Omapatrilat (2003)

Omapatrilat inhibits both angiotensin-converting enzyme (ACE) and neutral endopeptidase [1]. Because neutral endopeptidase metabolizes vasodilator peptides, including natriuretic peptide, adrenomedullin and bradykinin, omapatrilat has been proposed as a more effective agent in reversing both hypertension and its associated cardiovascular complications compared to ACE inhibitors. Moreover, because angiotensin II plays little effect in maintaining hypertension in common volume-dependent forms, it may have a much extended efficacy within the hypertensive population. In a contemporary study of patients with salt-sensitive hypertension, Ferrario et al. [2] showed that omapatrilat was almost twice as effective as lisinopril in reducing blood pressure. In this issue of the journal, Millette et al. [3] tested these concepts by contrasting omapatrilat and lisinopril on blood pressure, morphological vascular changes, endothelial function and overall survival in a deoxycorticosterone (DOCA)-salt hypertensive rat model. Surprisingly, there was a similar modest reduction in blood pressure with both agents. Similarly, both agents reduced media thickness in the small coronary arterioles and reduced aortic superoxide formation to the same extent. However, despite these similar effects on blood pressure and blood vessels, omapatrilat drastically reduced mortality in the severe model of DOCA-salt hypertension (12.5%), whereas the mortality with lisinopril (75.0%) was similar to that in non-treated control rats (87.5%). These observations of a dramatic improvement in survival in a model of severe hypertension clearly give support to pursuing drugs in this class, including sampatrilat, gemopatrilat and fasidotril, as new anti-hypertensive agents. The outcome of clinical trials comparing omapatrilat and enalapril have revealed that the drugs are equally effective in congestive heart failure and hypertension patients, but there has been a higher incidence of adverse effects, notably angio-oedema, in those randomized to omapatrilat. The OVERTURE (Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events) study of 5770 patients with New York Heart Association (NYHA) class II to IV heart failure showed no difference in the primary end-point of all cause mortality or hospitalization due to heart failure between the two drugs. However, angio-oedema was slightly more common with omapatrilat (24 cases, 0.8%) than enalapril (14 cases, 0.5%) [4]. The Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril (OCTAVE) study was a multinational, double-blind trial in 25 267 hypertensive patients [4]. Omapatrilat yielded a 3 mmHg greater reduction in blood pressure than enalapril. However, this study confirmed that angio-oedema developed more frequently in those randomized to omapatrilat (274 cases, 2.17%) compared to enalapril (86 cases, 0.68%). The rate of angio-oedema was even higher in Blacks (5.54% for omapatrilat and 1.62% for enalapril) and smokers (3.93% for omapatrilat and 0.81% for enalapril). The overall death rate was low and did not differ between omapatrilat (0.15%) and enalapril (0.18%) [4]. Most of the cases of angio-oedema occurred within the first few hours after the initial dose [5], corresponding to the period when plasma bradykinin levels are clearly elevated. Unfortunately, the study by Millette et al. [3] does not identify the mechanism for improved survival with omapatrilat, despite a similar and modest lowering of blood pressure and similar effects on vascular remodelling. Interestingly, only omapatrilat improved endothelial function. This may be ascribed, in part at least, to an improved cardiovascular response to bradykinin, which is a potent endothelial agonist. Alternatively, it may be due to enhanced levels of angiotensin 1–7 that activates endothelium-dependent relaxation [2]. Improved endothelial function could improve outcome by decreasing platelet aggregation and vasospasm. However, the mild amelioration of endothelial dysfunction in the 7.5-mg DOCA model is unlikely to explain the large difference in survival between omapatrilat and lisinopril in the severe 10-mg DOCA model. Despite its limitations and the rather small number of animals studied, the findings of the current study are consistent with another recent report. In a cardiomyopathic hamster model, omapatrilat prolonged survival ages from 328 to 472 days compared to 403 days for animals given captopril [6]. Similarly, in a study of patients with NYHA class III/IV heart failure, omapatrilat had a significant advantage over lisinopril in the combination end-point of mortality, admission for worsening heart failure or discontinuation of study medication for worsening heart failure by the end of the 7-month period of observation [7]. Thus, the benefits of omapatrilat in some high-risk patient populations with severe salt-sensitive hypertension [2] or severe heart failure may possibly outweigh the disadvantage of the higher incidence of angio-oedema. These questions need to be resolved in further studies aiming to clarify the mechanism of improvement in survival by vasopeptidase inhibitors.