There is no evidence of benefit for various initial administration or dosing strategies of furosemide therapy in patients with acute decompensated heart failure (ADHF). However, the high-intensification (2.5 x chronic daily oral dose) dosing strategy was associated with improvements or trends toward improvement in multiple areas. Findings from the Diuretic Optimization Strategies Evaluation in Acute Heart Failure (DOSE-AHF; NCT00577135) Study were presented by G. Michael Felker, MD, Duke Clinical Research Institute, Durham, NC.

Intravenous (IV) loop diuretics are commonly prescribed for patients with ADHF. However, there is some debate concerning the risk, benefit, and appropriate use of higherdose diuretics. There is also an absence of prospective studies and trial evidence to provide clinicians with consistent guidelines for diuretic management. In light of current uncertainty pertaining to the appropriate administration and dosing of diuretics, DOSE-AHF investigators set out to evaluate the safety and efficacy of two administration (bolus Q 12 hours vs continuous infusion) and two dosing (low intensification of 1 x chronic daily oral dose furosemide vs high intensification of 2.5 x chronic daily oral dose furosemide) strategies.

DOSE-AHF was a double-blind, randomized trial with a 2×2 factorial design that included 308 patients with prior clinical diagnosis of acute heart failure (AHF; defined by at least one symptom and one sign) who were identified within 24 hours of hospital admission. All patients were taking oral furosemide 80 mg to 240 mg daily with an anticipated need for IV loop diuretics for at least 48 hours. Patients were excluded from participation if they received or planned to receive IV vasoactive therapy or ultrafiltration therapy for HF; had acute coronary syndrome within 4 weeks; and had systolic blood pressure <90 mmHg, serum creatinine>3.0 mg/dL at baseline, B-type natriuretic peptide (BNP) <250 pg/mL, or N-terminal pro-BNP (NT-proBNP) <1000 pg/mL.

The coprimary endpoints were the efficacy endpoint of patient global assessment by visual analog scale (VAS) over 72 hours using area under the curve (AUC) and the safety endpoint of renal function assessment, defined as change in creatinine from baseline to 72 hours. The study was 88% powered for detecting a creatinine difference of 0.2 mg/dL and a 600-point difference in VAS. Statistical significance for the two primary endpoints was p≤0.25. VAS was assessed at 6, 12, 24, 48, and 72 hours. The secondary endpoints are contained in Table 1.

The difference in global symptom relief and renal function was not statistically significant at 72 hours with regard to administration method (bolus vs continuous infusion) or dose (low vs high intensification). Additionally, results for all secondary endpoints were similar, regardless of the method of furosemide administration. Though transient changes in renal function occurred in patients who received high-intensification therapy prior to 60 days, the difference between the two groups dissipated by Day 60. High-intensification therapy was associated with improvements or trends toward improvement in multiple domains, including dyspnea, change in weight, change in NT-proBNP, and net volume loss (Table 1).

It is important to note that this study evaluated only patients with a history of chronic HF and moderate to high diuretic requirements. Therefore, these results may not apply to de novo HF patients, concluded Dr. Felker. DOSE protocol also allowed for changes in therapeutic strategy at 48 hours, based on clinical response. This and the study's limited power to detect differences in clinical events may have influenced results with regard to observed differences between the groups.