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 A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function)

• Published in: Journal of the American College of Cardiology 2011-05, Vol.57 (19), p.1899-1907
• Main Authors: VOORS, Adriaan A, DITTRICH, Howard C, CLELAND, John G. F, O'CONNOR, Christopher M, GIVERTZ, Michael M, MASSIE, Barry M, DELUCCA, Paul, MANSOOR, George A, METRA, Marco, COTTER, Gad, WEATHERLEY, Beth D, PONIKOWSKI, Piotr, TEERLINK, John R
• Format: Article
• Language: English
• Subjects: Acute Disease; Adenosine A1 Receptor Antagonists - pharmacology; Adenosine A1 Receptor Antagonists - therapeutic use; Biological and medical sciences; Cardiology. Vascular system; Double-Blind Method; Female; Heart; Heart Failure - complications; Heart Failure - drug therapy; Heart Failure - physiopathology; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Hospitalization; Humans; Kidney - drug effects; Kidney - physiology; Kidney Diseases - complications; Kidney Diseases - drug therapy; Kidney Diseases - physiopathology; Male; Medical sciences; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Pilot Projects; Renal failure; Stroke Volume - drug effects; Stroke Volume - physiology; Treatment Outcome; Xanthines - pharmacology; Xanthines - therapeutic use
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2010.11.057

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). 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. 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. 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). 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).