The effects of KW-3902, an adenosine A1-receptor antagonist,on diuresis and renal function in patients with acute decompensated heart failure and renal impairment or diuretic resistance.
OBJECTIVE
This study sought to evaluate the dose-dependent effects of adenosine A1-receptor blockade on diuresis and renal function in patients with acute decompensated heart failure (ADHF) and renal impairment or diuretic resistance.


BACKGROUND
Intravenous loop diuretics are the mainstay of therapy for patients with ADHF. Treatment, however, may be complicated by diuretic resistance and/or worsening renal function.


METHODS
We carried out a pair of randomized, double-blind, placebo-controlled, proof-of-concept studies in 2 clinically challenging ADHF populations.


RESULTS
In the ADHF protocol, 146 patients with volume overload and an estimated creatinine clearance (CrCl) of 20 to 80 ml/min were randomized to placebo or 1 of 4 doses of KW-3902 (rolofylline) infused over 2 h daily for up to 3 days. On day 1, KW-3902 monotherapy increased urine output during the first 6 h (445, 531, 631, and 570 ml in the 2.5-, 15-, 30-, and 60-mg groups, respectively) compared with placebo (374 ml; p = 0.02). On day 2, serum creatinine decreased in all KW-3902 groups and increased with placebo (p = 0.04). By day 4 or day of discharge if earlier, intravenous furosemide administration tended to be lower in the KW-3902 groups compared with placebo (p = 0.10). In the diuretic-resistant protocol, 35 patients with an average CrCl of 34 ml/min were randomized to a single infusion of placebo, 10, 30, or 60 mg of KW-3902. Compared with placebo, KW-3902 increased hourly urine volume and estimated CrCl with peak effects occurring at 2 to 3 h and at 24 h, respectively. Adverse events were not different between placebo and KW-3902.


CONCLUSIONS
In patients with ADHF and volume overload, KW-3902, an adenosine A1-receptor antagonist, enhances the response to loop diuretics and may have a renal protective effect.
Givertz
Michael M
MM
Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. mgivertz@partners.org
Massie
Barry M
BM
Fields
Tara K
TK
Pearson
Leeanne L
LL
Dittrich
Howard C
HC
D000368:Aged; D003404:Creatinine / Q000097:blood; D004231:Diuresis / Q000187:drug effects*; D004232:Diuretics / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004351:Drug Resistance; D005260:Female; D005665:Furosemide / Q000008:administration & dosage; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D051437:Renal Insufficiency / Q000188:drug therapy*; D012964:Sodium / Q000652:urine; D016896:Treatment Outcome; D014970:Xanthines / Q000008:administration & dosage*
D004232:Diuretics; D014970:Xanthines; C073525:rolofylline; D005665:Furosemide; D012964:Sodium; D003404:Creatinine