Comparison of the short-term effects of candoxatril, an orally active neutral endopeptidase inhibitor, and frusemide in the treatment of patients with chronic heart failure

Abstract

Background: Candoxatril is a novel neutral endopeptidase inhibitor that increases plasma concentrations of atrial natriuretic factor and thereby produces natriuresis, diuresis, and vasorelaxation. This profile of action offers theoretical advantages over standard diuretic therapy in the treatment of patients with heart failure. The aims of the study were to compare the effects of candoxatril with those of frusemide in the treatment of patients with mild heart failure.

Methods: Male patients with mild heart failure were randomly assigned to 9 days of therapy with 20 mg frusemide twice a day, 200 mg candoxatril twice a day, or 400 mg candoxatril twice a day (n = 10 per group) after a 14-day placebo washout phase. Systemic hemodynamic measurements, exercise tolerance, and urinary and plasma hormone concentrations were assessed during the placebo run-in and at the beginning and end of the double-blind therapy.

Results: Frusemide and candoxatril caused similar diuresis and natriuresis. Candoxatril caused a slight decrease in systolic blood pressure and a dose-dependent increase in plasma and urinary concentrations of atrial natriuretic factor without elevating plasma renin activity. Frusemide reduced plasma concentrations of atrial natriuretic factor and increased plasma renin activity. Treadmill exercise capacity decreased 30 +/- 26 seconds after use of frusemide, compared with increases of 12 +/- 35 seconds after use of 200 mg candoxatril twice a day and 35 +/- 31 seconds after use of 400 mg candoxatril twice a day (P =.13; frusemide versus 400 mg candoxatril twice a day).

Conclusions: In the treatment of patients with mild heart failure, candoxatril has diuretic effects equivalent to those of 20 mg frusemide twice a day without the associated and potentially detrimental activation of the renin-angiotensin-aldosterone system. The trend for improved exercise capacity with candoxatril warrants further investigation.