Study Design

Study Design:

Patients Screened: 2,740
Patients Enrolled: 1,532
Mean Follow Up: Six months
Mean Patient Age: 18 to 85
Female: 35

Patient Populations:

Age 18 to 85 years, a clinical diagnosis of heart failure, symptoms compatible with NYHA class II to IV, an abnormality of the heart, and current treatment for heart failure

Exclusions:

Significant valvular disease, unstable angina, recent myocardial infarction, uncontrolled hypertension, hypotension, advanced pulmonary disease, serum potassium <3.2 mmol/l, or contraindications to ACE inhibitors. Patients could not have been previously treated with an ACE inhibitor.

Primary Endpoints:

First occurrence of a primary event of mortality, heart failure-related hospitalization, or worsening heart failure. Heart failure-related hospitalization was defined as hospital admission for worsening signs or symptoms of heart failure, for complications of medical therapy, for syncope, or for arrhythmias. Worsening heart failure was defined as increasing symptoms of or worsening signs of heart failure, an increase in the baseline dose of furosemide by at least 40 mg, addition of a new vasodilator, addition of spironolactone, addition of a diuretic, or addition of digoxin.

Secondary Endpoints:

Adherence to enalapril therapy, and occurrence of stroke, myocardial infarction, or change in NYHA class

Drug/Procedures Used:

Patients were randomly assigned to one of three doses of enalapril: 2.5 mg, 5 mg, or 10 mg bid. Patients entered a two-week placebo run-in period where the diagnosis of heart failure, adherence to inclusion and exclusion criteria, and stability of clinical status were determined.

All potential patients received a test dose of 2.5 mg once daily of enalapril for three days. Following this, all patients received 2.5 mg bid for four days. Patients were then randomized to one of the three arms. Patients in the 5 mg bid and 10 mg bid arms had their doses increased over a two-week period.

Titration was conducted in a double blind fashion, provided that systolic blood pressure (BP) did not fall <80 mm Hg, that no postural fall in BP of >20 mm Hg occurred, and that renal function did not deteriorate. If required, enalapril could be downtitrated in a blinded fashion. Patients were followed for six months.

Concomitant Medications:

For the three groups, enalapril 2.5 mg, 5 mg, and 10 mg: diuretics (94%, 93%, 94%), digoxin (26%, 24%, 22%), beta-blockers (11%, 10%, 11%), calcium channel blockers (27%, 26%, 27%), warfarin or equivalent (12%, 13%, 9%), nitrates (27%, 26%, 27%), and aspirin (38%, 38%, 41%)