Rolofylline Fails to PROTECT in Acute Heart Failure

September 01, 2009

September 1, 2009 (Barcelona, Spain) — The selective A1 adenosine receptor antagonist rolofylline (Merck), showed no difference from placebo in the main efficacy end points in the PROTECT trial in acute heart-failure patients. The drug was also associated with an increased rate of seizures and strokes compared with placebo.

These results are particularly disappointing given that an earlier pilot trial with rolofylline in this indication showed much promise. The drug, previously known as KW-3902, has now been dropped from development.

Presenting the results of the PROTECT study at the European Society of Cardiology 2009 Congress, Dr Marco Metra (University of Brescia, Italy) explained that patients with acute decompensated heart failure often develop worsening renal function, and adenosine has been implicated as a mediator as it causes a reduction in renal blood flow and glomerular filtration rate and decreases sodium excretion. In the PROTECT-Pilot study, rolofylline was associated with trends toward symptom improvement, less worsening of renal function, and fewer deaths or readmissions for heart failure or renal dysfunction over the next 60 days. The PROTECT trial was therefore designed to try to confirm these benefits.

The trial involved 2033 patients hospitalized for heart failure within 24 hours with signs of fluid overload and impaired renal function who were randomized 2:1 to rolofylline 30 mg/day or placebo, administered as a four-hour daily infusion repeated for three days. The primary end point was made up of three categories--treatment success, patient unchanged, or treatment failure. Treatment success was defined as improved dyspnea at 24 and 48 hours in the absence of any criteria for treatment failure, which included death or readmission for heart failure, worsening symptoms of heart failure, or persistent renal impairment. Patients were categorized as unchanged if they did not meet criteria for either treatment success or treatment failure. Results showed no significant difference between rolofylline and placebo with respect to the primary end point. Although more rolofylline patients showed improvement in dyspnea than placebo patients, this was counterbalanced by a lack of effect on persistent renal impairment. 

PROTECT: Primary End Point

Outcome Placebo (%) Rolofylline (%)
Success 36.0 40.6
Unchanged 44.2 37.5
Failure 19.8 21.8

The odds ratio for the primary end point as a whole with rolofylline vs placebo was 0.92 (95% CI 0.78–1.09; p=0.348).

Serious adverse events occurred in 13.8% of rolofylline and 14.7% of placebo patients. There was a trend toward a lower incidence of adverse cardiac events with rolofylline, but a higher rate of neurological events, specifically seizures (0.8% vs 0%), a known adverse effect of A1 receptor antagonists, and strokes (1.2% vs 0.5%) .

Metra concluded: "Although there was a pharmacological basis on which to expect improvement, the benefits seen in a small pilot trial, as frequently happens, could not be replicated in a larger trial." He added that he could not say how these results would affect other drugs in this class but noted that another trial is still ongoing with an oral adenosine A1 antagonist.

To access complete presentation slides (pdfs), click here.


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