Effect of Angiotensin-Converting Enzyme or Vasopeptidase Inhibition on Ventricular Size and Function in Patients With Heart Failure: The Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE) Echocardiographic Study

Scott D. Solomon, MD; Hicham Skali, MD; Mikhail Bourgoun, MD; James Fang, MD; Jalal K. Ghali, MD; Michel Martelet, MD; Dariusz Wojciechowski, MD; Baiba Ansmite, MD; Janis Skards, MD; Toivo Laks, MD; David Henry, PhD; Milton Packer, MD; Marc A. Pfeffer, MD, PhD


Am Heart J. 2005;150(2):257-262. 

In This Article

Abstract and Introduction

Background: Angiotensin-converting enzyme (ACE) inhibition attenuates ventricular remodeling and improves ventricular function in heart failure patients. Vasopeptidase inhibition has shown similar effects in experimental models.
Objectives: The OVERTURE echocardiographic study was designed to test the hypothesis that the vasopeptidase inhibitor omapatrilat would attenuate ventricular remodeling and improve ventricular function to a greater extent than an ACE inhibitor.
Methods: Three hundred twenty-one patients with heart failure (New York Heart Association class ≥2) were included in the OVERTURE echocardiographic substudy and were randomized to receive enalapril (10 mg twice a day) or omapatrilat (40 mg every day). Echocardiograms were performed at baseline and at 1 year (n = 214). Left ventricular size was estimated by summation of ventricular areas in apical and short-axis views and by calculation of ventricular volumes. Ejection fraction was calculated from ventricular volumes.
Results: Combined diastolic and systolic areas and volumes decreased significantly (mean diastolic area change -8.36 cm2, 95% CI -9.4 to -7.3 cm2; mean systolic change -8.4 cm2, 95% CI -9.5 to -7.3 cm2), and ejection fractions increased significantly (3.6%, 95% CI 2.6% to 4.6%) in both treatment groups from baseline to 1 year. There were no differences in the magnitude of improvement in ventricular size or function based on treatment assignment. Patients who died or were hospitalized for heart failure subsequent to the final assessment demonstrated the least degree of reverse remodeling.
Conclusion: Ventricular size and function improved similarly after 1 year with ACE or vasopeptidase inhibition in patients with heart failure. Reverse remodeling was associated with improved outcome.

Angiotensin-converting enzyme (ACE) inhibitors have been shown to attenuate left ventricular (LV) remodeling and improve ventricular function in patients with LV dysfunction or heart failure in association with improvement in morbidity and mortality.[1,2,3,4,5] Omapatrilat, a vasopeptidase inhibitor, inhibits both ACE and neutral endopeptidase and produces greater reductions in blood pressure than ACE inhibitors.[6,7,8] Omapatrilat was similar to captopril in attenuating ventricular remodeling in a rat model of myocardial infarction.[9] In a pilot study comparing omapatrilat and enalapril in heart failure patients, omapatrilat was associated with improvement in a combined end point of death, or hospitalization or discontinuation of study medication for heart failure.[10]

The OVERTURE trial was designed to compare the efficacy of omapatrilat to an ACE inhibitor in patients with heart failure. OVERTURE enrolled 5770 patients with moderate to severe heart failure, defined by New York Heart Association class II or greater, or LV ejection fraction <30% in patients who had been hospitalized for heart failure in the last 12 months. At the time of enrollment, all patients were receiving optimal therapy and were randomized to receive enalapril (10 mg twice a day) or omapatrilat (40 mg once daily). The primary end point of combined risk of death for hospitalization for heart failure was achieved in 973 patients in the enalapril group and 914 patients in the omapatrilat group (hazard ratio 0.94, 95% CI 0.8-1.03). These Results fulfilled prespecified criteria for noninferiority but not superiority.[11]

The OVERTURE echocardiographic study was a prespecified substudy of the larger study and was designed to test the hypothesis that omapatrilat would attenuate or reduce LV enlargement, and/or improve LV function, to a greater extent than enalapril.