The trial used a 2-by-2 factorial design. Patients were randomly assigned, in a 1:1:1:1 ratio, to either a low-dose strategy (total intravenous furosemide dose equal to their total daily oral loop diuretic dose in furosemide equivalents) or a high-dose strategy (total daily intravenous furosemide dose 2.5 times their total daily oral loop diuretic dose in furosemide equivalents) and to administration of furosemide either by intravenous bolus every 12 hours or by continuous intravenous infusion. Randomization was performed with the use of permuted blocks, stratified according to clinical site. A double-blind, double-dummy design was used so that all patients received both intravenous boluses every 12 hours and a continuous infusion, one of which contained furosemide and the other a saline placebo.
The study treatment, with group assignments concealed, was continued for up to 72 hours. At 48 hours, the treating physician had the option of adjusting the diuretic strategy on the basis of the clinical response. At this time, the physician could increase the dose by 50% (with the study treatment remaining concealed), maintain the same strategy (with the study treatment remaining concealed), or discontinue intravenous treatment and change to open-label oral diuretics. After 72 hours, all treatment was open-label at the discretion of the treating physician, who did not have knowledge of the prior study-treatment assignment. An assessment of biomarkers, including creatinine, cystatin C, and N-terminal pro-brain natriuretic peptide, was performed at a central core laboratory at baseline, 72 hours, and 60 days. Patients were followed for clinical events to day 60.
The study treatment, with group assignments concealed, was continued for up to 72 hours. At 48 hours, the treating physician had the option of adjusting the diuretic strategy on the basis of the clinical response. At this time, the physician could increase the dose by 50% (with the study treatment remaining concealed), maintain the same strategy (with the study treatment remaining concealed), or discontinue intravenous treatment and change to open-label oral diuretics. After 72 hours, all treatment was open-label at the discretion of the treating physician, who did not have knowledge of the prior study-treatment assignment. An assessment of biomarkers, including creatinine, cystatin C, and N-terminal pro-brain natriuretic peptide, was performed at a central core laboratory at baseline, 72 hours, and 60 days. Patients were followed for clinical events to day 60.
