Deterioration in renal function during the acute treatment of heart failure is a common problem, limiting the ability to up-titrate therapy, and is associated with adverse outcomes. Accrued evidence has implicated physiologically released adenosine as an important mediator of both worsening renal function and diuretic resistance. Adenosine, acting on adenosine A1 receptors in the afferent arterioles, reduces renal blood flow and the glomerular filtration rate, stimulating the release of renin and also enhancing proximal tubular sodium reabsorption.
In earlier pilot studies rolofylline, an adenosine A1-receptor antagonist, has been shown to enhance diuresis while maintaining or improving renal function when coadministered with loop diuretics. To confirm these results the phase III multicenter, double-blind, placebo-controlled PROTECT study was undertaken and recruited 2033 patients within 24 h of presentation with heart failure symptoms, a raised BNP and impaired renal function, randomising them in a 2:1 ratio to daily intravenous rolofylline (30 mg) or placebo for up to 3 days along with conventional therapy. The primary end point was treatment success, treatment failure, or no change in the patient’s clinical condition, this being 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.
Rolofylline failed to demonstrate a benefit with respect to the primary end point (OR, 0.92; 95% CI, 0.78 to 1.09; P=0.35). Alongside this, 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.
In this large phase III study, rolofylline did not have a favourable effect with respect to the primary clinical composite end point, nor did it improve renal function or 60-day outcomes. Further development has been suspended.
▶ Massie BM, O’Connor CM, Metra M, et al. Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N Engl J Med 2010;363:1419–28.