Vasopeptidase inhibition with omapatrilat in chronic heart failure: acute and long-term hemodynamic and neurohumoral effects.

Abstract

OBJECTIVES:

We investigated the acute and long-term hemodynamic and neurohumoral effects of the vasopeptidase inhibitor omapatrilat in human heart failure.

BACKGROUND:

Angiotensin-converting enzyme (ACE) inhibition constitutes a major advance in the treatment of chronic heart failure (CHF). Simultaneous inhibition of both neutral endopeptidase and ACE with omapatrilat may represent a new treatment strategy in CHF.

METHODS:

Three hundred and sixty-nine patients with symptomatic heart failure were randomized to double-blind treatment with omapatrilat (first 190 patients: 2.5 mg, 5 mg or 10 mg; last 179 patients: 2.5 mg, 20 mg or 40 mg once daily) for 12 weeks.

RESULTS:

Acutely, the 10 mg, 20 mg and 40 mg doses of omapatrilat produced greater reductions in pulmonary capillary wedge pressure (PCWP), systolic blood pressure (SBP) and systemic vascular resistance compared with 2.5 mg. Higher doses were associated with greater increases in vasodilator and natriuretic peptides, in addition to ACE inhibition. After 12 weeks, omapatrilat 20 mg and 40 mg showed greater falls from baseline in PCWP (40 mg: 0 h to 12 h average change -7.3 +/- 0.8 mm Hg) and SBP (40 mg: -11.7 +/- 1.7 mm Hg) than 2.5 mg (both p < 0.01 vs. 2.5 mg). The incidence of adverse experiences and patient withdrawal were similar in all groups.

CONCLUSIONS:

In CHF, the acute hemodynamic benefit seen with higher doses of omapatrilat was associated with increases in plasma vasodilator and natriuretic peptide levels in addition to ACE inhibition. After 12 weeks, the hemodynamic benefit was maintained. Omapatrilat may be a promising new agent in CHF.

• Authors: Dougal R McClean, Hamid Ikram, Sukh Mehta, J Thomas Heywood, Michel F Rousseau, Alan L Niederman, Rafael F Sequeira, Eckart Fleck, Steven N Singh, Benoit Coutu, Peter Hanrath, Michel Komajda, Catherine C Bryson, Chunlin Qian, James J Hanyok, Omapatrilat Hemodynamic Study Group
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 39 Issue 12 Pg. 2034-41 (Jun 19 2002) ISSN: 0735-1097 [Print] United States
• PMID: 12084605 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Neurotransmitter Agents
• Protease Inhibitors
• Pyridines
• Thiazepines
• Natriuretic Peptide, Brain
• omapatrilat
• Atrial Natriuretic Factor

Topics

• Aged
• Atrial Natriuretic Factor (blood)
• Double-Blind Method
• Heart Failure (drug therapy)
• Hemodynamics (drug effects)
• Humans
• Middle Aged
• Natriuretic Peptide, Brain (blood)
• Neurotransmitter Agents (blood)
• Protease Inhibitors (administration & dosage, therapeutic use)
• Pulmonary Wedge Pressure (drug effects)
• Pyridines (administration & dosage, therapeutic use)
• Thiazepines (administration & dosage, therapeutic use)
• Time Factors
• Vascular Resistance (drug effects)