Levosimendan in Severe Renal Insufficiency: Efficacy and Safety from a Systematic Review and Meta-Analysis

Levosimendan is a calcium-sensitizing inotropic agent recommended for Heart Failure (HF) treatment but contraindicated in patients with Creatinine Clearance (Ccr) below 30 mL/min. This study aims to systematically evaluate its efficacy and safety in patients with severe renal insufficiency.

A systematic literature search was conducted in PubMed, Embase, and the Cochrane Library. Randomized Controlled Trials (RCTs) and cohort studies comparing the efficacy and safety of levosimendan in patients with severe renal insufficiency were included. Studies reporting outcomes only in patients with normal renal function or those with Ccr greater than 30 mL/min were excluded. The primary outcome was all-cause mortality.

A total of 1541 records were identified, and seven studies enrolling 814 patients were included in the meta-analysis. There was no significant difference in all-cause mortality between levosimendan and control groups [odds ratio (OR) 1.13, 95% confidence interval (CI) 0.66 to 1.94, p = 0.67, I2 = 23%]. Subgroup analyses showed no significant differences in 30-day mortality [OR 1.17, 95% CI (0.69, 1.99), p = 0.55, I2 = 15%] or 180-day mortality [OR 1.09, 95% CI (0.39, 13.06), p = 0.87, I2 = 57%].

The absence of mortality benefit may reflect levosimendan's altered pharmacokinetics and competing uremic risks in severe renal insufficiency. However, renoprotective mechanisms have been primarily characterized in populations without renal impairment, and the prolonged half-life of OR-1896 in this setting may potentiate both hemodynamic effects and adverse events.

This study found that available evidence from small, heterogeneous observational studies is insufficient to determine whether levosimendan affects mortality in severe renal insufficiency. These findings do not support any clinical recommendation, provide no basis to modify the existing contraindication for Ccr below 30 mL/min, and highlight the need for further RCTs with comprehensive endpoints.