Low-dose levosimendan infusions in advanced heart failure: efficacy, safety, and factors associated with outcomes

Background In advanced heart failure (AdHF), repeated levosimendan infusions between 0.1 and 0.2 μg/kg/min for 6–24 h every 2–4 weeks were associated with inconsistent outcomes and trends towards worse prognosis. Treatment effect with lower dosing is however unknown. The aims of this retrospective study were to assess the impact of 24-h levosimendan cycles at 0.05 μg/kg/min every 4 weeks on HF therapy, outcomes, and safety and to identify predictors of treatment efficacy. Methods Among 286 AdHF patients, 39 levosimendan-treated subjects (4.19 ± 2.6 infusions) and 39 standard-of-care (SOC) subjects matched 1:1 based on a propensity score accounting for age, sex, ischemic heart disease, left ventricular (LV) ejection fraction, creatinine, heart rhythm, and heart transplantation (HTx) listing underwent comparison of their outcome. Efficacy was defined as 1-year survival without LV-assist-device, urgent HTx and urgent hospitalization for HF. Adverse events (AE) included permanent levosimendan interruption, sustained arrhythmias, or hypotension occasioning permanent infusion hold. Results Beta-blocker (BB) dose increased with levosimendan [34.7% (18.4–50%) of target-dose at 6-months vs. 21.9% (6.25–25%) at baseline (P = 0.022)]. At 1 year, 26 patients reached the efficacy endpoint in the levosimendan group vs. 14 in the SOC group (HR = 0.42; 95% CI = 0.22–0.83; P = 0.01). The benefit of levosimendan was essentially driven by the reduction of HF hospitalization (HR = 0.367; 95% CI = 0.16–0.85; P = 0.014), with no difference in the reduction of death, LVAD or SU-HTx (HR = 0.8; 95% CI = 0.3–21.4; P = 0.65). No AE occurred. We found no prognostic factor at baseline but BB therapy (95.6% vs. 50%; P = 0.005), higher BB dosing (33 ± 20% vs. 9 ± 20% of target-dose; P = 0.036), and lower heart rate (71 ± 10.4 vs. 81 ± 14 bpm; P = 0.039) at 3 months were associated with treatment efficacy. Conclusion Our findings raise the hypotheses that low-dose levosimendan is safe, enables BB up-titration, and is associated with improved outcomes. Heart rate, BB therapy, and BB dosing at 3 months may predict event-free survival.