Omapatrilat Reduces Pulse Pressure and Proximal Aortic Stiffness in Patients with Systolic Hypertension. Results of the Conduit Hemodynamics of Omipatrilat International Research Study. - Omapatrilat Reduces Pulse Pressure and Proximal Aortic Stiffness in Patients with Systolic Hypertension. Results of the Conduit Hemodynamics of Omipatrilat International Research Study.

Description:

Increased pulse pressure is an indicator of vascular stiffness and a major correlate of CV events in hypertension. The goal of this study was to determine if the administration of omapatrilat, a vasopeptidase with both ACE and neutral endopeptidase inhibitor activity, is associated with changes in vascular stiffness among patients with hypertension.

Study Design

Study Design:

Drug/Procedures Used:

In this 12 week double blind randomized clinical trial monotherapy with omapatrilat 80 mg daily (n=87) was compared to 40 mg of enalapril (n=80) in patients with predominantly systolic hypertension. Eligible patients had a SBP >160 mmHg but <200 mmHg and diastolic BP <110 mmHg following a 1-2 week placebo run in phase. Exclusions included intolerance to at least 40 mg of omapatrilat or 20 mg of enalapril, CHF, and peripheral vascular disease. Pulse wave velocity (PWV) was obtained by multi-site arterial tonometry with an ECG reference, and aortic compliance/stiffness using pulse volumes and echo-Doppler derived stroke volumes.

Principal Findings:

There was no difference between groups with respect to age (mean 61 years), male gender (62%), documented CAD (3-5%), current smoking (12%), use of lipid lowering drugs (25%), or percent of women taking estrogens (39%). THere was a trend for the omapatrilat group to have more diabetics (13% vs 5% on enalapril, p 0.066). There was no difference between groups in baseline BP [163/85(117) mmHg], mean flow rate, peripheral resistance, central stiffness, carotid-radial PWV, or carotid-femoral PWV. After 12 weeks, patients treated with omapatrilat group had a lower SBP, dBP, pulse pressure, mean pressure, borderline lower PWV, improved waveform morphology with a decrease in reflectance wave, and significantly reduced measures of central aortic stiffness.

Interpretation:

Greater reductions in pulse pressure and central aortic stiffness in hypertensive subjects treated with omapatrilat compared with enalapril suggest that aortic stiffness is maintained by specific, partially reversible mechanisms, and underscore a potential for drug modulation of natriuretic peptides in treatment of hypertension. The vasopeptidase inhibitors like omapatrilat increase natriuretic and vasodilatory peptides including ANP, BNP of myocardial cell origin, C-type NP of endothelial cell origin, bradykinin and adrenomedullin. The sum effect is to block vasoconstriction, enhance vasodilation, and reduce vascular smooth muscle cell proliferation, hypertrophy, and fibrosis. The fact that these agents reduce pulse pressure and aortic stiffness, two factors associated with increased risk for CHF, stroke, and MI, suggest that there may be an advantage to these agents beyond ACEi, but omapatrilat was no better than standard therapy in a recent CHF trial. The clinical trial OPERA is designed to compare omapatrilat to standard therapy for reducing CV events in 12,600 elderly with hypertension and will be completed in about 5 years.

References:

Mitchell GF, Izzo JL, Lacourciere Y, et al. Omapatrilat Reduces Pulse Pressure and Proximal Aortic Stiffness in Patients with Systolic Hypertension. Results of the Conduit Hemodynamics of Omipatrilat International Research Study. Circulation 2002;105:2955-61.

Clinical Topics: Heart Failure and Cardiomyopathies, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Heart Failure and Cardiac Biomarkers, Hypertension, Smoking

Keywords: Cell Proliferation, Protease Inhibitors, Electrocardiography, Vasoconstriction, Manometry, Stroke Volume, Hypertrophy, Hypertension, Bradykinin, Enalapril, Stroke, Vasodilation, Pulse Wave Analysis, Pyridines, Smoking, Adrenomedullin, Peripheral Vascular Diseases, Vascular Stiffness, Estrogens, Thiazepines, Vascular Resistance, Muscle, Smooth, Vascular, Atrial Natriuretic Factor, Endothelial Cells, Diabetes Mellitus


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