The study is being conducted to examine whether KW-3902IV will result in greater improvement in signs and symptoms of heart failure, with less treatment failure than standard therapy, when it is added to IV loop diuretics in subjects with acute heart failure syndrome and renal impairment.

Loop diuretics are generally first line therapy in patients hospitalized with acute heart failure syndrome (AHFS). Their use far exceeds that of vasoactive agents. Tubuloglomerular feedback (TGF) is the body's compensatory response to avoid excess fluid loss, and it is activated when elevated sodium concentrations in the distal tubule are detected. TGF is proposed as a contributing factor for the observed diuretic resistance that occurs in patients with heart failure. Higher doses of diuretics are required to overcome the decreased natriuresis and reduced RBF induced by TGF. Ultimately, this action creates a vicious cycle of worsening renal function and diminished diuretic effectiveness.

The primary pharmacologic rationale for the use of KW-3902 in subjects with AHFS is its mechanism of action as an adenosine A1 receptor antagonist. TGF promotes release of adenosine, and adenosine binding to A1 receptors causes vasoconstriction of the afferent arteriole, decreased RBF, and enhanced sodium reabsorption by the proximal tubule. This action results in a decrease in GFR, diminished renal function, and sodium and water retention. Blocking adenosine A1 receptors via a selective adenosine receptor antagonist may limit sodium reabsorption by the proximal tubules without triggering TGF. It promotes vasodilation of the afferent arteriole of the glomerulus, and thus, this strategy offers the potential to overcome diuretic resistance or enhance diuretic responsiveness. It may also reduce the need for increasing diuretic doses that have been associated with worse outcomes.

The objectives of this study are to evaluate the effect of KW-3902IV in addition to intravenous (IV) loop diuretics (such as furosemide) on heart failure signs and symptoms, renal function, and safety in subjects hospitalized with AHFS, volume overload, and renal impairment, and to estimate and compare within-trial medical resource utilization and direct medical costs between patients treated with KW-3902IV versus placebo.

Inclusion Criteria:

1. History of heart failure of at least 14 days duration for which diuretic therapy has been prescribed
2. Hospitalized for acute heart failure syndrome requiring IV diuretic therapy.
3. Impaired renal function

Exclusion Criteria:

1. Acute contrast induced nephropathy
2. Ongoing or planned IV therapy for heart failure with positive inotropic agents, vasopressors, vasodilators, or mechanical support with the exception of IV nitrates
3. BNP <500 pg/mL or NT-pro-BNP <2000 pg/mL
4. Ongoing or planned treatment with ultrafiltration, hemofiltration, or dialysis
5. Severe pulmonary disease
6. Significant stenotic valvular disease
7. Heart transplant recipient or admitted for cardiac transplantation
8. Clinical evidence of acute coronary syndrome in the 2 weeks prior to screening
9. Heart failure due to significant arrhythmias
10. Acute myocarditis or hypertrophic obstructive, restrictive, or constrictive cardiomyopathy.
11. Known hepatic impairment
12. Non-cardiac pulmonary edema, including suspected sepsis
13. Allergy to soybean oil or eggs
14. History of seizure
15. Stroke within 2 years
16. History of or current brain tumor of any etiology
17. Brain surgery within 2 years
18. Encephalitis/meningitis within 2 years
19. History of penetrating head trauma
20. Closed head injury with loss of consciousness (LOC) over 30 minutes within 2 years
21. History of, or at risk for, alcohol withdrawal seizures
22. Advanced Alzheimer's disease
23. Advanced multiple sclerosis
24. Hgb <8 g/dL, Hct <25%, or the need for a blood transfusion
25. Previous exposure to KW-3902