BARCELONA — In its pivotal phase III clinical trial for treatment of patients in acute heart failure with renal impairment, the selective adenosine A1 receptor antagonist rolofylline has failed in every respect, and Merck has announced it will discontinue the drug's development.
Rolofylline had shown promise in an earlier 301-patient pilot study, with favorable effects on dyspnea and renal function and trends for lower mortality and readmission rates than with standard therapy, Dr. Marco Metra said at the annual congress of the European Society of Cardiology.
The negative findings in a definitive study for a drug with a novel mechanism of action are a setback in the effort to find new, more effective treatments for acute heart failure. AHF is the No. 1 cause of hospitalization in patients over age 65, it carries a dismal prognosis, and there have been no significant advances in its medical treatment, he said at a press conference in which he discussed the PROTECT trial.
Most patients who are hospitalized with AHF have underlying chronic kidney disease or experience worsening renal function during their hospital stay. This is associated with a worse prognosis. Adenosine mediates diuretic resistance and worsening renal function, so rolofylline, as a selective adenosine blocker, was an attractive drug, explained Dr. Metra of the University of Brescia (Italy).
In PROTECT, 2,033 patients were randomized 2:1 to 30 mg/day of intravenous rolofylline given over 4 hours for 3 days or placebo. All participants were hospitalized with signs of fluid overload requiring intravenous loop diuretics, mild to moderate impairment of renal function, and an elevated concentration of either brain natriuretic peptide or N-terminal pro-B-type natriuretic peptide.
The primary outcome was treatment success, defined as moderate to marked improvement in dyspnea 24 and 48 hours after the start of treatment in the absence of persistent renal impairment or other negative outcomes. This was achieved in 41% of the rolofylline group and 36% of controls, a nonsignificant difference.
The drug proved to have no impact on the roughly 15% rate of persistent renal failure, the 60-day readmission rate of just under 26%, or 60-day mortality, which was 8.9% with rolofylline and 9.5% with placebo.
Particularly concerning was the finding that seizures or stroke occurred in 1.5% of the rolofylline group, compared with 0.6% of the placebo group, said Dr. Metra, who has been a consultant and advisory board member for Merck.
Seizures or stroke occurred in 1.5% of the rolofylline group, compared with 0.6% of the placebo group.
Source Dr. metra