Clinical benefit including increased cardiac output was gained with the calcium–sensitizing inotrope levosimendan, although the co–primary endpoints were not significantly improved in the LEVO–CTS trial evaluating the effect of the drug to prevent low cardiac output syndrome (LCOS) and its associated adverse outcomes in patients with a low left ventricular ejection fraction undergoing cardiac surgery, according to results presented by John H. Alexander, MD, FACC, on March 19 at ACC.17, and simultaneously published in the New England Journal of Medicine.

LEVO–CTS, the first large trial to investigate levosimendan for this reason, randomized 882 patients (median age 65 years, 19 percent women) at 70 sites in North America with a left ventricular ejection fraction <35 percent (median 26 percent) to an intravenous infusion of levosimendan that continued for 24 hours. Most patients (66 percent) underwent CABG.

Both co–primary composite endpoints occurred at a similar rate in both the levosimendan and placebo groups and were adjusted for age, sex, type of surgery, and ejection fraction. The first co–primary endpoint of death or dialysis through day 30, myocardial infarction or the use of a mechanical assist device through day five occurred in 24.5 percent of each group (odds ratio [OR], 1.01; p = 0.9775). The second co–primary endpoint of death through day 30 or mechanical assist device through day five occurred in 13.1 percent of the levosimendan group and 11.4 percent of the placebo group (OR, 1.18; p = 0.4501).

Of the components of the primary endpoints, myocardial infarction was the most frequent at 15.7 percent and 15.0 percent with levosimendan and placebo, respectively, followed by a mechanical assist device by day five in 11 percent and 9 percent, respectively. The rates of death were 3.5 percent and 4.5 percent with levosimendan and placebo, respectively, and the rates of dialysis were 2.1 percent and 3.8 percent. The cardiac index was significantly higher with levosimendan than placebo; it was a mean 2.86 in 359 patients taking levosimendan and a mean 2.68 in 340 patients taking placebo (p < 0.0001).

LCOS, a secondary endpoint occurred in 18.2 percent of the levosimendan group and 25.7 percent of the placebo group (OR, 0.62; p = 0.007). Fewer patients taking levosimendan required an additional inotropic drug compared with placebo (54.9 percent vs 62.7 percent; OR, 0.71; p = 0.017). Mortality at 90 days was 4.7 percent with levosimendan and 7.1 percent with placebo (hazard ratio, 0.64; p = 0.123). The 30–day safety outcomes were similar in both groups.

"The drug had its intended biologic effect in increasing cardiac output and reducing low cardiac output syndrome, but that did not translate into a reduction in our endpoints," said Alexander. "In countries where levosimendan is available, if you want a drug that increases cardiac output and has good safety data, levosimendan is a reasonable option, because other available inotropes have less well known or adverse safety data."