REVIVE II - REVIVE II

Description:

The goal of the trial was to evaluate treatment with levosimendan, a novel calcium sensitizer drug, compared with placebo among patients with acute decompensated heart failure.

Study Design

Study Design:

Patients Enrolled: 600
Mean Follow Up: 90 days
Mean Patient Age: Mean age 63 years
Female: 27
Mean Ejection Fraction: Baseline ejection fraction 23%

Patient Populations:

Hospitalized for worsening heart failure, LV ejection fraction ≤35%, dyspnea at rest despite IV diuretics

Primary Endpoints:

Change in clinical course through 5 days after randomization, based on death or worsening heart failure or changes in symptoms

Secondary Endpoints:

BNP at 24 hours, global patient assessment score at 6 hours, patient assessed dsyspnea at 6 hours, death or worsening heart failure, duration of hospitalization, all-cause mortality at 90 days

Drug/Procedures Used:

Patients were randomized in a double-blind manner to treatment with levosimendan (6-12 µg/kg bolus followed by 0.1-0.2 µg/kg/min infusion for 24 hours) (n=299) or matching placebo (n=301). Other standard medications for treatment of acute decompensated heart failure were to be used. Levosimendan is a novel calcium sensitizer drug designed to have actions of both inotropic agents and vasodilators.

Principal Findings:

Baseline ejection fraction was 23%. The primary endpoint of change in clinical course through 5 days was more often improved (by 33%) in the levosimendan group compared with placebo and was less often worsened (by 26%) in the levosimendan group (p=0.015). The percentage of patients requiring rescue therapy was lower in the levosimendan group (15% vs 26%), including worsening dyspnea or tachypnea (7% vs 12%) and unresponsive symptoms (6% vs 10%). BNP at 24 hours was lower in the levosimendan group (p<0.001), a finding that was maintained through 5 days but did not differ at 30 days. Patient global assessment score was improved in the levosimendan group at 24 hours (p=0.026). Duration of hospitalization was shorter in the levosimendan group (7.0 days vs 8.9 days, p=0.006).

Among the adverse events, hypotension occurred more frequently in the levosimendan group (n=147 vs n=107), as did atrial fibrillation (n=25 vs n=6). Mortality at 90 days did not differ significantly by treatment group (15.1% for levosimendan vs 11.6% for placebo).

Interpretation:

Among patients with acute decompensated heart failure, treatment with levosimendan, a novel calcium sensitizer drug, was associated with greater improvements in clinical course through 5 days compared with placebo.

Levosimendan acts by maintaining the amount of calcium in the heart but increasing the sensitivity of the heart to the calcium. It also facilitates the opening of potassium channels. The primary endpoint and many of the secondary endpoints, including BNP, patient global assessment, and length of hospitalization were improved in the levosimendan group. The RUSSLAN trial demonstrated a reduction in mortality at 6 months with levosimendan among patients with left ventricular failure after acute MI. Despite the improvements in surrogate endpoints in the present study, there was no difference in mortality. Likewise, in the SURVIVE-W trial, there was no difference in mortality between levosimendan and dobutamine.

References:

Presented by Dr. Milton Packer at the American Heart Association Scientific Session, Dallas, Texas, November 2005.

Clinical Topics: Arrhythmias and Clinical EP, Dyslipidemia, Heart Failure and Cardiomyopathies, EP Basic Science, Lipid Metabolism, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Potassium Channels, Dobutamine, Biological Markers, Tachypnea, Heart Failure, Hypotension, Dyspnea, Hydrazones, Vasodilator Agents, Pyridazines, Calcium


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