title: Effects of the adenosine A1 receptor antagonist rolofylline on renal function in patients with acute heart failure and renal dysfunction: results from PROTECT (Placebo-Controlled Randomized Study of the Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function).
abstract: OBJECTIVE
  This study sought to assess the effects of rolofylline on renal function in patients with acute heart failure (AHF) and renal dysfunction randomized in PROTECT (Placebo-Controlled Randomized Study of the Selective A(1) Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function).
  
  
  BACKGROUND
  Small studies have indicated that adenosine A(1) receptor antagonists enhance diuresis and may improve renal function in patients with chronic heart failure or AHF.
  
  
  METHODS
  A total of 2,033 patients with AHF, volume overload, estimated creatinine clearance between 20 and 80 ml/min, and elevated natriuretic peptide levels were randomized (2:1) within 24 h of hospital presentation to rolofylline 30 mg/day or intravenous placebo for up to 3 days. Creatinine was measured daily until discharge or day 7 and on day 14. Persistent worsening renal function was defined as an increase in serum creatinine ≥0.3 mg/dl at both days 7 and 14, or initiation of hemofiltration or dialysis or death by day 7.
  
  
  RESULTS
  At baseline, mean ± SD estimated creatinine clearance was 51.0 ± 20.5 ml/min in the placebo group and 50.4 ± 20.0 ml/min in the rolofylline group. Changes in creatinine and estimated creatinine clearance were similar between placebo- and rolofylline-treated patients during hospitalization and at day 14. After 4 days, mean body weight was reduced by 2.6 and 3.0 kg in placebo and rolofylline patients, respectively (p = 0.005). Persistent worsening renal function occurred in 13.7% of the placebo group and 15.0% of the rolofylline group (odds ratio vs. placebo: 1.11 [95% confidence interval: 0.85 to 1.46]; p = 0.44).
  
  
  CONCLUSIONS
  In this large, phase III clinical trial, the adenosine A(1) receptor antagonist rolofylline did not prevent persistent worsening renal function in AHF patients with volume overload and renal dysfunction. (A Study of the Selective A1 Adenosine Receptor Antagonist KW-3902 for Patients Hospitalized With Acute HF and Volume Overload to Assess Treatment Effect on Congestion and Renal Function [PROTECT-1], NCT00328692; and [PROTECT-2], NCT00354458).
authors.affiliation: University of Groningen, Groningen, the Netherlands.
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Voors
authors.forename: Howard C
authors.initials: HC
authors.lastname: Dittrich
authors.forename: Barry M
authors.initials: BM
authors.lastname: Massie
authors.forename: Paul
authors.initials: P
authors.lastname: DeLucca
authors.forename: George A
authors.initials: GA
authors.lastname: Mansoor
authors.forename: Marco
authors.initials: M
authors.lastname: Metra
authors.forename: Gad
authors.initials: G
authors.lastname: Cotter
authors.forename: Beth D
authors.initials: BD
authors.lastname: Weatherley
authors.forename: Piotr
authors.initials: P
authors.lastname: Ponikowski
authors.forename: John R
authors.initials: JR
authors.lastname: Teerlink
authors.forename: John G F
authors.initials: JG
authors.lastname: Cleland
authors.forename: Christopher M
authors.initials: CM
authors.lastname: O'Connor
authors.forename: Michael M
authors.initials: MM
authors.lastname: Givertz
mesh_terms: D000208:Acute Disease; D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D006760:Hospitalization; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D007674:Kidney Diseases / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D010865:Pilot Projects; D013318:Stroke Volume / Q000187:drug effects / Q000502:physiology; D016896:Treatment Outcome; D014970:Xanthines / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D014970:Xanthines; C073525:rolofylline