Development of a comprehensive new endpoint for the evaluation of new treatments for acute decompensated heart failure: results with levosimendan in the REVIVE 1 study

Traditionally, intravenous (IV) drugs in decompensated heart failure (HF) have been evaluated based on their hemodynamic effects. Thus, no endpoint to measure symptomatic improvement in decompensated HF has yet been validated. To do so, we adapted the clinical composite (which has been validated in trials of chronic HF) to the evaluation of IV levosimendan in a pilot trial of acute decompensated HF (REVIVE-1).

A total of 100 patients who were hospitalized for worsening HF and had dyspnea at rest despite IV diuretics were randomized (double-blind) to receive placebo (PBO) (n = 49) or IV levosimendan (LS) (n = 51), given as a loading dose of 12 μg/kg over 10 min and followed by a continuous infusion (0.1 μg/kg/hour for 50 min and 0.2 μg/kg/hour for 23 hours); patients were then followed closely for an additional 4 days. Patients were classified as improved if they reported their HF to be moderately or markedly improved at specific time points. Patients were classified as worse if they died or received an IV medication for worsening HF during the 5-day study period. Patients were considered unchanged if they were neither improved nor worse. Different models using different definitions for improvement and worsening were prospectively and retrospectively examined.

The initial model defined improvement based on the responses at 24 hours and at 5 days and restricted the definition of worsening to the use of IV vasodilators or inotropic agents. Using this model, improvement was observed more frequently with LS than with PBO (49% vs 33%), with no between-group difference in the proportion of patients who were worse (overall P = 0.229). When the definition of worsening was expanded to include the use of IV diuretics for worsening HF and confined to the occurrence of clinical events, LS-treated patients not only were more likely to show improvement (51% vs 33%) but were less likely to exhibit worsening (20% vs 35%) (overall P = 0.043). When the definition of improvement was expanded to include the responses at 6 hours (in addition to 24 hours and 5 days), the separation between the treatment groups increased even further (improvement in 33% vs 14% and worsening in 24% vs 37%) (overall P = 0.029) (LS vs PBO). The greater level of improvement in the clinical composite on levosimendan was supported by significant reductions in median plasma B-type natriuretic peptide concentrations compared with placebo at both 24 hours (-303 pg/ml vs -77.5 pg/ml, P = 0.001) and 5 days (-376 pg/ml vs -99.5 pg/ml, P = 0.027).

These findings indicate that a clinical composite approach can be used to develop an endpoint that distinguishes the effects of IV LS in the setting of acute decompensated HF. The new endpoint is now being used prospectively to evaluate the effects of LS in a definitive second study (REVIVE-2).