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Musical Trials of an Antihypertensive: Omapatrilat in OVERTURE and OCTAVEReviewer: KW Tim Park, MD
Life-threatening cardiovascular events (stroke or myocardial infarction) are estimated to occur in hypertensive patients at a rate of 100 to 300 per 10,000 patients per year.1 Fewer than half of adults treated for hypertension in the U.S. reach the recommendations of <140 mmHg systolic and <90 mmHg diastolic pressure. Several endogenous peptides such as natriuretic peptides, bradykinin, and adrenomedullin can attenuate vasoconstriction and sodium retention as well as retard cardiac and vascular hypertrophy and remodeling.2-4 These peptides are broken down by Neutral EndoPeptidase (NEP). To enhance the effects of the peptides, omapatrilat, an inhibitor of NEP, that also inhibits the Angiotensin Converting Enzyme (ACE), has been developed for treatment of hypertension and Congestive Heart Failure (CHF). Initial clinical trials of omapatrilat, that involved a small number of patients and short follow-up periods, were promising for the treatment of hypertension and CHF. In the IMPRESS trial,5 573 patients with NYHA class II-IV were randomized to either omapatrilat or lisinopril and followed for 12 weeks. At 12 weeks, the incidence of adverse cardiovascular events was lower in the omapatrilat group (7% vs. 12%, P=0.04). Among those in NYHA class III or IV, functional status improved more in the omapatrilat group. Other small studies demonstrated that omapatrilat was superior to lisinopril in lowering both systolic and diastolic pressures in salt-sensitive hypertensive patients,6 was effective in hypertensive patients refractory to hydrochlorothiazide alone,7 and reduced arterial stiffness more than enalapril.8 In contrast to these early studies, larger clinical trials that followed have yielded less encouraging results. In the OVERTURE (Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events) trial, investigators randomized 5,770 patients with heart failure to either omapatrilat or enalapril. Patients were followed for a mean of 14.5 months. Primary end points (death or hospitalization for CHF requiring intravenous medication) was not significantly different between the drugs (914/2,886 for omapatrilat vs. 973/2,884 for enalapril, P=0.19). However, a post hoc analysis, using a different definition of hospitalization for CHF (any hospitalization for CHF requiring change in regimen, oral or intravenous), showed omapatrilat to be superior (941/2886 vs. 1041/2884, P=0.012). In subgroup analyses, an advantage of omapatrilat over enalapril was found among those who had hypertension (systolic pressure >140 mmHg) at the start of the study, those without diabetes, those with nonischemic cardiomyopathy, and women. Renal impairment and hypotension/dizziness were less frequent in the omapatrilat group. Among those with preexisting hypertension, the incidence of renal impairment was lower for the omapatrilat group (3.9% vs. 7.1%). The OCTAVE (Omapatrilat Cardiovascular Treatment vs. Enalapril) trial was a multinational, 24-week study that compared omapatrilat and enalapril in treatment of hypertension in 25,302 patients. Omapatrilat reduced systolic pressure 3.6 mmHg more than enalapril and was associated with less use of adjunctive antihypertensive therapy (19% vs. 27%, P <0.001). A disturbing finding, however, was that angioedema was more frequent with omapatrilat than enalapril (2.17% vs. 0.68%, P <0.005). Two omapatrilat-treated patients (a rate of 1.6 per 10,000 treated with omapatrilat) experienced severe airway compromise, one of them requiring endotracheal intubation, though both recovered without sequelae. Since life-threatening cardiovascular events occur at a rate of 100 - 300 per 10,000 hypertensive patients per year, the OCTAVE investigators estimate that differences of 3 mmHg in systolic pressure may be translatable to reductions in cardiovascular events of 15-20% (15-60 fewer significant cardiovascular events per 10,000), so that the cardiovascular benefit of omapatrilat would outweigh the risk of significant angioedema. With both drugs, the rate of angioedema was increased substantially in blacks (5.54% vs. 1.62%) and smokers (3.93% vs. 0.81%). In summary, omapatrilat represents a prototypal drug in a new class of antihypertensives called NEP inhibitors that may be useful in select groups of patients for control of blood pressure and amelioration of CHF. However, it may be associated with significant angioedema, especially among blacks and smokers. The initial trials of the medication gave an 'OVERTURE' of a hope of efficacy; however, before one jumps an 'OCTAVE' leap of faith in the drug, additional studies will be needed to better define the group of patients who will benefit from the medication without significant risk of side effects. References
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