Inferential characterization of the dose-response relationships of neurohormonal antagonists in chronic heart failure: A novel approach based on large-scale trials with active comparators.

BACKGROUND: Current guidelines for the treatment of heart failure strongly recommend the use of inhibitors of the renin-angiotensin system and sympathetic nervous system in all patients with a reduced ejection fraction who can tolerate these drugs. Yet, there is no consensus about the efficacy of low doses of these drugs or the likely shape of the dose-response relationship for these agents.

METHODS: Inferences were made by examining the effects of drugs in placebo-controlled trials before the protocol-specified opportunity for uptitration and by reassessing the results of large-scale trials with active comparators that inadvertently produced different intensities of neurohormonal blockade.

RESULTS: In the case of inhibitors of the renin-angiotensin system, low starting doses appear to be effective in many patients, and 3-5 fold increases in dose do not have a mortality advantage over low doses. By contrast, in the case of beta-adrenergic blockers, although low starting doses appear effective in improving outcomes, achievement of target doses may yield substantial incremental mortality benefits, even such doses are accompanied by only small additional decreases in heart rate.

CONCLUSION: When treating patients with heart failure to reduce mortality, the totality of evidence supports a relatively flat dose-response relationship for inhibitors of the renin-angiotensin system but a steep dose-response relationship for beta-adrenergic receptor blockers.