Comparison of Omapatrilat and Enalapril in Patients With Chronic Heart Failure

Abstract

MD; for the OVERTURE Study Group* Background-Combined inhibition of the angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) may produce greater benefits in heart failure than ACE inhibition alone. Methods and Results-We randomly assigned 5770 patients with New York Heart Association class II to IV heart failure to double-blind treatment with either the ACE inhibitor enalapril (10 mg BID, nϭ2884) or to the ACE-NEP inhibitor omapatrilat (40 mg once daily, nϭ2886) for a mean of 14.5 months. The primary end point-the combined risk of death or hospitalization for heart failure requiring intravenous treatment-was used prospectively to test both a superiority and noninferiority hypothesis (based on the effect of enalapril in the Studies of Left Ventricular Dysfunction [SOLVD] Treatment Trial). A primary end point was achieved in 973 patients in the enalapril group and in 914 patients in the omapatrilat group (hazard ratio 0.94; 95% CI: 0.86 to 1.03, Pϭ0.187)-a result that fulfilled prespecified criteria for noninferiority but not for superiority. The omapatrilat group also had a 9% lower risk of cardiovascular death or hospitalization (Pϭ0.024) and a 6% lower risk of death (Pϭ0.339). Post hoc analysis of the primary end point with the definition used in the SOLVD Treatment Trial (which included all hospitalizations for heart failure) showed an 11% lower risk in patients treated with omapatrilat (nominal Pϭ0.012). Conclusion-Omapatrilat reduces the risk of death and hospitalization in chronic heart failure but was not more effective than ACE inhibition alone in reducing the risk of a primary clinical event. Between-group differences in favor of omapatrilat observed in secondary and post hoc analyses warrant further study. (Circulation. 2002;106:920-926.)

A prospective, randomized, double‐blind, placebo‐controlled pilot study of sacubitril/valsartan (Entresto) in dogs with cardiomegaly secondary to myxomatous mitral valve disease

“…On the other hand, clinically irrelevant systemic hypotension was seen more frequently in human patients taking S/V than in those taking enalapril, but S/V did not significantly alter SAP over time in the dogs of our study 24. Sacubitril/valsartan and related drugs have been shown to be a safe and effective treatment for systemic hypertension in humans and have been shown to delay the progression of chronic and proteinuric kidney diseases 46, 47, 48, 49, 50. Increased NEP concentrations are present in human patients with end‐stage renal dysfunction, suggesting an additional indication for use of S/V in patients with renal disease 51.…”

Angiotensin receptor neprilysin inhibitor treatment is safe and potentially efficacious in end‑stage hypertrophic cardiomyopathy

“…However, in the much larger OVERTURE study, 13 omapatrilat was not superior to enalapril (ACEI) alone in reducing the risk of primary clinical event. Furthermore, any clinical benefit of omapatrilat was overshadowed by the significant increase of adverse effects, including severe angioedema and hypotension.…”

“…Furthermore, any clinical benefit of omapatrilat was overshadowed by the significant increase of adverse effects, including severe angioedema and hypotension. 13 Therefore, the combination of NEPi and ACEI was abandoned due to lack of safety.…”

Efficacy of angiotensin–neprilysin inhibition versus enalapril in patient with heart failure with a reduced ejection fraction

“…Combined inhibition of the renin-angiotensin system and neprilysin was superior to those of either approach alone in experimental studies but in clinical trials, the combined inhibition of ACE and neprilysin was associated with serious angioedema [4].…”