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Meta-Analysis
. 2020 Nov 5;11(11):CD009669.
doi: 10.1002/14651858.CD009669.pub4.

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

Konstantin Uhlig  1 , Ljupcho Efremov  2 , Jörn Tongers  3 , Stefan Frantz  4 , Rafael Mikolajczyk  2 , Daniel Sedding  3 , Julia Schumann  1
Affiliations
Meta-Analysis

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

Konstantin Uhlig et al. Cochrane Database Syst Rev. .

Abstract

Background: Cardiogenic shock (CS) and low cardiac output syndrome (LCOS) are potentially life-threatening complications of acute myocardial infarction (AMI), heart failure (HF) or cardiac surgery. While there is solid evidence for the treatment of other cardiovascular diseases of acute onset, treatment strategies in haemodynamic instability due to CS and LCOS remains less robustly supported by the given scientific literature. Therefore, we have analysed the current body of evidence for the treatment of CS or LCOS with inotropic and/or vasodilating agents. This is the second update of a Cochrane review originally published in 2014.

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

Search methods: We conducted a search in CENTRAL, MEDLINE, Embase and CPCI-S Web of Science in October 2019. We also searched four registers of ongoing trials and scanned reference lists and contacted experts in the field to obtain further information. No language restrictions were applied.

Selection criteria: Randomised controlled trials (RCTs) enrolling patients with AMI, HF or cardiac surgery complicated by CS or LCOS.

Data collection and analysis: We used standard methodological procedures according to Cochrane standards.

Main results: We identified 19 eligible studies including 2385 individuals (mean or median age range 56 to 73 years) and three ongoing studies. We categorised studies into 11 comparisons, all against standard cardiac care and additional other drugs or placebo. These comparisons investigated the efficacy of levosimendan versus dobutamine, enoximone or placebo; enoximone versus dobutamine, piroximone or epinephrine-nitroglycerine; epinephrine versus norepinephrine or norepinephrine-dobutamine; dopexamine versus dopamine; milrinone versus dobutamine and dopamine-milrinone versus dopamine-dobutamine. All trials were published in peer-reviewed journals, and analyses were done by the intention-to-treat (ITT) principle. Eighteen of 19 trials were small with only a few included participants. An acknowledgement of funding by the pharmaceutical industry or missing conflict of interest statements occurred in nine of 19 trials. In general, confidence in the results of analysed studies was reduced due to relevant study limitations (risk of bias), imprecision or indirectness. Domains of concern, which showed a high risk in more than 50% of included studies, encompassed performance bias (blinding of participants and personnel) and bias affecting the quality of evidence on adverse events. All comparisons revealed uncertainty on the effect of inotropic/vasodilating drugs on all-cause mortality with a low to very low quality of evidence. In detail, the findings were: levosimendan versus dobutamine (short-term mortality: RR 0.60, 95% CI 0.36 to 1.03; participants = 1701; low-quality evidence; long-term mortality: RR 0.84, 95% CI 0.63 to 1.13; participants = 1591; low-quality evidence); levosimendan versus placebo (short-term mortality: no data available; long-term mortality: RR 0.55, 95% CI 0.16 to 1.90; participants = 55; very low-quality evidence); levosimendan versus enoximone (short-term mortality: RR 0.50, 0.22 to 1.14; participants = 32; very low-quality evidence; long-term mortality: no data available); epinephrine versus norepinephrine-dobutamine (short-term mortality: RR 1.25; 95% CI 0.41 to 3.77; participants = 30; very low-quality evidence; long-term mortality: no data available); dopexamine versus dopamine (short-term mortality: no deaths in either intervention arm; participants = 70; very low-quality evidence; long-term mortality: no data available); enoximone versus dobutamine (short-term mortality RR 0.21; 95% CI 0.01 to 4.11; participants = 27; very low-quality evidence; long-term mortality: no data available); epinephrine versus norepinephrine (short-term mortality: RR 1.81, 0.89 to 3.68; participants = 57; very low-quality evidence; long-term mortality: no data available); and dopamine-milrinone versus dopamine-dobutamine (short-term mortality: RR 1.0, 95% CI 0.34 to 2.93; participants = 20; very low-quality evidence; long-term mortality: no data available). No information regarding all-cause mortality were available for the comparisons milrinone versus dobutamine, enoximone versus piroximone and enoximone versus epinephrine-nitroglycerine.

Authors' conclusions: At present, there are no convincing data supporting any specific inotropic or vasodilating therapy to reduce mortality in haemodynamically unstable patients with CS or LCOS. Considering the limited evidence derived from the present data due to a high risk of bias and imprecision, it should be emphasised that there is an unmet need for large-scale, well-designed randomised trials on this topic to close the gap between daily practice in critical care of cardiovascular patients and the available evidence. In light of the uncertainties in the field, partially due to the underlying methodological flaws in existing studies, future RCTs should be carefully designed to potentially overcome given limitations and ultimately define the role of inotropic agents and vasodilator strategies in CS and LCOS.

PubMed Disclaimer

Conflict of interest statement

Konstantin Uhlig: no relevant conflicts of interests Ljupcho Efremov: no relevant conflicts of interests Jörn Tongers: lecture honoraria and travel support from Orion Pharma Stefan Frantz: advisory boards, lectures, and study support from AMGEN Europe, AstraZeneca, Bayer Vital, Boehringer Ingelheim, Bristol Myers Squibb GmbH, Daiichi Sankyo, MSD, Novartis, Pfizer, Sanofi, Servier, Vifor Rafael Mikolajczyk: no relevant conflicts of interests Daniel Sedding: no relevant conflicts of interests Julia Schumann: no relevant conflicts of interests

Figures

1
1
Study flow diagram
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
1.1
1.1. Analysis
Comparison 1: Levosimendan versus dobutamine, Outcome 1: All‐cause short‐term mortality
1.2
1.2. Analysis
Comparison 1: Levosimendan versus dobutamine, Outcome 2: All‐cause short‐term mortality: sensitivity analysis
1.3
1.3. Analysis
Comparison 1: Levosimendan versus dobutamine, Outcome 3: All‐cause long‐term mortality
1.4
1.4. Analysis
Comparison 1: Levosimendan versus dobutamine, Outcome 4: All‐cause long‐term mortality: sensitivity analysis
1.5
1.5. Analysis
Comparison 1: Levosimendan versus dobutamine, Outcome 5: MACE (Perioperative infarction)
1.6
1.6. Analysis
Comparison 1: Levosimendan versus dobutamine, Outcome 6: MACE (Cerebrovascular accidents)
1.7
1.7. Analysis
Comparison 1: Levosimendan versus dobutamine, Outcome 7: Haemodynamics (Cardiac index)
1.8
1.8. Analysis
Comparison 1: Levosimendan versus dobutamine, Outcome 8: Haemodynamics (Pulmonary capillary wedge pressure)
1.9
1.9. Analysis
Comparison 1: Levosimendan versus dobutamine, Outcome 9: Haemodynamics (Mean arterial pressure)
2.1
2.1. Analysis
Comparison 2: Levosimendan versus placebo, Outcome 1: All‐cause long‐term mortality
2.2
2.2. Analysis
Comparison 2: Levosimendan versus placebo, Outcome 2: All‐cause long‐term mortality: sensitivity analysis
2.3
2.3. Analysis
Comparison 2: Levosimendan versus placebo, Outcome 3: Haemodynamics (Cardiac index)
2.4
2.4. Analysis
Comparison 2: Levosimendan versus placebo, Outcome 4: Haemodynamics (Pulmonary capillary wedge pressure)
2.5
2.5. Analysis
Comparison 2: Levosimendan versus placebo, Outcome 5: Haemodynamics (Mean arterial pressure)
3.1
3.1. Analysis
Comparison 3: Levosimendan versus enoximone, Outcome 1: All‐cause short‐term mortality
3.2
3.2. Analysis
Comparison 3: Levosimendan versus enoximone, Outcome 2: All‐cause short‐term mortality: sensitivity analysis
3.3
3.3. Analysis
Comparison 3: Levosimendan versus enoximone, Outcome 3: MACE (Cerebrovascular accidents)
4.1
4.1. Analysis
Comparison 4: Epinephrine versus norepinephrine‐dobutamine, Outcome 1: All‐cause short‐term mortality
4.2
4.2. Analysis
Comparison 4: Epinephrine versus norepinephrine‐dobutamine, Outcome 2: All‐cause short‐term mortality: sensitivity analysis
4.3
4.3. Analysis
Comparison 4: Epinephrine versus norepinephrine‐dobutamine, Outcome 3: Haemodynamics (Cardiac index)
4.4
4.4. Analysis
Comparison 4: Epinephrine versus norepinephrine‐dobutamine, Outcome 4: Haemodynamics (Pulmonary capillary wedge pressure)
4.5
4.5. Analysis
Comparison 4: Epinephrine versus norepinephrine‐dobutamine, Outcome 5: Haemodynamics (Mean arterial pressure)
5.1
5.1. Analysis
Comparison 5: Dopexamine versus dopamine, Outcome 1: MACE (Perioperative infarctions)
5.2
5.2. Analysis
Comparison 5: Dopexamine versus dopamine, Outcome 2: Haemodynamics (Cardiac index)
5.3
5.3. Analysis
Comparison 5: Dopexamine versus dopamine, Outcome 3: Hemodynamics (Pulmonary capillary wedge pressure)
5.4
5.4. Analysis
Comparison 5: Dopexamine versus dopamine, Outcome 4: Haemodynamics (Mean arterial pressure)
6.1
6.1. Analysis
Comparison 6: Milrinone versus dobutamine, Outcome 1: Haemodynamics (Cardiac index)
6.2
6.2. Analysis
Comparison 6: Milrinone versus dobutamine, Outcome 2: Haemodynamics (Pulmonary capillary wedge pressure)
6.3
6.3. Analysis
Comparison 6: Milrinone versus dobutamine, Outcome 3: Haemodynamics (Mean arterial pressure)
7.1
7.1. Analysis
Comparison 7: Enoximone versus dobutamine, Outcome 1: All‐cause short‐term mortality
7.2
7.2. Analysis
Comparison 7: Enoximone versus dobutamine, Outcome 2: All‐cause short‐term mortality: sensitivity analysis
7.3
7.3. Analysis
Comparison 7: Enoximone versus dobutamine, Outcome 3: Haemodynamics (Cardiac index)
7.4
7.4. Analysis
Comparison 7: Enoximone versus dobutamine, Outcome 4: Haemodynamics (Pulmonary capillary wedge pressure)
7.5
7.5. Analysis
Comparison 7: Enoximone versus dobutamine, Outcome 5: Haemodynamics (Mean arterial pressure)
8.1
8.1. Analysis
Comparison 8: Epinephrine versus norepinephrine, Outcome 1: All‐cause short‐term mortality
8.2
8.2. Analysis
Comparison 8: Epinephrine versus norepinephrine, Outcome 2: All‐cause short‐term mortality: sensitivity analysis
8.3
8.3. Analysis
Comparison 8: Epinephrine versus norepinephrine, Outcome 3: All‐cause long‐term mortality
8.4
8.4. Analysis
Comparison 8: Epinephrine versus norepinephrine, Outcome 4: All‐cause long‐term mortality: sensitivity analysis
8.5
8.5. Analysis
Comparison 8: Epinephrine versus norepinephrine, Outcome 5: Haemodynamics (Pulmonary capillary wedge pressure)
8.6
8.6. Analysis
Comparison 8: Epinephrine versus norepinephrine, Outcome 6: Haemodynamics (Mean arterial pressure)
9.1
9.1. Analysis
Comparison 9: Dopamine‐milrinone versus dopamine‐dobutamine, Outcome 1: All‐cause short‐term mortality
9.2
9.2. Analysis
Comparison 9: Dopamine‐milrinone versus dopamine‐dobutamine, Outcome 2: All‐cause short‐term mortality: sensitivity analysis
9.3
9.3. Analysis
Comparison 9: Dopamine‐milrinone versus dopamine‐dobutamine, Outcome 3: Haemodynamics (Cardiac index)
9.4
9.4. Analysis
Comparison 9: Dopamine‐milrinone versus dopamine‐dobutamine, Outcome 4: Haemodynamics (Pulmonary capillary wedge pressure)
9.5
9.5. Analysis
Comparison 9: Dopamine‐milrinone versus dopamine‐dobutamine, Outcome 5: Haemodynamics (Mean arterial pressure)
10.1
10.1. Analysis
Comparison 10: Enoximone versus piroximone, Outcome 1: Haemodynamics (Cardiac index)
10.2
10.2. Analysis
Comparison 10: Enoximone versus piroximone, Outcome 2: Haemodynamics (Pulmonary capillary wedge pressure)
10.3
10.3. Analysis
Comparison 10: Enoximone versus piroximone, Outcome 3: Haemodynamics (Mean arterial pressure)
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References to other published versions of this review

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