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 - PROTECT (rolofylline vs. placebo)


The goal of the trial was to evaluate the efficacy and safety of rolofylline, a selective adenosine A1-receptor antagonist, compared with placebo, among patients with acute heart failure and impaired renal function.


Treatment of acute heart failure patients with the selective adenosine A1-receptor antagonist rolofylline will be associated with improved treatment success compared with placebo.

Study Design

  • Blinded
  • Parallel
  • Placebo Controlled

Patients Enrolled: 2,033
Mean Follow Up: 180 days
Mean Patient Age: 70 years
Female: 33%

Patient Populations:

  • History of heart failure ≥14 days for which diuretic therapy had been prescribed
  • Hospitalized for HF within 24 hours with signs of fluid overload
  • Impaired renal function (estimated glomerular filtration rate 20-80 ml/min)
  • High B-type natriuretic peptide (BNP) or NT-proBNP plasma levels (>500 pg/ml or >2000 pg/ml, respectively)
  • Systolic blood pressure ≥95 mm Hg but <160 mm Hg at randomization


  • Severe pulmonary disease
  • Significant cardiac valve stenosis
  • Clinical evidence of acute coronary syndrome in the 2 weeks prior to screening
  • High risk for seizures

Primary Endpoints:

  • Primary outcome was defined as a composite of treatment success, treatment failure, and no change in clinical status. 
  • Treatment success was defined as a moderate to marked better dyspnea at 24 and 48 hours after the start of study drug compared to baseline, in the absence of any criteria for treatment failure.
  • Treatment failure included any of the following criteria: death or readmission for heart failure any time through day 7; OR worsening symptoms and/or signs of heart failure occurring >24 hours after the start of study drug to day 7 or discharge, whichever occurred first; OR persistent renal impairment as defined by a serum creatinine increase of ≥0.3 mg/dl from randomization to day 7, confirmed at day 14, or the initiation of hemofiltration or dialysis through day 7.

Secondary Endpoints:

  • Death or rehospitalization for cardiovascular or renal causes through day 60
  • Persistent renal impairment, defined as a serum creatinine increase of ≥0.3 mg/dl from randomization to day 7, confirmed at day 14, or the initiation of hemofiltration or dialysis or death through day 7

Drug/Procedures Used:

Patients were randomized in a double-blind manner 2:1 to rolofylline (n = 1,356; 30 mg/day) or placebo (n = 677). Treatment was administered as a 4-hour daily infusion for 3 days. Serum creatinine was measured daily until discharge and again at day 7 and 14.

Concomitant Medications:

At baseline, in the rolofylline group, angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker (76%), beta-blocker (77%), aldosterone inhibitor (45%), and digoxin (27%) were used.

Principal Findings:

At study entry, in the rolofylline group, 71% of patients had ischemic heart disease, 80% had hypertension, and 54% had atrial fibrillation/flutter. Mean body mass index was 29 kg/m2 and mean systolic blood pressure was 124 mm Hg. Creatinine clearance at baseline was 50 ml/min. Two or three doses of study drug was administered in 91% of patients.

There was no difference in the primary endpoint between groups, treatment success, treatment failure, or no change (odds ratio 0.92, p = 0.35), respectively, for the rolofylline group versus placebo. Treatment success occurred in 40.6% vs. 36.0% (p = 0.04), treatment failure occurred in 21.8% vs. 19.8% (p = 0.30), and no change occurred in 37.5% vs. 44.2% (p = NS).

Death by 7 days occurred in 1.7% vs. 2.1%, heart failure readmission by 7 days occurred in 0.4% vs. 0.6%, worsening heart failure between 3 and 7 days occurred in 9.1% vs. 9.7%, and persistent renal impairment occurred in 12.7% vs. 11.1% (p = NS for all comparisons), respectively.

Adverse events did not differ between groups overall (62.9% for rolofylline and 61.4% for placebo) or for serious adverse events (13.8% vs. 14.7%). There was a marginal increase in strokes with rolofylline (1.1% vs. 0.3%, p = 0.06), as well as seizures (0.8% vs. 0%, p = 0.02).


Among patients with acute heart failure, treatment with the selective adenosine A1-receptor antagonist rolofylline was not associated with a difference in the primary outcome compared with placebo.

The PROTECT Pilot study (n = 301) showed promising results with rolofylline on dyspnea and renal function, leading to the development of the larger PROTECT trial to validate these findings. Rolofylline was expected to prevent worsening renal impairment, which would in turn prevent worsening heart failure. Despite the promising results in the smaller pilot trial, no benefit with rolofylline was found in the larger study.

Although the overall safety results were similar between groups, seizures were more frequent with rolofylline. Given the lack of efficacy and possible safety concerns, research on rolofylline for acute heart failure has been discontinued by the trial sponsor. However, another trial is underway with a different selective adenosine A1-receptor antagonist.


Massie BM, O'Connor CM, Metra M, et al., on behalf of the PROTECT Investigators and Committees. Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N Engl J Med 2010;363:1419-28.

Presented by Dr. Marco Metra at the European Society of Cardiology Congress, Barcelona, Spain, September 2009.

Clinical Topics: Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Hypertension

Keywords: Treatment Failure, Seizures, Odds Ratio, Myocardial Ischemia, Stroke, Diuretics, Creatinine, Dyspnea, Body Mass Index, Heart Failure, Glomerular Filtration Rate, Xanthines, Hypertension, Natriuretic Peptide, Brain

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