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

• Subjects hospitalized for worsening heart failure and randomized within 36 hours of initial presentation.
• Males and females 18 years of age or older.
• NYHA Class III or IV on admission to the hospital.
• Able to understand content of and willing to provide written informed consent
• 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.

• 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)
• 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

• Positive urine pregnancy test for women of child bearing potential.
• Inability to provide written informed consent.
• Cardiac surgery within 60 days prior to study randomization.
• Acute Coronary Syndrome (ACS) or percutaneous coronary intervention within 30 days prior to study randomization.
• Planned revascularization procedures, cardiac mechanical support implantation, cardiac transplantation, or other cardiac surgery within 30 days following study randomization.
• Planned electrophysiologic (EP) device implantation within 7 days following study randomization.
• Subjects who are on cardiac mechanical support.
• Co-morbid condition with an expected survival less than six months.
• History of a cerebrovascular accident within the last 30 days.
• Hemodynamically significant uncorrected primary cardiac valvular disease.
• Hypertrophic cardiomyopathy (obstructive or non-obstructive).
• Uncorrected thyroid disease, active myocarditis or known amyloid cardiomyopathy.
• History of primary significant liver disease or acute hepatic failure, as defined by the investigator.
• Chronic uncontrolled diabetes mellitus as determined by the investigator.
• Supine systolic arterial blood pressure < 90 mmHg.
• Serum creatinine > 3.5 mg/dL or undergoing dialysis.
• Hemoglobin < 9 g/dL
• History of hypersensitivity and/or idiosyncratic reaction to benzazepine derivatives (such as benazepril).
• Inability to take oral medications.
• 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.
• Previous exposure to tolvaptan within 7 days prior to randomization.
• 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.
• Ultrafiltration within 7 days prior to randomization or planned.
• Active gout
• Serum sodium >144 mEq/L