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CHEETAH: Levosimendan fails to lower mortality rate after cardiac surgery
Among patients who underwent cardiac surgery and needed perioperative hemodynamic support, low-dose levosimendan did not confer lower 30-day mortality rates than placebo.
Cardiac surgery is performed in more than 1 million patients in the United States and Europe annually, and up to 20% of those are affected by acute perioperative left ventricular dysfunction, which leads to an increased risk for mortality, researchers wrote in The New England Journal of Medicine. Levosimendan (Tenax Therapeutics; outside the United States: Simdax, Orion) was previously linked to reducing the risk for mortality in patients after cardiac surgery vs. other inotropic agents.
The CHEETAH trial was designed by researchers to analyze the effect of levosimendan on patients’ mortality rates after cardiac surgery. It was a randomized, placebo-controlled, double blind trial that featured 14 centers throughout Italy, Brazil and Russia.
A total of 506 patients with perioperative LV dysfunction after cardiac surgery were enrolled into the trial from November 2009 to April 2016; the trial was stopped early for futility. Levosimendan was randomly assigned to 248 patients (median age, 66 years; 36% women) vs. 258 with placebo (median age, 66 years; 35% women).
A mixture of levosimendan (12.5 mg) and 5% glucose was administered to patients assigned the medication through a continuous infusion (0.05 µg/kg of body weight per minute). The same amount of continuous infusion was given to patients assigned placebo. Attending physicians for both groups were authorized to increase or decrease the dose if needed. The maximum dose was 0.2 µg/kg per minute, and the minimum was 0.025 µg/kg per minute. Levosimendan or placebo was administered for up to 48 hours or until the patient was discharged from ICU. Follow-up was performed via telephone after 30 days and 180 days from randomization.
Levosimendan was administered to the group for an average of 33 ± 14 hours vs. 32 ± 13.5 hours for placebo (P = .17). Physicians increased the initial dose of levosimendan in 127 patients (51.2%) vs. 159 patients (61.6%) assigned placebo (P = .02).
“A hemodynamic effect of levosimendan is suggested by the greater number of attempts to increase the dose in the placebo group and the higher mean dose in the placebo group,” Giovanni Landoni, MD, associate professor at Vita-Salute San Raffaele University in Milan and head of research in the department of anesthesia and intensive care at San Raffaele Scientific Institute, and colleagues wrote.
The primary outcome — 30-day mortality — occurred in 12.9% of the levosimendan group vs. 12.8% of the placebo group (absolute risk difference, 0.1 percentage points; 95% CI, –5.7 to 5.9). Secondary outcomes, including length of hospital/ICU stay, acute kidney injury, renal-replacement therapy, death and length of mechanical ventilation, did not demonstrate substantial differences between the treatment groups.
Among the levosimendan group, serious adverse events occurred in 43.7% vs. 51.6% in the placebo group (P = .08). Hypotension was noted during infusion in 25.2% of patients in the levosimendan group and 21.3% of patients in the placebo group (P = .31). No significant differences occurred between the two groups regarding arrhythmias, although 89 cases were reported.
“Despite the signals of a hemodynamic effect of levosimendan, we cannot rule out the possibility that higher doses might have been effective in reducing mortality, although higher doses might also have increased the risk of adverse effects such as hypotension and arrhythmias,” Landoni and colleagues wrote. – by Darlene Dobkowski
Disclosure: Landoni reports receiving nonfinancial support from Orion Corp. and personal fees from AbbVie, Orion Corp. and Tenax Therapeutics. Please see the full study for the other researchers’ relevant financial disclosures.