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Safety and Efficacy of an Intravenous Placebo-Controlled Randomized Infusion of Ularitide - SIRIUS-2
Description:
The goal of the trial was to evaluate the safety and efficacy of ularitide, a renally derived natriuretic peptide, among patients with symptomatic decompensated chronic heart failure.
Study Design
Study Design:
Patients Enrolled: 221
Mean Follow Up: 30 days
Mean Patient Age: Mean age 61 years
Female: 22
Patient Populations:
Symptomatic decompensated heart failure with dyspnea at rest or with minimal activity; and PCWP ≥18 mm Hg
Exclusions:
Systolic blood pressure ≤90, volume depletion or cardiogenic shock, or use of a mechanical ventilator
Primary Endpoints:
1) Change in PCWP at six hours, and 2) change in patient-assessed dyspnea at six hours
Secondary Endpoints:
Hemodynamic parameters (RAP, CO, CI, SVR, SV); renal function through 72 hours; safety; and mortality at 30 days
Drug/Procedures Used:
Patients were randomized in a double-blind manner to one of three doses of ularitide (7.5 ng/kg/min, n=60; 15 ng/kg/min, n=53; 30 ng/kg/min, n=55) or placebo (n=53). A right heart catheterization was performed to assess hemodynamic parameters.
Principal Findings:
Cause of heart failure was ischemic cardiomyopathy in 52% of patients, dilated cardiomyopathy in 36%, and hypertensive heart disease in 11%. Baseline systolic blood pressure was 125 mm Hg, and mean pulmonary capillary wedge pressure (PCWP) was 25 mm Hg. Ejection fraction was <30% in 72% of patients.
The primary endpoint of reduction in PCWP at six hours was greater in the ularitide groups versus placebo (p<0.05 for the 7.5 dose group and p<0.01 for the 15 and 30 dose groups), a finding that was similar through 24 hours. The coprimary endpoint of moderate or marked improvement in patient assessed dyspnea at six hours was higher in the ularitide groups compared with placebo (p<0.05 for all dose groups).
There was no difference in N-terminal portion of probrain natriuretic peptide (NT-proBNP) at six hours between the placebo and ularitide groups, but at 24 hours, NT-proBNP was lower in the ularitide groups versus placebo (p<0.05 for the 15 and 30 dose groups). Renal function through 72 hours was not worsened in the ularitide groups versus placebo as assessed by urine output, serum creatinine, or creatinine clearance.
Adverse events (AEs) occurred more frequently in the ularitide groups versus placebo, but serious AEs were more frequent in the placebo group. The most common AEs were hypotension (6.5%), blood pressure decrease (5.4%), and cardiac failure (4.8%). During 30-day follow-up, there were seven deaths in the placebo group, two deaths in both the 7.5 and 15 dose ularitide dose groups, and one death in the 30 dose group.
Interpretation:
Among patients with symptomatic decompensated chronic heart failure, treatment with ularitide, a renally derived natriuretic peptide, was associated with greater improvements in PCWP at six hours and patient-assessed dyspnea at six hours compared with placebo.
While the present trial demonstrated early efficacy of ularitide with no increase in serious AEs or renal impairment, larger studies are planned to more fully evaluate safety and clinical efficacy. The present trial showed favorable trends toward lower mortality at 30 days in the ularitide groups compared with placebo, but the small sample size (n=221) was not adequate to assess whether the mortality difference was significant.
References:
Presented by Dr. Veselin Mitrovic at the European Society of Cardiology Hot Line Session, September 2005.
Keywords: Pulmonary Wedge Pressure, Follow-Up Studies, Cardiac Catheterization, Human Rights, Diuretics, Hypotension, Blood Pressure, Creatinine, Dyspnea, Bronchodilator Agents, Heart Failure, Peptide Fragments, Atrial Natriuretic Factor, Cardiomyopathy, Dilated, Natriuretic Peptide, Brain
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