Determining Optimal Dose and Duration of Diuretic Treatment in People With Acute Heart Failure (The DOSE-AHF Study)

Heart failure is a common disorder in which the heart cannot pump enough blood to meet the
needs of the rest of the body. Heart failure symptoms include shortness of breath, swelling,
and fatigue. Standard treatment for the swelling associated with heart failure includes the
use of diuretic medications, such as furosemide, which cause urination and the removal of
excess fluids in the body. Although furosemide has been used to treat heart failure patients
for many years, it is still unclear how much of the drug to use, and over what time period
the drug should be given. This study will evaluate whether furosemide treatment is safer and
more effective when the drug is given in high doses versus low doses and in two to three
separate doses versus one continuous infusion.

Participants in this study will begin study procedures within the first 24 hours of their
hospital admission for heart failure. Participants will be randomly assigned to receive one
of the following four treatments: high dose furosemide via continuous intravenous (IV)
infusion and placebo every 12 hours via IV bolus; low dose furosemide via continuous IV
infusion and placebo every 12 hours via IV bolus; high dose furosemide every 12 hours via IV
bolus and placebo via continuous IV infusion; and low dose furosemide every 12 hours via IV
bolus and placebo via continuous IV infusion. Each participant will receive treatment for the
first 72 hours of his or her hospital stay. Participants will answer questionnaires and
undergo physical examinations and blood tests during the first 96 hours of hospitalization
and again before hospital discharge or on Day 7, if that occurs first. Participants will be
asked to return to their doctors 60 days following hospital discharge to evaluate their
responses to treatment.

Inclusion Criteria:

- Prior clinical diagnosis of heart failure that was treated with daily oral loop
diuretics for at least 1 month

- Current diagnosis of heart failure, as defined by the presence of at least 1 symptom
(dyspnea, orthopnea, or edema) AND 1 sign (rales on auscultation, peripheral edema,
ascites, pulmonary vascular congestion on chest radiography)

- Daily oral dose of furosemide between 80 mg and 240 mg (or equivalent)

- Identified within 24 hours of hospital admission

- Current treatment plan includes IV loop diuretics for at least 48 hours

Exclusion Criteria:

- Brain natriuretic peptide (BNP) less than 250 mg/mL or N-terminal prohormone brain
natriuretic peptide (NT-proBNP) less than 1000 mg/mL

- Received IV vasoactive treatment or ultra-filtration therapy for heart failure since
initial presentation

- Treatment plan during current hospitalization includes IV vasoactive treatment or
ultra-filtration for heart failure

- Substantial diuretic response to pre-randomization diuretic dosing such that higher
doses of diuretics would be medically inadvisable

- Systolic blood pressure less than 90 mm Hg

- Serum creatinine level greater than 3.0 mg/dL at baseline or currently undergoing
renal replacement therapy

- Hemodynamically significant arrhythmias

- Acute coronary syndrome within 4 weeks prior to study entry

- Active myocarditis

- Hypertrophic obstructive cardiomyopathy

- Severe stenotic valvular disease

- Restrictive or constrictive cardiomyopathy

- Complex congenital heart disease

- Constrictive pericarditis

- Non-cardiac pulmonary edema

- Clinical evidence of digoxin toxicity

- Need for mechanical hemodynamic support

- Sepsis

- Terminal illness (other than heart failure) with expected survival time of less than 1
year

- History of adverse reaction to the study drugs

- Use of IV iodinated radiocontrast material within 72 hours prior to study entry or
planned during hospitalization

- Enrollment or planned enrollment in another randomized clinical trial during this
hospitalization

- Inability to comply with planned study procedures