The Impact of Low-Dose Levosimendan for Hemodynamic Support After Cardiac Surgery

A low-dose infusion of levosimendan in patients with left ventricular dysfunction following cardiac surgery who need hemodynamic support did not lower the 30-day mortality rate any more than placebo, according to a recent study.

Conducted by Giovanni Landoni, MD, of the department of anesthesia and intensive care at the San Raffaele Scientific Institute, and colleagues, the study results also showed that levosimendan did not positively affect secondary outcome measures compared to placebo.

Cardiac surgery is common across the US and Europe with approximately one million patients having a procedure annually. Nearly 20% of those patients have acute perioperative left ventricular dysfunction, a major complication that is associated with higher mortality rates.

Clinicians commonly use inotropic drugs like catecholamines and phosphodiesterase type 3 inhibitors for hemodynamic support, but the authors said there have been no randomized, controlled trials to demonstrate, which such drugs are superior. They added, “Furthermore, meta-analyses and observational studies suggest that [inotropic drugs] may increase mortality.”

Levosimendan is an inotropic agent that has antioxidant and anti-inflammatory properties and has been associated with a higher rate of survival and the most likely inotropic agent to reduce mortality. The authors began the current study with the hypothesis that levosimendan would reduce mortality when administered at a low dose in patients with perioperative cardiovascular dysfunction.

The trial the researchers designed included participants drawn from 14 centers in Italy, Russia, and Brazil between November 2009 and April 2016. Patients were randomly assigned to receive levosimendan or placebo, and physicians, investigators, patients, outcome assessors, and data collectors were blinded. The primary outcome of the study was 30-day mortality, and acute kidney injury, duration of mechanical ventilation, need for renal-replacement therapy, and duration of hospital stay were secondary outcomes.

A total of 506 patients participated, and 248 were assigned to receive levosimendan and 258 to receive placebo. The researchers report that no patients were lost to follow up, and all were included in the intent-to-treat analysis. “At 30 days, there had been 32 deaths 912.9% of patients) in the levosimendan group and 33 deaths (12.8%) in the placebo group,” the researchers said. Additionally, there were no significant differences in cause of death or in secondary outcomes.

These findings contradict the results of previous analyses, which showed a higher rate of survival in patients receiving levosimendan. Another trial, LEVO-CTS, also did not show a higher rate of survival in patients receiving levosimendan. The authors say, “A similar pattern of positive results from small randomized trials and meta-analyses of randomized trials of levosimendan, contradicted by a subsequent pivotal trial, has been observed in patients with severe sepsis or heart failure.”

The authors do note that the current trial differed from previous ones because most of them focused on patients undergoing coronary artery bypass grafting (CABG) who were given levosimendan, and fewer than half the participants in CHEETAH underwent CABG. The researchers acknowledged that there could be differences in pathophysiological features, but add that in a prespecified subgroup analysis they did not find the type of surgery influenced the outcome.

There are some limitations, as well. According to the authors, the trial was stopped early “on the grounds of futility for the primary outcome (30-day mortality). They added that the situation might have increased the potential for type II error in the secondary outcomes.

A lower dose of levosimendan was used in this study than in previous ones, and the researchers say that the possibility that higher doses could be more effective. However, they were concerned about the risk of adverse events. The participants in this study were mixed and undergoing different cardiac procedures, and the researchers did not systematically collect cardiac-output data.

Acknowledging those limitations, the researchers concluded, “In patients with perioperative left ventricular dysfunction requiring hemodynamic support after cardiac surgery, a low-dose infusion of levosimendan did not result in lower 30-day mortality than placebo nor did it positively affect any secondary-outcome measures as compared with placebo.”

The full study can be found in The New England Journal of Medicine.

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