Clinical Outcome With Enalapril in Symptomatic Chronic Heart Failure: A Dose Comparison - NETWORK


NETWORK was a multicenter, double-blind, randomized parallel study of three dosages of the angiotensin-converting enzyme (ACE) inhibitor enalapril in patients with symptomatic heart failure.


Higher doses of enalapril will be more effective in preventing complications of heart failure.

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


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%)

Principal Findings:

The three arms were well matched at baseline in terms of age (mean 70), gender (~35% female), etiology of heart failure (~70% ischemic), New York Heart Association (NYHA) class (~65% class II), and concomitant medications. The percentage of patients achieving the goal dose of enalapril was 99.8% for the 2.5 mg group, 95.9% for the 5 mg group, and 84.7% for the 10 mg group. At study completion, the percentage of patients remaining on the goal dose of enalapril were 79.8% for the 2.5 mg group, 76.3% for the 5 mg group, and 59.7% for the 10 mg group. Rates of treatment withdrawals were similar for the 2.5 mg and 5 mg groups (19%), but higher for the 10 mg group (27%).

For the primary composite endpoint, there were no significant differences between groups (12.3% for the 2.5 mg group, 12.9% for the 5 mg group, and 14.7% for the 10 mg group). Among the three arms (2.5 mg, 5 mg, and 10 mg), rates of the individual components of the primary endpoint were similar for worsening heart failure (5.5% vs. 6.1% vs. 5.8%), heart failure-related hospitalization (4.0% vs. 4.7% vs. 6.6%), and death (2.8% vs. 2.2%, and 2.3%).

There were no significant differences between groups in occurrence of myocardial infarction, stroke, or change in NYHA class. For the three groups (2.5 mg, 5 mg, and 10 mg), rates of patients judging their symptoms to be improved were 66%, 68%, and 66%.


Among patients with heart failure, there was no associated reduction in the rates of heart failure-related hospitalizations, worsening heart failure, and death in patients treated with increasing doses of enalapril. This may imply that the dose-response curve for enalapril is flat. However, caution should be exercised in applying this trial to current practice since other large mortality trials have shown a mortality impact in patients treated with 10 mg bid enalapril compared to placebo.


Clinical outcome with enalapril in symptomatic chronic heart failure; a dose comparison. The NETWORK Investigators. Eur Heart J 1998;19:481-9.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: Myocardial Infarction, Stroke, Enalapril, Heart Failure, Blood Pressure

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