This pilot study will investigate the association between levels of the peptide copeptin and response to tolvaptan, a drug that blocks the action of the water retaining hormone vasopressin. The study will enroll stable outpatients with CHF with reduced LVEF (≤45) selected by targeting upper and lower quartile copeptin levels at screening (10 each). The treatment phase of the study will be a prospective, single-arm, open label protocol. All patients will receive active therapy consisting of a single oral dose of 30 mg of tolvaptan with body weight, fluid intake, and urine output monitored in a research unit for 24 hours.

For analysis of study endpoints, patients in the single intervention arm will be stratified by a prospectively determined cut-point of copeptin level into two groups (≥10 versus <10 pmol/L). The copeptin level used for the two group stratification will be the blinded copeptin value obtained at baseline from the hospital phase prior to administration of tolvaptan.

The study screening strategy will be designed to enroll an enriched patient population by identifying patients at the high or low end of the spectrum of copeptin levels for outpatients with stable heart failure. This will be accomplished by blinded review of copeptin levels obtained during screening.

The primary endpoints for analysis will be 24 hour urine output and the change in body weight over 24 hours during the inpatient stay.

Inclusion Criteria:

1. Male and female patients with a history of chronic symptomatic heart failure, defined as dyspnea on exertion or edema, due to cardiac dysfunction, of at least one month's duration
2. Left ventricular ejection fraction ≤ 45% as documented by quantitative assessment by an accepted imaging technique within one year of screening
3. Meet baseline copeptin criteria for entry
4. Currently taking a diuretic (with diuretic defined as any loop or thiazide diuretic or aldosterone antagonist at any dose)

Exclusion Criteria:

1. Current New York Heart Association Functional Class IV heart failure
2. Patients who are felt to be volume depleted based on clinical examination or need to reduce diuretic administration
3. Presence of clinical contraindications to tolvaptan
4. Episode of acute myocardial infarction or acute coronary syndrome within the past 3 months
5. Cardiovascular surgical procedure within the past 4 weeks
6. CHF due to uncorrected thyroid disease, active myocarditis, or known amyloid cardiomyopathy.
7. History of primary significant liver disease or acute hepatic failure, as defined by the investigator.
8. Chronic uncontrolled diabetes mellitus as determined by the investigator.
9. Supine systolic arterial blood pressure < 90 mmHg at screening
10. Serum creatinine > 3.5 mg/dL at screening
11. Serum potassium > 5.5 mEq/L or < 3.5 mEq/L at screening
12. Subjects currently treated with hemofiltration or dialysis

j. Subjects judged by the investigator to be unable to maintain accurate intake and output during their hospitalization related to medical or other problems

All patients in Low Copeptin group were included in analysis. One patient in High Copeptin group had reduced renal function at baseline versus screening and transient hypovolemia during hospitalization indicative of volume depletion. This patient was excluded prior to review of blinded copeptin results and study data analysis for a final N of 20.

24 hours