Clinical Research
Heart Failure
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)

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Objectives

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 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).

Background

Small studies have indicated that adenosine A1 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 A1 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)

Key Words

adenosine receptor antagonist
diuretics
heart failure
renal function
rolofylline

Abbreviations and Acronyms

AHF
acute heart failure
BUN
blood urea nitrogen
CI
confidence interval
eCrCl
estimated creatinine clearance
GFR
glomerular filtration rate
HF
heart failure
IV
intravenous
OR
odds ratio
WRF
worsening renal function

Cited by (0)

This study was funded by NovaCardia, Inc. As of September 2007, NovaCardia is a wholly owned subsidiary of Merck & Co, Inc. Dr. Voors has received speakers' fees from and served as a consultant to Merck. Dr. Dittrich has ownership in NovaCardia, and has served as a consultant to and is a minor shareholder in Merck. Dr. Massie has received speaking honorarium from CME providers for satellite symposia supported by Merck-NovaCardia, and has received compensation from Averion for his role as Co-Principal Investigator of the PROTECT trial. Drs. DeLucca and Mansoor are employees of Merck. Dr. Metra has received honoraria and travel reimbursement from NovaCardia, Merck, Corthera, Novartis, Cardiokine, and Servier. Dr. Ponikowski has received honoraria from Merck, NovaCardia, and Corthera. Drs. Cotter and Weatherley are employees of Momentum Research. Drs. Teerlink, Cleland, and Givertz have received research grants from NovaCardia and served as consultants to Merck. Gregg Fonarow, MD, served as Guest Editor for this paper. Please note: Based upon the results of the Phase III PROTECT trial assessing the effects of rolofylline on short- and long-term outcomes presented at the European Society of Cardiology in 2009, Merck and Co., Inc. determined that the lack of efficacy did not support further development of this compound for the treatment of patients with acute decompensated HF.