Levosimendan does not significantly impact mortality following cardiac surgery: The CHEETAH trial

1. Levosimendan was not associated with a significant mortality benefit in cardiac surgery patients with perioperative ventricular dysfunction compared to placebo.

2. No significant differences were found in other secondary endpoints including duration of mechanical ventilation, intensive care unit (ICU) stay, hospital stay, or serious adverse events.

Evidence Rating Level: 1 (Excellent) 

Study Rundown: Left ventricular dysfunction following cardiac surgery is a major complication and often treated with inotropic medications or mechanical support. However, studies suggest these agents may be associated with increased mortality rates. Meta-analyses have indicated the calcium sensitizer levosimendan may provide a perioperative mortality benefit, but other studies have not substantiated these results in pre- or postoperative patients with left ventricular dysfunction. This trial assessed the efficacy of levosimendan in patients requiring hemodynamic support following cardiac surgery. No significant difference between levosimendan and placebo was found in the primary outcome, 30-day mortality, resulting in early termination of the trial. Furthermore, no significant differences in secondary outcomes including duration of mechanical ventilation, hospital stay, and rates of hypotension or arrhythmias were found. Though the authors speculate that higher doses may have produced different results, the findings do not support the use of levosimendan for the management of cardiac dysfunction following surgery.

This was a randomized, double-blind, placebo-controlled trial that enrolled approximately equal numbers of patients undergoing coronary artery bypass grafting (CABG) and mitral-valve surgery with ongoing cardiac dysfunction requiring hemodynamic support. Limitations of the study include the early termination on analysis of the secondary outcomes, patients undergoing various types of cardiac surgery, and a lower levosimendan dose than used in other studies.

Click to read the study, published in NEJM

Relevant Reading: Levosimendan in patients with left ventricular dysfunction undergoing cardiac surgery

In-Depth [randomized controlled trial]: This multinational study randomized 506 patients with an indication for hemodynamic support following cardiac surgery to continuous infusion with either levosimendan (n = 248) or placebo (n = 258), in addition to standard treatment. Perioperative cardiac dysfunction was defined as: high-dose inotropic treatment in the ICU (primary criterion 65.0% of enrollees), preoperative intra-aortic balloon pump support (18.6%), high-dose inotropic support to taper from cardiopulmonary bypass (12.1%), or preoperative left ventricular ejection fraction under 25% (4.3%). The primary outcome was 30-day mortality. Secondary outcomes included acute kidney injury, indication for renal-replacement therapy, and a composite outcome of death and need for renal replacement therapy, duration of mechanical ventilation, and duration of ICU and hospital stay.

For patients in the levosimendan and placebo groups, 32 (12.9% of patients) and 33 (12.8%) deaths were reported at 30 days, respectively (absolute risk difference 0.1%; 95%CI, -5.7 to 5.9; p = 0.97). No between-group difference in mortality rates was shown over time (HR 1.02; 95% CI, 0.65 to 1.59; p = 0.94). No significant treatment-by-subgroup interactions or differences in rates of acute kidney injury, renal-replacement therapy, duration of mechanical ventilation, or duration of ICU or hospital stay were found (p > 0.05 for all outcome comparisons). Serious adverse events were reported in 107 (43.7%) and 131 (51.6%) of patients in the levosimendan vs. placebo groups, respectively (p = 0.08). In the two groups, 62 (25.2%) vs. 54 (21.3%) of patients experienced hypotension (p = 0.31).

Image: PD

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