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J Am Coll Cardiol, 2007; 50:1551-1560, doi:10.1016/j.jacc.2007.07.019 (Published online 1 October 2007).
© 2007 by the American College of Cardiology Foundation
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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{dagger},2, Tara K. Fields, BA{ddagger},3, Leeanne L. Pearson, RN, BS{ddagger},3, Howard C. Dittrich, MD, FACC{ddagger},§,3 on behalf of the CKI-201 and CKI-202 Investigators

* Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts
{dagger} Cardiology Division, San Francisco Veterans Affairs Medical Center, San Francisco, California
{ddagger} 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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