Targeting Acute Congestion With Tolvaptan in Congestive Heart Failure

This study will be a randomized, double blind, placebo controlled, multi-center clinical
trial of patients with signs and symptoms consistent with acute heart failure (AHF) within
24 hours of presentation at Emergency Department. A total of approximately 250 patients will
be enrolled in the trial.

Patients will be randomized in a 1:1 ratio to either of 2 treatment regimens:

- Fixed-dose IV furosemide (1 x total daily oral dose) given intravenously in divided
doses every 12 hours or 40 mg IV Q12 hours, whichever is greater + oral Tolvaptan
(given at 0, 12, 24 and 48 hours)

- Fixed-dose IV furosemide (1 x total daily oral dose) given intravenously in divided
doses every 12 hours or 40 mg IV Q12 hours, whichever is greater + oral placebo (given
at 0, 12, 24 and 48 hours)

The study treatment regimen will be administered from randomization through 48 hours, at
which point Tolvaptan/placebo will be discontinued and all diuretic treatment will be
adjusted at the treating physician's discretion.

The primary endpoint will be the proportion of patients with at least moderate improvement
in dyspnea by Likert scale at both 8 AND 24 hours AND without the need for escalation of
therapy due to worsening heart failure (rescue therapy) or death within 24 hours.

Patients will be followed daily for the duration of hospitalization or for 7 days (whichever
is shortest).

All patients will have Day 30 follow up phone contact for assessment of vital status and
interval hospitalizations.

Inclusion Criteria:

- ≥ 18 years of age

- Daily oral dose of furosemide between ≥ 40 mg(or equivalent)

- Identified within 24 hours of presentation, defined for purposes of this study as the
time of initial dose of intravenous loop diuretic

- Prior clinical HF diagnosis that was treated with oral loop diuretics for at least 1
month

- Admission for acute decompensated Heart Failure (HF) as determined by

- dyspnea at rest or with minimal exertion

- Brain Natriuretic Peptide (BNP) > 400 or NTproBNP > 2000 pg/mL

AND at least one of the following additional signs and symptoms:

- Orthopnea

- Peripheral edema

- Elevated JVP (Jugular Venous Pressure)

- Pulmonary rales

- Congestion on Chest X-ray

- No plan for revascularization, cardiac transplant, of ventricular assist device
implantation, or other cardiac surgery within 60 days of randomization

- Signed informed consent

Exclusion Criteria:

- Serum Na > 140 meq/L

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

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

- Systolic Blood Pressure (SBP)<90mmHg

- Serum-Cr>3.5mg/dl or currently undergoing renal replacement therapy

. Known underlying liver disease

- Hemodynamically significant arrhythmias

- ACS(Acute coronary syndrome) within 4 weeks prior to study entry

- Active myocarditis

- Hypertrophic obstructive, restrictive, constrictive cardiomyopathy

- Severe stenotic valvular disease

- Complex congenital heart disease

- Constrictive pericarditis

- Clinical evidence of digoxin toxicity

- Need for mechanical hemodynamic support

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

- History of adverse reaction to Tolvaptan

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

- Pregnant or breast-feeding

- Inability to comply with planned study procedures