Enoximone Plus Extended-Release Metoprolol Succinate in Subjects With Advanced Chronic Heart Failure

Over the last decade, it has become evident that certain beta-blocking agents (beta-blockers) exert a favorable effect on the natural history of mild to moderate chronic heart failure (CHF), including reducing mortality and hospitalization rate. However, as heart failure becomes more severe, beta-blockers become difficult to administer because of myocardial depression leading to hemodynamic intolerance. A recent clinical study demonstrated that subjects who could not tolerate the beta-blocker metoprolol experienced improved tolerability when low-dose, oral enoximone was administered prior to the introduction of metoprolol and during ongoing treatment. This study will investigate the hypotheses that by stabilizing subjects on enoximone first, advanced CHF subjects who are intolerant of beta-blockade will be able to 1) tolerate the effects of beta-blocker therapy, and 2) have clinical benefit that is due to the combination of both enoximone and extended-release metoprolol succinate (ER metoprolol). Support for these hypotheses will be sought by demonstrating that, as compared to placebo, low-dose, oral enoximone plus ER metoprolol will increase left ventricular ejection fraction (LVEF), improve symptoms of heart failure, and improve submaximal exercise tolerance in subjects with CHF.