Journal of Cardiac Failure
Volume 16, Issue 9 , Pages 714-719, September 2010

The Effects of Adenosine A1 Receptor Antagonism in Patients With Acute Decompensated Heart Failure and Worsening Renal Function: The REACH UP Study

  • Stephen S. Gottlieb, MD

      Affiliations

    • University of Maryland, Baltimore, MD
    • Corresponding Author InformationReprint requests: Stephen Gottlieb, MD, University of Maryland School of Medicine, 22 S. Greene St, Baltimore, MD 21209. Tel: (410) 328-8788; Fax: (410) 328-1048.
    • ,
  • Michael M. Givertz, MD

      Affiliations

    • Brigham and Women's Hospital, Boston, MA
    • ,
  • Marco Metra, MD

      Affiliations

    • University of Brescia, Brescia, Italy
    • ,
  • Kevin Gergich, MA

      Affiliations

    • Merck & Co., Inc, Whitehouse Station, NJ
    • ,
  • Steven Bird, MS

      Affiliations

    • Merck & Co., Inc, Whitehouse Station, NJ
    • ,
  • Charlotte Jones-Burton, MD, MS

      Affiliations

    • Merck & Co., Inc, Whitehouse Station, NJ
    • ,
  • Barry Massie, MD

      Affiliations

    • University of California, San Francisco
    • ,
  • Gad Cotter, MD

      Affiliations

    • Momentum Research, Durham, NC
    • ,
  • Piotr Ponikowski, MD

      Affiliations

    • Military Hospital, Department of Health Sciences, Medical University, Wroclaw, Poland
    • ,
  • Beth Weatherley, PhD

      Affiliations

    • Momentum Research, Durham, NC
    • ,
  • Christopher O'Connor, MD

      Affiliations

    • Duke University Medical Center, Durham, NC
    • ,
  • Howard Dittrich, MD

      Affiliations

    • NovaCardia, Inc, San Diego, CA

Received 11 February 2010; received in revised form 16 April 2010; accepted 21 April 2010. published online 07 June 2010.

Abstract 

Background

Worsening renal function (WRF) portends a poor prognosis, and recent deterioration in creatinine might identify patients with elevated intrarenal adenosine in whom adenosine A1 antagonism may improve renal hemodynamics and function. The purpose of this pilot study was to assess whether rolofylline, an adenosine A1 antagonist (A1RA), would facilitate diuresis while maintaining renal function in patients with acutely decompensated heart failure (ADHF) and recent WRF.

Methods and Results

Seventy-six patients with ADHF, volume overload, and recent renal deterioration received rolofylline (30 mg, n = 36) or placebo (n = 40) for 3 days. Rolofylline did not demonstrate a beneficial effect on the primary end points of worsening heart failure or renal function after admission or death or readmission within 30 days. Similar proportions of patients receiving rolofylline (33%) and placebo (30%) were treatment failures within 30 days. However, persistent renal impairment (through Day 14) tended to be less common with rolofylline (6%) than placebo (18%). At Day 14, 11 patients receiving placebo and 13 patients receiving rolofylline had a decrease in creatinine ≥0.3 mg/dL. There were fewer heart failure readmissions with rolofylline (n = 2) than with placebo (n = 7) through Day 60.

Conclusions

The Placebo-Controlled Study of the Effects of KW-3902 Injectable Emulsion on Heart Failure Signs and Symptoms, Diuresis, Renal Function, and Clinical Outcomes in Subjects Hospitalized with Worsening Renal Function and Heart Failure Requiring Intravenous Therapy (ie, REACH UP) study did not demonstrate any clear benefit of rolofylline in patients with ADHF and worsening renal function. However, beneficial trends raise the possibility that A1RAs might prevent renal dysfunction in these high risk patients. To test this hypothesis, further larger studies need to evaluate the effects of adenosine A1 antagonists in patients with progressive renal dysfunction in the face of active heart failure therapy.

Key Words: Heart failure, adenosine, cardiorenal syndrome, outcomes

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 Funded by NovaCardia, Inc. As of September 2007, NovaCardia is a wholly owned subsidiary of Merck & Co, Inc. Based on the lack of a benefit on the predefined end points in the PROTECT trial, Merck has reported it will not pursue further development of rolofylline.

 All decisions regarding this manuscript were made by a guest editor.

 See page 719 for disclosure information.

PII: S1071-9164(10)00196-X

doi:10.1016/j.cardfail.2010.04.006

Journal of Cardiac Failure
Volume 16, Issue 9 , Pages 714-719, September 2010

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