Journal of Cardiac Failure
Volume 14, Issue 8 , Pages 631-640, October 2008

The PROTECT Pilot Study: A Randomized, Placebo-Controlled, Dose-Finding Study of the Adenosine A1 Receptor Antagonist Rolofylline in Patients With Acute Heart Failure and Renal Impairment

  • Gad Cotter, MD

      Affiliations

    • Momentum Research, Inc, Durham, North Carolina
    • Drs Cotter and Dittrich contributed equally to the study.
    • ,
  • Howard C. Dittrich, MD

      Affiliations

    • NovaCardia Inc, San Diego, California
    • Drs Cotter and Dittrich contributed equally to the study.
    • ,
  • Beth Davison Weatherley, PhD

      Affiliations

    • Momentum Research, Inc, Durham, North Carolina
    • ,
  • Daniel M. Bloomfield, MD

      Affiliations

    • Merck Research Laboratories, Rahway, New Jersey
    • ,
  • Christopher M. O'connor, MD

      Affiliations

    • Duke University Medical Center, Durham, North Carolina
    • ,
  • Marco Metra, MD

      Affiliations

    • University of Brescia, Brescia, Italy
    • ,
  • Barry M. Massie, MD

      Affiliations

    • University of California, San Francisco, San Francisco, California
    • Corresponding Author InformationReprint requests: Barry M. Massie, MD, University of California San Francisco, San Francisco VA Medical Center, Department of Cardiology, 111C, 4150 Clement Street, San Francisco, CA 94121-1545.
    • ,
  • for the PROTECT Steering Committee, Investigators, and Coordinators

Received 15 August 2008; received in revised form 28 August 2008; accepted 29 August 2008. published online 16 September 2008.

Abstract 

Background

Rolofylline, an adenosine A1 receptor antagonist, facilitates diuresis and preserves renal function in patients with acute heart failure (AHF) with renal impairment. Although not powered around any specific hypothesis, this pilot study was designed to identify an efficacious dose while refining inclusion criteria and end points.

Methods

A total of 301 patients hospitalized for AHF with an estimated creatinine clearance of 20 to 80 mL/min and elevated natriuretic peptide levels were enrolled within 24 hours of presentation to placebo or rolofylline 10, 20, or 30 mg administered as 4-hour infusions for 3 days in addition to intravenously administered loop diuretics. Post hoc analyses for end points chosen for subsequent Phase III studies were performed.

Results

Compared with placebo, rolofylline produced trends toward greater proportions of patients with marked or moderately improved dyspnea and fewer patients with worsening heart failure or renal function. Serum creatinine increased in patients receiving placebo and remained stable or tended to decrease in those receiving rolofylline. On day 14 the absolute differences between placebo and rolofylline for change in creatinine increased with increasing rolofylline dose, reflecting the lesser increase in creatinine in rolofylline-treated patients (r = −0.12, P = .030). Treatment with 30 mg, the dose selected for the pivotal trials, was associated with a trend toward reduced 60-day mortality or readmission for cardiovascular or renal cause (hazard ratio, 0.55; 95% confidence interval, 0.28–1.04).

Conclusion

These results demonstrate that adenosine A1 receptor blockade with rolofylline can prevent renal impairment in patients with AHF and may positively affect acute symptoms and 60-day outcome. A 2000-patient trial of this agent is now under way.

Key Words: Adenosine receptor antagonists, chronic kidney disease, heart failure, renal function, rolofylline

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 All decisions regarding this manuscript were made by a Guest Editor.

 This study was funded by NovaCardia, Inc. As of September 2007, NovaCardia is a wholly owned subsidiary of Merck & Co, Inc. Drs Cotter, Massie, Metra, and O'Connor are members of the PROTECT Steering Committee and receive grant support from Merck and NovaCardia. Dr Bloomfield is an employee of Merck. Drs Cotter and Weatherley are employees of Momentum Research Inc. and are consultants to Merck. Dr Dittrich was an employee of NovaCardia and is now a consultant to Merck. Dr Metra has occasionally received honoraria and reimbursement for travel expenses from Actelion, Corthera, Merck, and Servier. Dr Massie receives consulting fees from BAS Medical, Duke Clinical Research Institute, Merck, Niles Therapeutics, and Scios.

 The PROTECT study is registered on www.clinicaltrials.gov as NCT00328692 (PROTECT-1) and NCT00354458 (PROTECT-2).

PII: S1071-9164(08)00980-9

doi:10.1016/j.cardfail.2008.08.010

Journal of Cardiac Failure
Volume 14, Issue 8 , Pages 631-640, October 2008

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