Objective: To discuss the controversy associated with the optimal dosing of angiotensin-converting enzyme (ACE) inhibitors in the management of patients with systolic heart failure; specifically, to review data related to the use of high-dose ACE inhibitors related to both neurohormonal and clinical outcomes associated with doses similar to, lower than, and higher than those used in the large, randomized clinical trials.
Data sources: Primary, review, and meta-analysis articles were identified by MEDLINE search (1987-September 2002) and through secondary sources.
Study selection and data extraction: All of the articles identified from the data sources were evaluated, and all information deemed relevant was included in this discussion. All available comparative dose trials, both prospective and retrospective, were evaluated for clinical and neurohormonal outcomes.
Data synthesis: The majority of data comparing the effect of high- with low-dose ACE inhibitors on neurohormonal outcomes demonstrate dose-related reduction in various neurohormonal measurements including plasma ACE, aldosterone, atrial natriuretic peptide, B-type natriuretic peptide, and interleukin-6 levels. Clinical endpoints including New York Heart Association class and heart failure-related hospitalizations were reduced by higher doses, but a dose-related survival benefit has not been demonstrated. Differences in duration of therapy and study design may account for variability in neurohormonal and morbidity results among various studies.
Conclusions: Despite documented underutilization in clinical practice of doses of ACE inhibitors demonstrated in large controlled trials to improve morbidity and mortality, clinicians should attempt to reach these target doses if possible in patients with heart failure. Higher doses may improve surrogate markers for heart failure without impacting survival.