High- versus low-dose ACE inhibition in chronic heart failure: a double-blind, placebo-controlled study of imidapril

J Am Coll Cardiol. 1998 Dec;32(7):1811-8. doi: 10.1016/s0735-1097(98)00464-1.


Objectives: To determine dose-related clinical and neurohumoral effects of angiotensin-converting enzyme (ACE) inhibitors in patients with chronic heart failure (CHF), we conducted a double-blind, placebo-controlled, randomized study of three doses (2.5 mg, 5 mg and 10 mg) of the long-acting ACE inhibitor imidapril.

Background: The ACE inhibitors have become a cornerstone in the treatment of CHF, but whether high doses are more effective than low doses has not been fully elucidated, nor have the mechanisms involved in such a dose-related effect.

Methods: In a parallel group comparison, the effects of three doses of imidapril were examined. We studied 244 patients with mild to moderate CHF (New York Heart Association class II-III: +/-80%/20%), who were stable on digoxin and diuretics. Patients were treated for 12 weeks, and the main end points were exercise capacity and plasma neurohormones.

Results: At baseline, the four treatment groups were well-matched for demographic variables. Of the 244 patients, 25 dropped out: 3 patients died, and 9 developed progressive CHF (3/182 patients on imidapril vs. 6/62 patients on placebo, p < 0.05). Exercise time increased 45 s in the 10-mg group (p = 0.02 vs. placebo), but it did not significantly change in the 5-mg (+16 s), and 2.5-mg (+11 s) imidapril group, compared to placebo (+3 s). Physical working capacity also increased in a dose-related manner. Plasma brain and atrial natriuretic peptide decreased (p < 0.05 for linear trend), while (nor)epinephrine, aldosterone and endothelin were not significantly affected. Renin increased in a dose-related manner, but plasma ACE activity was suppressed similarly (+/-60%) on all three doses.

Conclusions: Already within 3 months after treatment initiation, high-dose ACE inhibition (with imidapril) is superior to low-dose. This is reflected by a more pronounced effect on exercise capacity and some of the neurohormones, but it does not appear to be related to the extent of suppression of plasma ACE.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use*
  • Atrial Natriuretic Factor / blood
  • Double-Blind Method
  • Exercise Test
  • Female
  • Heart Failure / blood
  • Heart Failure / drug therapy*
  • Humans
  • Imidazoles / pharmacology
  • Imidazoles / therapeutic use*
  • Imidazolidines*
  • Male
  • Middle Aged
  • Natriuretic Peptide, Brain / blood
  • Renin-Angiotensin System / drug effects


  • Angiotensin-Converting Enzyme Inhibitors
  • Imidazoles
  • Imidazolidines
  • Natriuretic Peptide, Brain
  • Atrial Natriuretic Factor
  • imidapril