Interaction between renal function and the effect of levosimendan on long-term mortality of patients with low-output heart failure

Renal dysfunction is an adverse prognostic sign in patients with chronic stable heart failure. We used pooled data from the LIDO (n = 203) and RUSSLAN (n = 498) trials to explore the influence of renal function on outcome in severe, unstable heart failure, and to evaluate the effects of the novel calcium sensitising agent, levosimendan, in those patients with severe heart failure with different levels of renal impairment. Patients in the LIDO study with low-output heart failure received infusions of either levosimendan, loading dose 24 μg/kg over 10 min, followed by a continuous infusion of 0.1 μg/kg per min, or dobutamine, 5 μg/kg per min with no loading dose, for 24 hours. In patients with < 30% increase in cardiac output after 2 hours the infusion rate of both drugs was doubled for the rest of the treatment period. Patients in the RUSSLAN study with heart failure following an acute ischaemic event were given either levosimendan, loading dose 6–24 μg/kg over 10 min, then 0.1–0.4 μg/kg, or placebo, for 6 hours. Six patients were excluded as baseline serum creatinine values were unavailable. Patients were classified according to their baseline renal function by calculating creatinine clearance (CLcr) values from baseline serum creatinine by the formula of Cockroft and Gault. The groups were, normal renal function (CLcr > 80 ml/min; n = 236); mild impairment (CLcr 50–80 ml/min; n = 274); moderate impairment (CLcr 30–49 ml/min; n = 151); and severe impairment (CLcr < 30 ml/min; n = 40). The overall 180-day mortality rate in the total study population increased significantly in relation to the severity of renal impairment (overall hazard ratio [HR] for each incremental increase in renal impairment, 1.5 [1.2, 1.9]; P = 0.001). Mortality was 18% for patients with normal renal function, 23% for mild impairment, 43% for moderate impairment and 45% for severe impairment. However, the 180-day mortality rate was significantly lower in patients treated with levosimendan compared with patients treated with dobutamine or placebo in LIDO and RUSSLAN, respectively (HR 0.64 [0.47, 0.88]; P = 0.006). The HRs for the reduction in mortality within each class of renal impairment were similar. These results suggest that levosimendan has a long-term beneficial effect on patient survival, independent of the degree of observed renal impairment.