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

Objectives. To determine dose-related clinical and neurohumoral effects of angiotensin-converting enzyme (ACE) inhibitors in patients with chronic hea rt failure (CHF), we conducted a double-blind, placebo-controlled, randomiz ed study of three doses (2.5 mg, 5 mg and 10 mg) of the long-acting ACE inh ibitor imidapril. Background. The ACE inhibitors have become a cornerstone in the treatment o f CHF, but whether high doses are more effective than low doses has not bee n 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 imid april were examined. We studied 244 patients with mild to moderate CHF (New York Heart Association class II-III: +/-80%/20%), who were stable on digox in and diuretics. Patients were treated for 12 weeks, and the main end poin ts were exercise capacity and plasma neurohormones. Results. At baseline, the four treatment groups were well-matched for demog raphic 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 (n or)epinephrine, aldosterone and endothelin were not significantly affected. Renin increased in a dose-related manner, but plasma ACE activity was supp ressed 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 neurohormo nes, but it does not appear to be related to the extent of suppression of p lasma ACE. (J Am Coll Cardiol 1998;32:1811-8) (C)1998 by the American Colle ge of Cardiology.