Background:
Worsening renal function, which is associated with adverse outcomes, often develops
in patients with acute heart failure. Experimental and clinical studies suggest that
counterregulatory responses mediated by adenosine may be involved. We tested the
hypothesis that the use of rolofylline, an adenosine A1−receptor antagonist, would
improve dyspnea, reduce the risk of worsening renal function, and lead to a more
favorable clinical course in patients with acute heart failure.
Methods:
We conducted a multicenter, double-blind, placebo-controlled trial involving patients
hospitalized for acute heart failure with impaired renal function. Within 24 hours
after presentation, 2033 patients were randomly assigned, in a 2:1 ratio, to receive
daily intravenous rolofylline (30 mg) or placebo for up to 3 days. The primary end
point was treatment success, treatment failure, or no change in the patient’s clinical
condition; this end point was defined according to survival, heart-failure status,
and changes in renal function. Secondary end points were the post-treatment development
of persistent renal impairment and the 60-day rate of death or readmission
for cardiovascular or renal causes.
Results:
Rolofylline, as compared with placebo, did not provide a benefit with respect to the
primary end point (odds ratio, 0.92; 95% confidence interval, 0.78 to 1.09; P=0.35).
Persistent renal impairment developed in 15.0% of patients in the rolofylline group
and in 13.7% of patients in the placebo group (P=0.44). By 60 days, death or readmission
for cardiovascular or renal causes had occurred in similar proportions of patients
assigned to rolofylline and placebo (30.7% and 31.9%, respectively; P=0.86).
Adverse-event rates were similar overall; however, only patients in the rolofylline
group had seizures, a known potential adverse effect of A1-receptor antagonists.
Conclusions:
Rolofylline did not have a favorable effect with respect to the primary clinical composite
end point, nor did it improve renal function or 60-day outcomes. It does not
show promise in the treatment of acute heart failure with renal dysfunction. (Funded
by NovaCardia, a subsidiary of Merck; ClinicalTrials.gov numbers, NCT00328692
and NCT00354458.