Safety of Repeated Levosimendan Use in Chronic Heart Failure

This study evaluated the clinical efficacy and safety of repeated levosimendan administration, both as monotherapy and in combination with dapagliflozin, in outpatients with chronic heart failure (CHF) and reduced ejection fraction (<40%). We conducted a multicenter, randomized, double-blind, placebo-controlled trial across five outpatient clinics in Moscow, Russia. A total of 393 patients were randomized into three groups: levosimendan (0.1 µg/kg/min, 24-hour infusions every 3 weeks), placebo, and combination therapy (levosimendan plus dapagliflozin 10 mg/day). All patients in the combination group were SGLT2 inhibitor–naïve. The primary outcomes included changes in NT-proBNP levels and hospitalization rates, while secondary outcomes assessed quality of life using the Minnesota Living with Heart Failure Questionnaire (MLHFQ), functional parameters, and safety. Combination therapy produced the greatest clinical benefit, with significant reductions in NT-proBNP (p = 0.03) and hospitalization rates (p = 0.04), and a significantly lower risk of hospitalization or death compared with placebo (HR = 0.58, 95% CI: 0.36–0.92, p = 0.021). Improvements in quality of life were also most pronounced in the combination group, with significant MLHFQ score changes at 3 months (p = 0.02) and 6 months (p = 0.04). Levosimendan monotherapy led to moderate improvements, but effects were consistently smaller than those observed with combination therapy. Safety and tolerability were acceptable across all groups, with no clinically meaningful changes in hematologic or biochemical markers. The combination of levosimendan and dapagliflozin provides superior clinical benefits in CHF outpatients, including reduced hospitalizations and improved quality of life, while maintaining a favorable safety profile.