© 2003 European Society of Cardiology
Vasopeptidase inhibitors for heart failure: where do we go from here?
Christchurch Cardioendocrine Research Group, Christchurch School of Medicine and Health Sciences Christchurch, New Zealand E-mail address: mark.richards{at}cdhb.govt.nz
Vasopeptidase inhibitors are a class of drugs which inhibit angiotensin converting enzyme and neutral endopeptidase (NEP) (EC 3.4.24.11 [EC] ). Converting enzyme inhibitors (ACEIs) have a well established clinical role in heart failure and hypertension. NEP is a membrane-bound metalloprotease which plays a role in the initial enzymatic degradation of the bioactive carboxyterminal portions of atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and C-type natriuretic peptide. In addition to this, the enzyme participates in degradation of bradykinin. It is a ubiquitous enzyme and has a large number of alternative substrates including the enkephalins, both angiotensins I and II, oxytocin, gastrin, interleukin-1β, luteinizng hormone releasing hormone and substance P among others [1]. Hence, NEP inhibition has the potential to induce a complex array of effects, but the potential benefit for cardiovascular disease appears to lie in enhancement of both tissue and circulating concentrations of the natriuretic peptides and augmented tissue levels of bradykinin. These effects would be expected to promote reductions in blood pressure and a beneficial array of actions upon renal function together with some inhibition of the renin–angiotensin–aldosterone and sympathetic nervous systems.
Experience with pure NEP inhibitors in clinical studies conducted in the early to mid-1990s was disappointing and this strategy appears to lack efficacy as monotherapy in either hypertension or congestive heart failure. More recently, companies have developed molecules capable of simultaneous inhibition of both ACE and NEP. Pre-clinical studies and clinical studies with surrogate end points proved promising. Mortality was improved in cardiomyopathic hamsters and other models of experimental heart failure [2,3]. The combination of actions appeared to be effective in producing substantial reductions in blood pressure in all experimental hypertensive models and in human hypertension, with particular potential for greater efficacy in systolic hypertension. In experimental heart failure, combined inhibition appeared to offer additional haemodynamic and neurohormonal effects and also appeared to spare renal function relative to ACE inhibition alone.
This promising early work led onto clinical trials in heart failure and there are now a handful of publications addressing the effects of combined ACE and NEP inhibition in this condition. The drug which is most advanced in clinical development is omapatrilat. In an initial report from a dose-ranging study, McClean and colleagues documented dose-dependent improvements in left ventricular ejection fraction and left ventricular end systolic wall stress together with a reduction in systolic blood pressure [4]. Omapatrilat increased post-dose plasma ANP levels when given in high dose and, over time, reduced pre-dose BNP levels (presumably reflecting reduction in cardiac filling pressures) and plasma adrenaline over 12 weeks of therapy. The treatment was well tolerated. Renal function was well preserved and there appeared to be a natriuretic effect with introduction of omapatrilat. These initial findings were extended to a larger group of 369 patients with stable symptomatic heart failure (NYHA class II–IV) and LVEF <40% in sinus rhythm [5]. Over 12 weeks of therapy omapatrilat given at 20 and 40 mg/day induced falls in capillary wedge pressure and systolic blood pressure in excess of that observed with the comparator dose of 2.5 mg/day. These haemodynamic effects were associated with increases in plasma ANP, BNP, cGMP, adrenomedullin and, at the 40 mg dose, norepinephrine. This profile of neurohormonal effects is distinct from that seen with ACE inhibition alone. Notably the increments in endothelin and norepinephrine appear to be outweighed by augmentation of tissue and circulating levels of vasodilator agents (including the cardiac natriuretic peptides and adrenomedullin), resulting in a net beneficial haemodynamic effect.
The effect of omapatrilat therapy on mortality and morbidity in heart failure has been addressed through the IMPRESS and OVERTURE studies [6,7]. The former, published in 2000 was a prospective, randomised, double blind, parallel trial of 573 patients with NYHA class II–IV congestive heart failure and LVEF
40% receiving an ACE inhibitor. They were randomly assigned to omapatrilat at a target dose of 40 mg/day or lisinopril at a target dose of 20 mg/day over 24 weeks. The study was initially aimed at assessing effects upon exercise tolerance as assessed by treadmill testing but, in fact, found a suggestive trend for a favourable effect of omapatrilat on mortality and morbidity. Whilst the effects on exercise tolerance were similar, there was a suggestive trend in favour of omapatrilat on the combined end point of death or admission for worsening heart failure (P=0.052; rr 0.53 (95% CI 0.27–1.02)). For the composite end-point of death, admission or discontinuation of study treatment for worsening heart failure, omapatrilat appeared better than lisinopril (P=0.035; 0.52 (0.28–0.96)). This composite end-point was incurred by 16 out of 289 patients taking omapatrilat (6%) compared with 29 out of 284 patients receiving lisinopril (10%).
These results encouraged initiation of the larger scale OVERTURE study in which 5770 patients with left ventricular ejection fraction <30% in NYHA classes II–IV admitted to hospital for heart failure within the previous 12 months, were randomised to omapatrilat 40 mg/day or enalapril 10 mg twice daily. Most patients were male (80%), the average age was 63 years, and the mean LVEF was 24%. Half of the patients were on concurrent beta blocker therapy and 40% were receiving spironolactone. For cardiovascular death or admission to hospital, omapatrilat exhibited a slight advantage over enalapril, this composite end-point being incurred by 1178 people out of 2886 receiving omapatrilat (40.8%) compared with 1275 out of 2884 receiving enalapril (44.2%) giving an RR of 0.91 (0.84–0.99) with P=0.024. Trends for omapatrilat to reduce the composite of death or admission with heart failure, all-cause mortality, or the composite end-point of death/MI/stroke/revascularisation all failed to attain statistical significance. Subgroup analysis suggested outcome in patients with low blood pressure favoured enalapril whereas those with systolic arterial pressure 
140 mmHg did better with omapatrilat. It is uncertain whether this comparison between the ACE inhibitor and combined inhibitor applies across the dose range. Notably the difference between omapatrilat and enalapril in the OVERTURE study is somewhat less than that seen between low and high dose ACEI in the ATLAS study.
The other major issue aside from efficacy on surrogate and mortal/morbid end points is that of safety. In view of the substrates for NEP, it is not surprising that a higher incidence of angioedema is becoming apparent on the combined inhibitor when compared with pure ACE inhibition [8]. In OVERTURE, 24 out of 2886 patients (0.83%) incurred this complication whereas the rate with enalapril was 14 out of 2884 (0.49%). This was not a statistically significant difference. In addition, the rate in heart failure appeared to be lower than that seen in hypertension. The OCTAVE study compared omapatrilat and enalapril in 25 000 patients with systolic hypertension and found 2.17% of patients on omapatrilat developed angioedema and 0.68% on enalapril. Rates were higher in African–American patients and smokers. Notably, some angioedema events were severe requiring intubation and there was no clear association with early dosing.
Conversely, renal function may be better preserved with a combined inhibitor than with ACE inhibition alone. In the IMPRESS study, a pre-defined level of deterioration in renal function was incurred by 6.1% of patients receiving lisinopril but only 1.8% of those taking omapatrilat (P=0.009) [6]. Similarly, in the OVERTURE study there was a trend to better preservation of renal function in patients receiving the combined inhibitor [7]. It is well recognised that decline in renal function is one of the limiting factors in escalation of anti-heart failure therapy and, in fact, renal dysfunction is a strong independent predictor of mortality in heart failure.
Where to from here? Currently the evidence suggests that at least one combined inhibitor (omapatrilat) at the doses that have been tested to date has only a slight advantage to offer over converting enzyme inhibition in a broad spectrum of patients with congestive heart failure. However, it is likely a niche indication will emerge. Areas that require further investigation are the comparative safety and efficacy of combined inhibitors vs. ACE inhibitors in patients with baseline renal dysfunction or in those that have demonstrated very vulnerable renal dysfunction with a decline in GFR and early onset of azotaemia with introduction of standard anti-failure therapy. It may be warranted to conduct a randomised controlled trial in such patients.
Whether or not omapatrilat has more to offer than converting enzyme inhibitors in heart failure complicated by diabetic nephropathy warrants testing. The comparative efficacy of combining vasopeptidase inhibitors with beta blockers compared with an ACE inhibitor/beta blocker combination should also be addressed. Whether a combination of vasopeptidase inhibitor with spironolactone offers more than ACEI plus spironolactone should also be further investigated. Finally, the results from IMPRESS and OVERTURE cannot be unreservedly extrapolated to other combined inhibitors, and further controlled trials of such dual inhibitors remain warranted.
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- Erdös E.G., Skidgel R.A. Neutral endopeptidase 24.11 (enkephalinase) and related regulators of peptide hormones. FASEB J (1989) 3:145–151.[Abstract]
- Trippodo N.C., Fox M., Monticello T.M., Panchal B.C., Asaad M.M. Vasopeptidase inhibition with omapatrilat improves cardiac geometry and survival in cardiomyopathic hamsters more than does ACE inhibition with captopril. J Cardiovasc Pharmacol (1999) 34:782–790.[CrossRef][Web of Science][Medline]
- Troughton R.W., Rademaker M.T., Powell J.D., et al. Beneficial renal and hemodynamic effects of omapatrilat in mild and severe heart failure. Hypertension (2000) 36:523–530.
[Abstract/Free Full Text] - McClean D.R., Ikram H., Garlick A.H., Richards A.M., Nicholls M.G., Crozier I.G. The clinical, cardiac, renal, arterial and neurohormonal effects of omapatrilat, a vasopeptidase inhibitor, in patients with chronic heart failure. J Am Coll Cardiol (2000) 36:479–486.
[Abstract/Free Full Text] - McClean D.R., Ikram H., Mehta S., et al. Vasopeptidase inhibition with omapatrilat in chronic heart failure: acute and long-term hemodynamic and neurohormonal effects. J Am Coll Cardiol (2002) 39:2034–2041.
[Abstract/Free Full Text] - Rouleau J.L., Pfeffer M.A., Stewart D.J., et al. Comparison of vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomised trial. Lancet (2000) 356:615–620.[CrossRef][Web of Science][Medline]
- Coletta A., Thackray S., Nikitin N., Cleland J.G.F. Clinical trials update: highlights of the scientific sessions of the American College of Cardiology : LIFE, DANAMI 2, MADIT-2, MIRACLE-ICD, OVERTURE, OCTAVE, ENABLE 1 & 2, CHRISTMAS, AFFIRM, RACE, WIZARD, AZACS, REMATCH, BNP trial and HARDBALL. Eur J Heart Fail (2002) 4:381–388.
[Abstract/Free Full Text] - Messerli F.H., Nussberger J. Vasopeptidase inhibition and angio-oedema. Lancet (2000) 356:608–609.[CrossRef][Web of Science][Medline]
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