Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure

OBJECTIVES We sought to define the therapeutic dose range of levosimendan in patients with New York Heart Association class II-IV heart failure of ischemic origin. BACKGROUND Levosimendan is a calcium sensitizer for treatment of acute decompensated heart failure. METHODS A double-blind, placebo-controlled, randomized, multicenter, parallel-group study included 151 adult patients. Levosimendan was given as a 10-min intravenous bolus of 3, 6, 12, 24 or 36 μg/kg, followed by a 24-h infusion of 0.05, 0.1, 0.2, 0.4 or 0.6 μg/kg/min, respectively. Dobutamine, for comparative purposes, was given as an open-label infusion (6 μg/kg/min). The primary efficacy variable was the proportion of patients achieving in each treatment group at least one of the following: 1) a ≥15% increase in stroke volume (SV) at 23 h to 24 h; 2) a ≥25% decrease in pulmonary capillary wedge pressure (PCWP) (and ≥4 mm Hg) at 23 h to 24 h; 3) a ≥40% increase in cardiac output (CO) (with change in heart rate [HR] <20%); 4) a ≥50% decrease in PCWP during two consecutive measurements. RESULTS The response rate to levosimendan ranged from 50% at the lowest dose to 88% at the highest dose (compared with placebo 14%, dobutamine 70%). A dose-response relationship was demonstrated for levosimendan on increases in CO and SV, and reductions in PCWP during the infusion (for all, p ≤ 0.001). Headache (9%), nausea (5%) and hypotension (5%) were the most frequently reported adverse events at higher dosages. CONCLUSIONS Dosing of levosimendan with a 10-min bolus of 6 to 24 μg/kg followed by an infusion of 0.05 to 0.2 μg/kg/min is well tolerated and leads to favorable hemodynamic effects.