Conference Coverage

Levosimendan does not improve 30-day mortality following cardiac surgery


Adding a low dose of levosimendan to the standard care for patients on perioperative hemodynamic support does not improve outcomes to any significant extent, according to the findings of a new study presented at the annual congress of the European Society of Intensive Care Medicine and published simultaneously online in the New England Journal of Medicine.

“Levosimendan (Simdax, Orion) is an inotropic agent that has been shown to be associated with a higher rate of survival than other inotropic agents in meta-analyses, especially those involving patients undergoing cardiac surgery,” wrote the authors of the study, led by Giovanni Landoni, MD, of Vita-Salute San Raffaele University in Milan, adding, “Considering the pharmacologic properties of levosimendan and the results of previous studies, we hypothesized that the administration of levosimendan, in addition to standard treatment, might result in lower mortality in this context.”

Dr. Landoni and his colleagues conducted the Levosimendan to Reduce Mortality in High Risk Cardiac Surgery Patients: A Multicenter Randomized Controlled Trial, known more commonly as CHEETAH. Written consent was given by 4,725 patients from 14 centers located in Italy, Russia, and Brazil between November 2009 and April 2016. The investigators recruited a total of 506 patients. All subjects included in the study underwent cardiac surgery and experienced a perioperative cardiovascular dysfunction (N Engl J Med. 2017 Mar 21. doi: 10.1056/NEJMoa1616325).

Subjects were then randomized into a cohort receiving either a placebo or a low dose of levosimendan, which varied between 0.025 to 0.2 mcg/kg of body weight per minute continuously for up to 48 hours. A total of 248 subjects received levosimendan and 258 received placebo. All patients were administered the treatment while in the ICU; patients were taken off their regimen prior to 48 hours if they were discharged from the ICU. Anyone screened for inclusion who already had experienced a negative reaction to levosimendan was excluded from the study.

“We collected preoperative data on baseline characteristics and coexisting conditions, intraoperative and postoperative treatment data, postoperative laboratory values, duration of mechanical ventilation, durations of ICU and hospital stays, and major outcomes,” the authors explained, adding that “telephone follow-up was performed at 30 days and 180 days after randomization by an investigator who was unaware of the trial group assignments.”

The primary outcome of the study was 30-day mortality. The levosimendan cohort experienced 32 deaths (12.9%), while the placebo cohort saw 33 (12.8%), a nonsignificant difference (P = .97) between the two groups. Similarly, the median time spent on mechanical ventilation was 19 hours for those on levosimendan, versus 21 hours for those on placebo (P = .48), and median length of hospital stay was 14 days in both groups (P = .39).

“Previous meta-analyses of randomized, controlled trials showed a higher rate of survival with levosimendan than with other treatment regimens among patients undergoing cardiac surgery,” Dr. Landoni and his coauthors noted. Previous studies also had a number of key differences, such as the number of subjects who underwent coronary artery bypass grafting, the dosing of levosimendan, and inclusion of patients who had reduced preoperative ejection fraction instead of ones with myocardial dysfunction who needed inotropic support, which the current study used.

The study was funded by the Italian Ministry of Health. Dr. Landoni reported receiving nonfinancial support from the Orion Corporation while the study was ongoing; several other coauthors reported similar disclosures.

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