LAUSR

Background Loop diuretics are the mainstay of treatment and prevention of fluid overload in patients with heart failure (HF). A subcutaneous (SC) infusion of a novel, pH neutral formulation of furosemide (furo) demonstrated comparable drug exposures, diuresis and natriuresis compared to IV bolus injections. The purpose of this analysis was to compare blood pressure, heart rate and respiratory rates between SC infusion and IV bolus injection of furo in patients with HF. Methods A randomized, open label, 2-way crossover study was conducted to compare the pharmacokinetics and pharmacodynamics of a SC infusion of furo compared to IV bolus injections. SC furo (80mg) was administered over 5 hours in a biphasic regimen (30 mg 1st hour followed by 12.5 mg/hr for the subsequent 4 hours). IV furo was administered as two 40 mg intravenous boluses 2 hours apart consistent with approved FDA labeling. BP, HR and RR were screened at baseline and obtained at 0,1,2,3,4,5,8,12 and 24 hours. Differences were assessed at each time point relative to baseline by Wilcoxon-Mann-Whitney test and repeated measures multivariate analysis of variance was conducted (MANOVA) to assess differences across the 24-hour period. Results Sixteen patients were included in the safety population. Average age was 68 years, 94% male, 81% NYHA Class II and 100% had hypertension. At hour 3 and 4, subjects who received SC furo had a mean (SD) reduction in systolic BP of 2.56 (9.70) and 0.81 (13.51) mm-Hg compared to 9.56 (13.37) and 7.5 (11.31) with IV furo, respectively (p=0.073 (3 hour) and 0.070 (4 hour)). In the repeated measures assessment, there was a less reduction in systolic BP relative to baseline with SC furo compared to IV furo (p=0.034) (Figure). There were no significant differences observed in HR, RR or diastolic BP during the 5-hour dosing period or the subsequent follow up between SC and IV arms. Conclusion In patients with HF, a 5-hour subcutaneous infusion of 80 mg furo was associated with less reduction in the mean systolic BP compared to two-40 mg intravenous bolus injections.