 (81.3%)	16
		Urinary infections	0 (0%)	16	2 (12.5%)	16
		Ventricular tachycardia or fibrillation	8 (50.0%)	16	11 (68.8%)	16
Epinephrine versus norepinephrine‐dobutamine	Levy 2011	Supraventricular arrhythmia	2 (13.3%)	15	0 (0%)	15
Epinephrine versus norepinephrine‐dobutamine	Levy 2011	Sustained ventricular tachycardia	1 (6.7%)	15	0 (0%)	15
Dopexamine versus dopamine	Rosseel 1997	Abnormal blood loss	2 (5.7%)	35	1 (2.9%)	35
		Bradycardia	2 (5.7%)	35	4 (11.4%)	35
		Hypertension	3 (8.6%)	35	7 (20.0%)	35
		Junctional rhythm	0 (0%)	35	2 (5.7%)	35
		Kidney failure	1 (2.9%)	35	1 (2.9%)	35
		Premature atrial contractions	2 (5.7%)	35	6 (17.1%)	35
		Premature ventricular contractions	9 (25.7%)	35	11 (31.4%)	35
		ST elevation	2 (5.7%)	35	0 (0%)	35
Milrinone versus dobutamine	Feneck 2001	Atrial fibrillation	3 (5.0%)	60	11 (18.3%)	60
		Bradycardia	8 (13.3%)	60	1 (1.7%)	60
		Haemorrhage	9 (15.0%)	60	3 (5.0%)	60
		Hypertension	8 (13.3%)	60	24 (40.0%)	60
		Hypotension	12 (20.0%)	60	6 (10.0%)	60
		Oligouria	6 (10.0%)	60	2 (3.3%)	60
		Tachycardia	5 (8.3%)	60	11 (18.3%)	60
Enoximone versus dobutamine	Atallah 1990; Galinier 1990	Haemorrhage	0 (0%)	18	1 (5.3%)	19
		Hepatic cytolysis	0 (0%)	10	0 (0%)	10
		Tachycardia and/or hypertension	0 (0%)	18	4 (21.1%)	19
		Thrombocytopenia	0 (0%)	10	0 (0%)	10
		Ventricular hyperexcitability	0 (0%)	10	0 (0%)	10
Epinephrine versus norepinephrine	Levy 2018	Arrhythmia	11 (40.7%)	27	10 (33.3%)	30
		Need for extracorporeal life support	3 (11.1%)	27	1 (3.3%)	30
		Refactory shock	10 (37.0%)	27	2 (6.7%)	30
Enoximone versus piroximone	Patel 1993	Arrhythmia	1 (10.0%)	10	0 (0%)	10
Enoximone versus piroximone	Patel 1993	Hypotension	2 (20.0%)	10	2 (20.0%)	10
Enoximone versus epinephrine/nitroglycerine	Zwölfer 1995	Arrhytmia	0 (0%)	6	0 (0%)	6
Enoximone versus epinephrine/nitroglycerine	Zwölfer 1995	Tachycardia	0 (0%)	6	0 (0%)	6
LIDO: study title ("levosimendan infusion versus dobutamine") MACE: major adverse cardiac events MAP: mean arterial pressure ST: segment of the electrocardiogram SURVIVE: study title ("survival of patients with acute heart failure in need of intravenous inotropic support")

Table 2. Adverse events

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Comparison 1. Levosimendan versus dobutamine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 All‐cause short‐term mortality Show forest plot	4	1701	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.36, 1.03]

1.2 All‐cause short‐term mortality: sensitivity analysis Show forest plot	4	1701	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.58, 0.95]

1.3 All‐cause long‐term mortality Show forest plot	4	1591	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.63, 1.13]

1.4 All‐cause long‐term mortality: sensitivity analysis Show forest plot	4	1591	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.76, 1.05]

1.5 MACE (Perioperative infarction) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.6 MACE (Cerebrovascular accidents) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.7 Haemodynamics (Cardiac index) Show forest plot	3	224	Mean Difference (IV, Random, 95% CI)	0.45 [0.14, 0.76]

1.8 Haemodynamics (Pulmonary capillary wedge pressure) Show forest plot	3	386	Mean Difference (IV, Random, 95% CI)	‐4.14 [‐6.23, ‐2.06]

1.9 Haemodynamics (Mean arterial pressure) Show forest plot	2	178	Mean Difference (IV, Random, 95% CI)	‐2.15 [‐4.61, 0.31]

Comparison 1. Levosimendan versus dobutamine

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Comparison 2. Levosimendan versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 All‐cause long‐term mortality Show forest plot	2	55	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.16, 1.90]

2.2 All‐cause long‐term mortality: sensitivity analysis Show forest plot	2	55	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.15, 1.89]

2.3 Haemodynamics (Cardiac index) Show forest plot	2	192	Mean Difference (IV, Random, 95% CI)	0.35 [‐0.14, 0.84]

2.4 Haemodynamics (Pulmonary capillary wedge pressure) Show forest plot	2	192	Mean Difference (IV, Random, 95% CI)	‐5.50 [‐8.44, ‐2.56]

2.5 Haemodynamics (Mean arterial pressure) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

Comparison 2. Levosimendan versus placebo

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Comparison 3. Levosimendan versus enoximone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 All‐cause short‐term mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3.2 All‐cause short‐term mortality: sensitivity analysis Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3.3 MACE (Cerebrovascular accidents) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 3. Levosimendan versus enoximone

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Comparison 4. Epinephrine versus norepinephrine‐dobutamine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 All‐cause short‐term mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

4.2 All‐cause short‐term mortality: sensitivity analysis Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4.3 Haemodynamics (Cardiac index) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

4.4 Haemodynamics (Pulmonary capillary wedge pressure) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

4.5 Haemodynamics (Mean arterial pressure) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

Comparison 4. Epinephrine versus norepinephrine‐dobutamine

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Comparison 5. Dopexamine versus dopamine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 MACE (Perioperative infarctions) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5.2 Haemodynamics (Cardiac index) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

5.3 Hemodynamics (Pulmonary capillary wedge pressure) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

5.4 Haemodynamics (Mean arterial pressure) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

Comparison 5. Dopexamine versus dopamine

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Comparison 6. Milrinone versus dobutamine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Haemodynamics (Cardiac index) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

6.2 Haemodynamics (Pulmonary capillary wedge pressure) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

6.3 Haemodynamics (Mean arterial pressure) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

Comparison 6. Milrinone versus dobutamine

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Comparison 7. Enoximone versus dobutamine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 All‐cause short‐term mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

7.2 All‐cause short‐term mortality: sensitivity analysis Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

7.3 Haemodynamics (Cardiac index) Show forest plot	2	40	Mean Difference (IV, Random, 95% CI)	‐0.24 [‐0.64, 0.16]

7.4 Haemodynamics (Pulmonary capillary wedge pressure) Show forest plot	2	40	Mean Difference (IV, Random, 95% CI)	‐1.18 [‐4.97, 2.61]

7.5 Haemodynamics (Mean arterial pressure) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

Comparison 7. Enoximone versus dobutamine

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Comparison 8. Epinephrine versus norepinephrine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 All‐cause short‐term mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

8.2 All‐cause short‐term mortality: sensitivity analysis Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

8.3 All‐cause long‐term mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

8.4 All‐cause long‐term mortality: sensitivity analysis Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

8.5 Haemodynamics (Pulmonary capillary wedge pressure) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

8.6 Haemodynamics (Mean arterial pressure) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

Comparison 8. Epinephrine versus norepinephrine

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Comparison 9. Dopamine‐milrinone versus dopamine‐dobutamine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
9.1 All‐cause short‐term mortality Show forest plot	1		Risk Ratio (IV, Random, 95% CI)	Totals not selected

9.2 All‐cause short‐term mortality: sensitivity analysis Show forest plot	1		Risk Ratio (IV, Fixed, 95% CI)	Totals not selected

9.3 Haemodynamics (Cardiac index) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

9.4 Haemodynamics (Pulmonary capillary wedge pressure) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

9.5 Haemodynamics (Mean arterial pressure) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

Comparison 9. Dopamine‐milrinone versus dopamine‐dobutamine

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Comparison 10. Enoximone versus piroximone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 Haemodynamics (Cardiac index) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

10.2 Haemodynamics (Pulmonary capillary wedge pressure) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

10.3 Haemodynamics (Mean arterial pressure) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

Comparison 10. Enoximone versus piroximone

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