Abstract
The mechanisms of action of omapatrilat, an agent that inhibits both neutral endopeptidase 24.11 and angiotensin-converting enzyme, on arterial function in patients with heart failure have not been previously reported. Forty-eight patients in New York Heart Association functional class II to III, left ventricular ejection fraction ≤40%, and in sinus rhythm were randomized to a dose-ranging (2.5, 5, 10, 20, or 40 mg) study of omapatrilat for 12 weeks. Measurements were obtained at baseline and 12 weeks. Decreases in systolic (25.0 ± 4.5 vs 2.8 ± 5.0 mm Hg, p <0.05) and mean arterial (13.9 ± 3.0 vs 0.3 ± 3.3 mm Hg, p <0.05) pressure were seen after 12 weeks of therapy with higher doses. Ventricular-arterial coupling was improved with a dose-related decrease in augmentation index (−13.8 ± 1.7% vs +6.1 ± 2.1%, p <0.01). There was no change in resting forearm blood flow between groups; however, maximum forearm vasodilator response during reactive hyperemia increased in the high-dose groups compared with the control group (+266 ± 43% vs −14 ± 92%, p <0.05). Omapatrilat induced an increase in postdose plasma atrial natriuretic peptide levels (30 ± 11 vs −2 ± 7 pmol/L, p <0.01) in high-dose groups consistent with endopeptidase 24.11 inhibition. Omapatrilat shows beneficial changes in ventricular-vascular coupling and arterial function in heart failure.
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