Sustained hemodynamic effects of intravenous levosimendan

Background-The short-term infusion of levosimendan (Levo) improves hemodynamic function in patients with decompensated heart failure. The metabolites of Levo have a prolonged half-life, and one is hemodynamically active. The goal of this study was to determine whether the hemodynamic effects of Levo are sustained during a long-term infusion and beyond the discontinuation of drug infusion. Methods and Results-Patients with decompensated heart failure received escalating infusion rates of intravenous Levo (n=98) or placebo (n=48) for 6 hours. At the end of 6 hours, 85 of the Levo-treated patients were continued on open-label drug for a total of 24 hours. at which time they were randomized 1:1 to an additional 24 hours of Levo (n=43) or placebo (n=42). The hemodynamic effects observed at 24 hours were maintained at 48 hours in both the continuation and withdrawal groups and did not differ between groups. Although the plasma concentration of Levo decreased rapidly in the withdrawal group, concentrations of the active metabolite OR-1896 were similar in the continuation and withdrawal groups at 24 hours and increased further (3.5-fold to 4-fold) and to a similar extent in both groups at 48 hours. Conclusions-The hemodynamic effects of Levo were maintained during a 48-hour continuous infusion and for at least 24 hours after discontinuation of a 24-hour infusion. The active metabolite OR-1896 increased for at least 24 hours after cessation of drug infusion and may account for the prolonged hemodynamic effects of Levo.