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

Abstract

Cardiogenic shock (CS) and low cardiac output syndrome (LCOS) as complications of acute myocardial infarction (AMI), heart failure (HF) or cardiac surgery are life‐threatening conditions. While there is a broad body of evidence for the treatment of people with acute coronary syndrome under stable haemodynamic conditions, the treatment strategies for people who become haemodynamically unstable or develop CS remain less clear. We have therefore summarised here the evidence on the treatment of people with CS or LCOS with different inotropic agents and vasodilative drugs. This is the first update of a Cochrane review originally published in 2014. To assess efficacy and safety of cardiac care with positive inotropic agents and vasodilator strategies in people with CS or LCOS due to AMI, HF or cardiac surgery. We searched CENTRAL , MEDLINE, Embase and CPCI‐S Web of Science in June 2017. We also searched four registers of ongoing trials and scanned reference lists and contacted experts in the field to obtain further information. No language restrictions were applied. Randomised controlled trials in people with myocardial infarction, heart failure or cardiac surgery complicated by cardiogenic shock or LCOS. We used standard methodological procedures expected by Cochrane. We identified 13 eligible studies with 2001 participants (mean or median age range 58 to 73 years) and two ongoing studies. We categorised studies into eight comparisons, all against cardiac care and additional other active drugs or placebo. These comparisons investigated the efficacy of levosimendan versus dobutamine, enoximone or placebo, epinephrine versus norepinephrine‐dobutamine, amrinone versus dobutamine, dopexamine versus dopamine, enoximone versus dopamine and nitric oxide versus placebo. All trials were published in peer‐reviewed journals, and analysis was done by the intention‐to‐treat (ITT) principle. Twelve of 13 trials were small with few included participants. Acknowledgement of funding by the pharmaceutical industry or missing conflict of interest statements emerged in five of 13 trials. In general, confidence in the results of analysed studies was reduced due to serious study limitations, very serious imprecision or indirectness. Domains of concern, which show a high risk of more than 50%, include performance bias (blinding of participants and personnel) and bias affecting the quality of evidence on adverse events. Levosimendan may reduce short‐term mortality compared to a therapy with dobutamine (RR 0.60, 95% CI 0.37 to 0.95; 6 studies; 1776 participants; low‐quality evidence; NNT: 16 (patients with moderate risk), NNT: 5 (patients with CS)). This initial short‐term survival benefit with levosimendan vs. dobutamine is not confirmed on long‐term follow up. There is uncertainty (due to lack of statistical power) as to the effect of levosimendan compared to therapy with placebo (RR 0.48, 95% CI 0.12 to 1.94; 2 studies; 55 participants, very low‐quality evidence) or enoximone (RR 0.50, 95% CI 0.22 to 1.14; 1 study; 32 participants, very low‐quality evidence). All comparisons comparing other positive inotropic, inodilative or vasodilative drugs presented uncertainty on their effect on short‐term mortality with very low‐quality evidence and based on only one RCT. These single studies compared epinephrine with norepinephrine‐dobutamine (RR 1.25, 95% CI 0.41 to 3.77; 30 participants), amrinone with dobutamine (RR 0.33, 95% CI 0.04 to 2.85; 30 participants), dopexamine with dopamine (no in‐hospital deaths from 70 participants), enoximone with dobutamine (two deaths from 40 participants) and nitric oxide with placebo (one death from three participants). Apart from low quality of evidence data suggesting a short‐term mortality benefit of levosimendan compared with dobutamine, at present there are no robust and convincing data to support a distinct inotropic or vasodilator drug‐based therapy as a superior solution to reduce mortality in haemodynamically unstable people with cardiogenic shock or LCOS. Considering the limited evidence derived from the present data due to a generally high risk of bias and imprecision, it should be emphasised that there remains a great need for large, well‐designed randomised trials on this topic to close the gap between daily practice in critical care medicine and the available evidence. It seems to be useful to apply the concept of 'early goal‐directed therapy' in cardiogenic shock and LCOS with early haemodynamic stabilisation within predefined timelines. Future clinical trials should therefore investigate whether such a therapeutic concept would influence survival rates much more than looking for the 'best' drug for haemodynamic support. Inotropic and vasodilator strategies in people with cardiogenic shock or low cardiac output Review question We reviewed evidence of the treatment with different inotropic agents and vasodilative drugs for their effects on mortality in people with cardiogenic shock (CS) or low cardiac output syndrome (LCOS). Background CS and LCOS still remain life‐threatening complications. Inotropic and vasoactive drugs are potent, but potentially harmful agents. Their benefits and harms are associated with mortality. Study characteristics This evidence is current to June 2017. We included 13 studies with 2001 participants with CS or LCOS as complications of myocardial infarction, heart failure or cardiac surgery, with follow‐up periods between the length of the recovery period up to 12 months. Four studies were funded by a drug manufacturer. Key results We compared different approaches to standard therapies with possible addition of inotropic or vasoconstrictive drugs as levosimendan, dobutamine, enoximone, epinephrine. This review presents low‐quality evidence that levosimendan compared to dobutamine reduces short‐term mortality. The survival benefit with levosimendan vs. dobutamine is not confirmed on long‐term follow up. Very low‐quality evidence shows uncertainty around the effect of levosimendan compared to placebo or enoximone. Very low‐quality evidence shows uncertainty on the comparison of epinephrine with norepinephrine‐dobutamine, amrinone or enoximone with dobutamine, dopexamine with dopamine, and nitric oxide with placebo. Quality of evidence We have reduced confidence in the results of the studies that we analysed (low‐ or very low‐quality evidence) due to serious study limitations, very serious imprecision or indirectness.