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CLINICAL RESEARCH: HEART FAILURE

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

Michael M. Givertz, MD, FACC^_*,1,_*, Barry M. Massie, MD, FACC^,2, Tara K. Fields, BA^,3, Leeanne L. Pearson, RN, BS^,3, Howard C. Dittrich, MD, FACC^,,3 on behalf of the CKI-201 and CKI-202 Investigators

^_* Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts
Cardiology Division, San Francisco Veterans Affairs Medical Center, San Francisco, California
NovaCardia, Inc., San Diego, California
University of California, San Diego, California.

Manuscript received March 5, 2007; revised manuscript received May 22, 2007, accepted July 11, 2007.

^_* Reprint requests and correspondence: Dr. Michael M. Givertz, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115. (Email: mgivertz{at}partners.org).

Objectives: 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.

Abbreviations and Acronyms   ADHF = acute decompensated heart failure   CrCl = creatinine clearance   GFR = glomerular filtration rate   IV = intravenous   NYHA = New York Heart Association   SBP = systolic blood pressure   SCr = serum creatinine

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