Randomized, Double-Blind, Placebo Controlled Study of the Short Term Clinical Effects of Tolvaptan in Patients Hospitalized for Worsening Heart Failure With Challenging Volume Management

Inclusion Criteria:

1. Subjects hospitalized for worsening heart failure and randomized within 36 hours of
initial presentation.

2. Males and females 18 years of age or older.

3. NYHA Class III or IV on admission to the hospital.

4. Able to understand content of and willing to provide written informed consent

5. Dyspnea, measured by the 5-point current dyspnea scale (moderately short of breath or
worse), within 2 hours of randomization and dosing.

The following must be met within 12 hours of randomization.

6. The subject must have signs of extracellular volume expansion, defined as two or more
of the following five: Signs of RHF ( jugular venous distention, pitting edema (≥1+),
ascites) and/or Signs of LHF (pulmonary congestion on chest x-ray, pulmonary rales)

7. Have at least one of the following:

- eGFR < 60ml/min/1.73m2, OR

- serum sodium ≤ 134 mEq/L, OR

- urine output ≤ 125 ml/hr over anytime frame of at least 2 hours, following
administration of IV furosemide of at least 40mg. See table below.

Time Period (hr) Cumulative UO (mL) 2 <250 3 <375 4 <500 5 <625 6 <750 7 <875 8 <1000

Exclusion Criteria:

1. Positive urine pregnancy test for women of child bearing potential.

2. Inability to provide written informed consent.

3. Cardiac surgery within 60 days prior to study randomization.

4. Acute Coronary Syndrome (ACS) or percutaneous coronary intervention within 30 days
prior to study randomization.

5. Planned revascularization procedures, cardiac mechanical support implantation, cardiac
transplantation, or other cardiac surgery within 30 days following study
randomization.

6. Planned electrophysiologic (EP) device implantation within 7 days following study
randomization.

7. Subjects who are on cardiac mechanical support.

8. Co-morbid condition with an expected survival less than six months.

9. History of a cerebrovascular accident within the last 30 days.

10. Hemodynamically significant uncorrected primary cardiac valvular disease.

11. Hypertrophic cardiomyopathy (obstructive or non-obstructive).

12. Uncorrected thyroid disease, active myocarditis or known amyloid cardiomyopathy.

13. History of primary significant liver disease or acute hepatic failure, as defined by
the investigator.

14. Chronic uncontrolled diabetes mellitus as determined by the investigator.

15. Supine systolic arterial blood pressure < 90 mmHg.

16. Serum creatinine > 3.5 mg/dL or undergoing dialysis.

17. Hemoglobin < 9 g/dL

18. History of hypersensitivity and/or idiosyncratic reaction to benzazepine derivatives
(such as benazepril).

19. Inability to take oral medications.

20. Participation in another clinical drug or device trial where the last dose of drug was
within the past 30 days or an investigational medical device is currently implanted.

21. Previous exposure to tolvaptan within 7 days prior to randomization.

22. Subjects with refractory, end-stage, heart failure defined as subjects who are
appropriate candidates for specialized treatment strategies, such as ventricular
assist devices, continuous positive IV inotropic therapy, or hospice care.

23. Ultrafiltration within 7 days prior to randomization or planned.

24. Active gout

25. Serum sodium >144 mEq/L