Multicenter trial of oral enoximone in patients with moderate to moderately severe congestive heart failure: Lack of benefit compared with placebo

Abstract

A multicenter double-blind, randomized, placebo-controlled trial of oral enoximone, a phosphodiesterase inhibitor, was conducted in 102 outpatients (50 receiving enoximone and 52 receiving placebo) with moderate to moderately severe congestive heart failure. All were on a long-term regimen of digoxin and diuretics without vasodilators and converting enzyme inhibitors. Symptom score was obtained, and exercise testing was performed monthly for 4 months. There were no differences between groups in symptoms or exercise duration at the end of 4 months. A subgroup undergoing analysis of oxygen consumption with measurement of anaerobic threshold during exercise showed an increase (p<0.05) in anaerobic threshold at 1 month with enoximone (2.7±0.8 ml O2/kg/min) compared with placebo (-0.8±1.2 ml O2/kg/min). This improvement was not sustained at 4 months (0.5±1.7 ml O2/kg/min with enoximone and 0.2±1.5 ml O2/kg/min with placebo). The dropout rate was significantly higher (p<0.02) with enoximone (46%) than with placebo (25%). Adverse effects other than death were slightly, but not significantly, higher with enoximone (32%) than with placebo (22%). During therapy, five deaths occurred in the enoximone group, and none occurred in the placebo group (p<0.05). Two deaths were sudden, two were from progressive congestive heart failure, and one was from acute myocardial infarction. With intention-to-treat analysis and inclusion of patients who were removed from therapy because of lack of study drug effect, 10 deaths occurred in the enoximone group, and three occurred in the placebo group (p<0.05). All five enoximone- and three placebo-treated patients who died after therapy was discontinued died from terminal myocardial failure. This study does not demonstrate improvement in exercise capacity or symptoms with 16 weeks of enoximone therapy compared with placebo in patients with congestive heart failure receiving digoxin and diuretics without vasodilators and does not provide evidence that enoximone is beneficial in the long-term therapy of chronic heart failure. The unexpectedly worse survival rate with enoximone therapy raises concerns about a possible detrimental effect of enoximone in the dose range given in this study.