Efficacy and Safety of Tolvaptan in the Treatment of Cardiac-Induced Edema in Patients With Heart Failure

Inclusion Criteria:

2. Patients with history of chronic HF hospitalized primarily for worsening HF with signsor symptoms of volume congestion in spite of standard therapy 3. Patient should have HFsymptoms at rest or minimal exertion and signs of congestion (lower limb edema, jugularvenous distention, or pulmonary congestion due to extracellular volume expansion) at timeof randomization c. Anti-aldosterone drugs: Spironolactone, Triamterene 4. Patientsundergoing any of the following diuretic therapies:

• A loop diuretic at a daily dosage equivalent to 40 mg or more of furosemide

• Concomitant administration of a loop diuretic and a thiazide diuretic (at any doses)

• Concomitant administration of a loop diuretic and an anti-aldosterone drug (at anydoses) Note: The allowable types and dosages of the concomitantly administered diuretics arespecified as follows:

1. Loop diuretics equivalent to 40 mg of furosemide: Bumetanide: 1 mg, Piretanide: 6 mg, Azosemide: 60 mg, Torasemide: 8 mg

2. Thiazide diuretics: Hydrochlorothiazide, Trichloromethiazide, Benzylhydrochlorothiazide, Chlortalidone, Mefruside 5. Patients who had been taking anorally administered diuretic without any change in dose or mode of administrationduring Observation period 6. Patients whose body weight variation was within 1.0 kgduring the 2 days prior start of treatment 7. Patients able to accomplish with studyprocedures from Screening period to Post-study follow-up 8. Patients capable of givinginformed consent to participate in the study of their own free will.

Exclusion Criteria:

1. Cardiac surgery within 60 days of enrollment

2. Patients with an assisted cardiac mechanical device

3. Patients receiving CRT (Cardiac Resynchronization Therapy) within 60 days ofenrollment.

4. Patients with active or significant complications or symptoms as follow:

• Suspected decrease in circulatory blood flow

• Refractory end-stage HF (patients considered to require mechanical circulatorysupport, continuous intravenous positive inotropic therapy, referral of cardiactransplantation, or hospice care)

• Cardiac valvular disease with significant heart valve stenosis

• Sustained ventricular tachycardia or ventricular fibrillation within 30 daysprior to screening examination

• Acute myocardial infarction within 30 days prior to screening examination

• Cerebrovascular disorders within 6 months prior to screening examination (otherthan asymptomatic cerebral infarction)

• Patients with a definite diagnosis of active myocarditis or amyloidcardiomyopathy

• Poorly controlled Diabetes Mellitus (HbAlc 10%)

• Anuria (urinary output less than 100 ml per day)

• History of Hyperthyroidism

• Urination impaired due to urinary tract stricture, urinary calculus, tumor inurinary tract, or other cause

• Hemofiltration or dialysis

• Patients unable to sense thirst, inappropriately respond to thirst or those whohave impaired oral fluid intake.

5. Patients with a history of hypersensitivity or idiosyncratic reaction to benzazepinederivatives such as mozavaptan hydrochloride or benazepril hydrochloride

6. Patients who are severely obese (BMI exceeding 35 kg/m2)

7. Patients with systolic blood pressure in the decubitus position below 90 mmHg

8. Patients with any of following abnormal laboratory values: Total bilirubin exceeding 3.0 mg/dL, hemoglobin of less than 9 g/dL, serum creatinineexceeding 3.0 mg/dL, serum sodium exceeding 147 mEq/L, or serum potassium exceeding 5.5 mEq/L

9. Female patients who are pregnant, possibly pregnant, or lactating, or who plan tobecome pregnant

10. Patients who received any investigational drug other than Tolvaptan within 30 daysprior to the screening examination

11. Patients with general physical conditions, which may confound the results of thestudy, pose additional risk or preclude evaluation and assessments in this study