The Studies of Oral Enoximone Therapy in Advanced Heart Failure - ESSENTIAL


The goal of the trial was to evaluate the safety and efficacy of low-dose enoximone therapy among patients with advanced chronic heart failure already receiving optimal conventional therapy.

Study Design

Study Design:

Patients Enrolled: 1,854
NYHA Class: Class III 91%
Mean Follow Up: Median 16.4 months
Mean Patient Age: 62 years
Female: 20
Mean Ejection Fraction: Mean baseline 23.6%

Patient Populations:

Age ≥18 years, ischemic or nonischemic cardiomyopathy, NYHA class III or IV, one hospitalization or two outpatient visits for treatment of worsening heart failure in prior 12 months requiring the administration of intravenous heart failure therapy, impaired cardiac function (left ventricular ejection fraction ≤30%), and concomitant treatment with optimal conventional heart failure therapy (beta-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers)


Use of the following agents: calcium antagonists other than amlodipine or felodipine; flecainide, encainide, propafenone, dofetilide, or disopyramide; intravenous positive inotropic agents within seven days of screening or randomization; human B-type natriuretic peptide, including nesiritide, within seven days of screening or randomization; or phosphodiesterase III inhibitors, including levosimendan and cilostazol, within seven days of screening or randomization

Active hepatic, hematologic, gastrointestinal, immunologic, endocrine, metabolic, or central nervous system disease; serum potassium <4.0 mEq/l or >5.5 mEq/l at randomization; magnesium level <1.0 mEq/l at randomization; or serum digoxin >1.2 ng/ml or serum digitoxin >20 ng/ml at randomization

Primary Endpoints:

1) Reduction in time to all-cause mortality or cardiovascular hospitalization in the pooled components; 2) increase in the six-minute walk test distance in each component individually; and 3) symptomatic improvement on the PGA questionnaire in each component individually

Drug/Procedures Used:

Patients were randomized in a double-blind manner to oral enoximone (25 mg three times daily, uptitrated to 50 mg three times daily) (n=926) or placebo (n=928). The trial was comprised of two identical components that differed only by enrolling region, one in Eastern and Western Europe and one in North and South America.

Concomitant Medications:

Beta-blockers 87%, angiotensin-converting enzyme inhibitors 84%, angiotensin receptor blockers 13%, and diuretics 96%

Principal Findings:

Baseline characteristics were similar between treatment groups. The large majority of patients had New York Heart Association (NYHA) class III heart failure (91%), with a median duration of heart failure of 62 months. Ischemic heart failure etiology was present in 56% of patients. Baseline left ventricular ejection fraction was 23.6%.

Time to all-cause mortality was similar between groups (201/926 for enoximone vs. 210/928 for placebo, hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.80-1.17, p=0.73), meeting the criteria for safety of the 95% CI of the HR <1.30. The primary endpoint of cardiovascular hospitalization or all-cause mortality did not differ between groups (458 events for enoximone vs. 465 events for placebo, HR 0.98, p=0.71).

For distance walked on a six-minute walk test, the median difference in change from baseline to six months was 10.0 m longer with enoximone versus placebo (p=0.025) in the America cohort, and 1.5 m longer with enoximone versus placebo (p=0.82) in the European cohort. The lack of difference in the European cohort was influenced by a change from baseline to six months in the placebo group of +15 m, while there was no change from baseline in the placebo group in the American cohort.

For the third coprimary endpoint, there was no difference in change in symptomatic improvement on the Patient Global Assessment (PGA) questionnaire between groups, with marked improvement reported in 43% of the enoximone group versus 46% of the placebo group (p=0.79) in the America cohort and 29% versus 31% (p=0.11), respectively, in the European cohort.

Improvements in six-minute walk distance favoring enoximone compared with placebo were reported in the subgroup of patients with ejection fraction <25% (n=845) (+15 m for enoximone vs. 0 m for placebo; p=0.007), while there was no difference in patients with ejection fraction ≥25% (n=1,009) (+13.5 m for enoximone vs. +15 m for placebo, p=0.58).


Among patients with advanced chronic heart failure already receiving optimal conventional therapy, treatment with enoximone was not associated with improvements in all-cause mortality or cardiovascular hospitalization, walk distance on six-minute walk test, or symptomatic improvement compared with placebo.

Prior trials of inotropic therapy in heart failure patients have been associated with improvements in cardiac function, but often an increase in mortality. The present study sought to evaluate a lower dose of an inotropic agent, with the goal of showing similar safety in all-cause mortality but improvements in efficacy. Despite meeting the safety criteria of no increase in mortality, use of this low dose of enoximone was not associated with improvements in efficacy. While certain subgroups suggested a potential benefit in walk distance, these results should be interpreted with caution given the overall lack of benefit observed in the trial.


Presented by Dr. Marco Metra at the European Society of Cardiology Hot Line Session, September 2005.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: Angiotensin Receptor Antagonists, Cardiomyopathies, Heart Failure, Stroke Volume, Confidence Intervals, Questionnaires, Enoximone, Exercise Test

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