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 ,Revised 28 August 2008 ,Accepted 29 August 2008.

References 

  1. Al-Ahmad A, Rand WM, Manjunath G, et al. Reduced kidney function and anemia as risk factors for mortality in patients with left ventricular dysfunction. J Am Coll Cardiol. 2001;38:955–962
  2. Dries DL, Exner DV, Domanski MJ, et al. The prognostic implications of renal insufficiency in asymptomatic and symptomatic patients with left ventricular systolic dysfunction. J Am Coll Cardiol. 2000;35:681–689
  3. Fonarow GC, Adams KF, Abraham WT, et al. Risk stratification for in-hospital mortality in acutely decompensated heart failure: classification and regression tree analysis. JAMA. 2005;293:572–580
  4. Forman DE, Butler J, Wang Y, et al. Incidence, predictors at admission, and impact of worsening renal function among patients hospitalized with heart failure. J Am Coll Cardiol. 2004;43:61–67
  5. Damman K, Navis G, Voors AA, et al. Worsening renal function and prognosis in heart failure: systematic review and meta-analysis. J Card Fail. 2007;13:599–608
  6. Hillege HL, Nitsch D, Pfeffer MA, et al. Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Investigators. Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation. 2006;113:671–678
  7. Smilde TD, van Veldhuisen DJ, Navis G, et al. Drawbacks and prognostic value of formulas estimating renal function in patients with chronic heart failure and systolic dysfunction. Circulation. 2006;114:1572–1580
  8. Cowie MR, Komajda M, Murray-Thomas T, et al. Prevalence and impact of worsening renal function in patients hospitalized with decompensated heart failure: results of the prospective outcomes study in heart failure (POSH). Eur Heart J. 2006;27:1216–1222
  9. Gottlieb SS, Abraham W, Butler J, et al. The prognostic importance of different definitions of worsening renal function in congestive heart failure. J Card Fail. 2002;8:136–141
  10. Smith GL, Lichtman JH, Bracken MB, et al. Renal impairment and outcomes in heart failure: systematic review and meta-analysis. J Am Coll Cardiol. 2006;47:1987–1996
  11. Butler J, Forman DE, Abraham WT, et al. Relationship between heart failure treatment and development of worsening renal function among hospitalized patients. Am Heart J. 2004;147:331–338
  12. Vallon V, Muhlbauer B, Osswald H. Adenosine and kidney function. Physiol Rev. 2006;86:901–940
  13. Funaya H, Kitakaze M, Node K, et al. Plasma adenosine levels increase in patients with chronic heart failure. Circulation. 1997;95:1363–1365
  14. Dittrich HC, Gupta DK, Hack TC, et al. The effect of KW-3902, an adenosine A1 receptor antagonist, on renal function and renal plasma flow in ambulatory patients with heart failure and renal impairment. J Card Fail. 2007;13:609–617
  15. Givertz MM, Massie BM, Fields TK, et al. 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. J Am Coll Cardiol. 2007;50:1551–1560
  16. Gottlieb SS, Skettino SL, Wolff A, et al. Effects of BG9719 (CVT-124), an A1-adenosine receptor antagonist, and furosemide on glomerular filtration rate and natriuresis in patients with congestive heart failure. J Am Coll Cardiol. 2000;35:56–59
  17. Gottlieb SS. Renal effects of adenosine A1-receptor antagonists in congestive heart failure. Drugs. 2001;61:1387–1393
  18. Gottlieb SS, Brater DC, Thomas I, et al. BG9719 (CVT-124), an A1 adenosine receptor antagonist, protects against the decline in renal function observed with diuretic therapy. Circulation. 2002;105:1348–1353
  19. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41
  20. Dunwiddie TV, Worth T. Sedative and anticonvulsant effects of adenosine analogs in mouse and rat. J Pharmacol Exp Ther. 1982;220:70–76
  21. Teerlink JR. Dyspnea as an end point in clinical trials of therapies for acute decompensated heart failure. Am Heart J. 2003;145:S26–S33
  22. Teerlink JR, McMurray JJV, Cotter G, et al. for the VERITAS Investigators Effects of tezosentan on symptoms and clinical outcomes in patients with acute heart failure: the VERITAS randomized controlled trials. JAMA. 2007;298:2009–2019
  23. Packer M. Proposal for a new clinical end point to evaluate the efficacy of drugs and devices in the treatment of chronic heart failure. J Card Fail. 2001;7:176–182
  24. Packer M, McMurray J, Massie BM, et al. Clinical effects of endothelin receptor antagonism with bosentan in patients with severe chronic heart failure: results of a pilot study. J Card Fail. 2005;11:12–20
  25. Abraham WT. Rationale and design of a randomized clinical trial to assess the safety and efficacy of cardiac resynchronization therapy in patients with advanced heart failure: the Multicenter InSync Randomized Clinical Evaluation (MIRACLE). J Card Fail. 2000;6:369–380
  26. Cleland JG, Freemantle N, Coletta AP, et al. Clinical trials update from the American Heart Association: REPAIR-AMI, ASTAMI, JELIS, MEGA, REVIVE-II, SURVIVE, and PROACTIVE. Eur J Heart Fail. 2006;8:105–110
  27. Hahn GJ, Meeker WQ. Statistical intervals: a guide for practitioners. New York: John Wiley & Sons, Inc; 1991;
  28. Thomson S, Bao D, Deng A, Vallon V. Adenosine formed by 5’-nucleotidase mediates tubuloglomerular feedback. J Clin Invest. 2000;106:289–298
  29. Boison D. Adenosine and epilepsy: from therapeutic rationale to new therapeutic strategies. Neuroscientist. 2005;11:25–36
  30. Avsar E, Empson RM. Adenosine acting via A1 receptors, controls the transition to status epilepticus-like behaviour in an in vitro model of epilepsy. Neuropharmacology. 2004;47:427–437

 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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