Current Hypertension Reports

, Volume 5, Issue 4, pp 346–352 | Cite as

Recent clinical trials with omapatrilat: New developments

  • Anne Zanchi
  • Marc Maillard
  • Michel Burnier


Omapatrilat belongs to the vasopeptidase inhibitors, ie, drugs that possess the ability to inhibit simultaneously the membrane-bound zinc metalloproteases, angiotensin-converting enzyme (ACE), and the neutral endopeptidase EC (NEP). Omapatrilat was targeted to treat patients with hypertension and congestive heart failure. The preclinical and early clinical studies conducted with omapatrilat were very promising. Indeed, omapatrilat appeared to be a very potent antihypertensive agent with very favorable effects on cardiac function in heart failure patients. In contrast to these early studies, the large clinical trials were more disappointing. The results of the OCTAVE trial confirmed the antihypertensive efficacy of omapatrilat, but at the price of an angioedema rate more than threefold higher than that of an ACE inhibitor in the overall population (2.17% vs 0.68%), and close to fourfold higher in the black population. In OVERTURE, a large randomized control trial in heart failure, angioedema was also more common with omapatrilat, but the incidence was much lower (0.8% with omapatrilat vs 0.5% with enalapril). However, omapatrilat was not convincingly superior to the ACE inhibitor. Because angioedema is probably a class side effect of vasopeptidase inhibitors, the higher incidence of this potentially life-threatening complication with omapatrilat has likely stopped the development of this new class of agents. The future of vasopeptidase inhibitors will depend on the ability to improve the risk/benefit ratio either by developing agents that produce less angioedema, or by defining more precisely a high-risk population that could take advantage of dual ACE/NEP inhibition.


Enalapril Atrial Natriuretic Peptide Lisinopril Angioedema NYHA Functional Class 
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References and Recommended Reading

  1. 1.
    The ALLHAT officers and coordinators for the ALLHAT Collaborative Research Group: Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. The antihypertensive and lipid lowering treatment to prevent heart attack trial (ALLHAT). JAMA 2002, 288:2981–2997.CrossRefGoogle Scholar
  2. 2.
    Hansson L, Zanchetti A, Carruthers SG, et al.: Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998, 351:1755–1762.PubMedCrossRefGoogle Scholar
  3. 3.
    Brenner BM, Cooper ME, de Zeeuw D, et al.: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001, 345:861–869.PubMedCrossRefGoogle Scholar
  4. 4.
    Lewis EJ, Hunsicker LG, Clarke WR, et al.: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001, 345:851–860.PubMedCrossRefGoogle Scholar
  5. 5.
    Weber MA: Vasopeptidase inhibitors. Lancet 2001, 3358:1525–1532.An exhaustive review of the preclinical and early clinical studies conducted with vasopeptidase inhibitors before the results of the major trials were obtained.CrossRefGoogle Scholar
  6. 6.
    Messerli FH, Nussberger J: Vasopeptidase inhibition and angio-oedema. Lancet 2000, 356:608–609.A critical and well-documented comment on the mechanisms whereby vasopeptidase inhibitors produce angioedema.PubMedCrossRefGoogle Scholar
  7. 7.
    Trippodo NC, Robl JA, Asaad MM, et al.: Effects of omapatrilat in low, normal, and high renin experimental hypertension. Am J Hypertens 1998, 11(3 Pt 1):363–372.PubMedCrossRefGoogle Scholar
  8. 8.
    Intengan HD, Schiffrin EL: Vasopeptidase inhibition has potent effects on blood pressure and resistance arteries in stroke-prone spontaneously hypertensive rats. Hypertension 2000, 35:1221–1225.PubMedGoogle Scholar
  9. 9.
    Burrell LM, Droogh J, Man in’t Veld O, et al.: Antihypertensive and antihypertrophic effects of omapatrilat in SHR. Am J Hypertens 2000, 13:1110–1116.PubMedCrossRefGoogle Scholar
  10. 10.
    Quaschning T, d’Uscio LV, Shaw S, Luscher TF: Vasopeptidase inhibition exhibits endothelial protection in salt-induced hypertension. Hypertension 2001, 37:1108–1113.PubMedGoogle Scholar
  11. 11.
    Quaschning T, D’Uscio LV, Shaw S, et al.: Vasopeptidase inhibition restores renovascular endothelial dysfunction in saltinduced hypertension. J Am Soc Nephrol 2001, 12:2280–2287.PubMedGoogle Scholar
  12. 12.
    Millette E, Demeilliers B, Wu R, et al.: Comaprison of the cardiovascular protection by omapatrilat and lisinopril treatments in DOCA-salt hypertension. J Hypertens 2003, 21:125–135.PubMedCrossRefGoogle Scholar
  13. 13.
    Trippodo NC, Fox M, Monticello TM, et al.: 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.PubMedCrossRefGoogle Scholar
  14. 14.
    Cataliotti A, Boerrigter G, Chen HH, et al.: Differential actions of vasopeptidase inhibition versus angiotensin-converting enzyme inhibition on diuretic therapy in experimental congestive heart failure. Circulation 2002, 105:639–644.PubMedCrossRefGoogle Scholar
  15. 15.
    Campese VM, Lasseter KC, Ferrario CM, et al.: Omapatrilat versus lisinopril: efficacy and neurohormonal profile in salt-sensitive hypertensive patients. Hypertension 2001, 38:1342–1348.PubMedGoogle Scholar
  16. 16.
    Regamey F, Maillard M, Nussberger J, et al.: Renal hemodynamic and natriuretic effects of concomitant Angiotensinconverting enzyme and neutral endopeptidase inhibition in men. Hypertension 2002, 40:266–272.PubMedCrossRefGoogle Scholar
  17. 17.
    Azizi M, Lamarre-Cliche M, Labatide-Alanore A, et al.: Physiologic consequences of vasopeptidase inhibition in humans: effect of sodium intake. J Am Soc Nephrol 2002, 13:2454–2463.PubMedCrossRefGoogle Scholar
  18. 18.
    Ferdinand K, Saini R, Lewin A, et al.: Efficacy and safety of omapatrilat with hydrochlorothiazide for the treatment of hypertension in subjects nonresponsive to hydrochlorothiazide alone. Am J Hypertens 2001, 14:788–793.PubMedCrossRefGoogle Scholar
  19. 19.
    Mitchell GF, Izzo JL Jr, Lacourciere Y, et al.: Omapatrilat reduces pulse pressure and proximal aortic stiffness in patients with systolic hypertension: results of the conduit hemodynamics of omapatrilat international research study. Circulation 2002, 105:2955–2961.PubMedCrossRefGoogle Scholar
  20. 20.
    Klapholz M, Thomas I, Eng C, et al.: Effects of omapatrilat on hemodynamics and safety in patients with heart failure. Am J Cardiol 2001, 88:657–661.PubMedCrossRefGoogle Scholar
  21. 21.
    McClean DR, Ikram H, Garlick AH, et al.: 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.PubMedCrossRefGoogle Scholar
  22. 22.
    McClean DR, Ikram H, Garlick AH, Crozier IG: Effects of omapatrilat on systemic arterial function in patients with chronic heart failure. Am J Cardiol 2001, 87:565–569.PubMedCrossRefGoogle Scholar
  23. 23.
    McClean DR, Ikram H, Mehta S, et al., Omapatrilat Hemodynamic Study Group: Vasopeptidase inhibition with omapatrilat in chronic heart failure: acute and long-term hemodynamic and neurohumoral effects. J Am Coll Cardiol 2002, 39:2034–2041.PubMedCrossRefGoogle Scholar
  24. 24.
    Kostis JB, Cobbe S, Johnston C, et al., OPERA Study Group:Omapatrilat in persons with enhanced risk of atherosclerotic events. Design of the omapatrilat in persons with enhanced risk of atherosclerotic events (OPERA) trial. Am J Hypertens 2002, 15:193–198.PubMedCrossRefGoogle Scholar
  25. 25.
    Coats AJS: Omapatrilat-the story of Overture and Octave. Int J Cardiol 2002, 86:1–4.A critical comment on the results of the two major clinical trials performed with omapatrilat.PubMedCrossRefGoogle Scholar
  26. 26.
    Pickering TG: Effects of stress and behavioral interventions in hypertension: the rise and fall of omapatrilat. J Clin Hypertens 2002, 4:371–373.Google Scholar
  27. 27.
    Rouleau JL, Pfeffer MA, Stewart DJ, et al., for the IMPRESS investigators: 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.The first large clinical study suggesting that omapatrilat may be superior to an ACE inhibitor in the management of congestive heart failure.PubMedCrossRefGoogle Scholar
  28. 28.
    Sheth T, Parker T, Block A, et al., the IMPRESS Investigators:Comparison of the effects of omapatrilat and lisinopril on circulating neurohormones and cytokines in patients with chronic heart failure. Am J Cardiol 2002, 90:496–500.PubMedCrossRefGoogle Scholar
  29. 29.
    Eisenstein EL, Nelson CL, Simon TA, et al.: Vasopeptidase inhibitor reduces inhospital costs for patients with congestive heart failure: results from the IMPRESS trial. Inhibition of metallo protease by BMS-186716 in a randomized exercise and symptoms study in subjects with heart failure. Am Heart J 2002, 143:1112–1117.PubMedCrossRefGoogle Scholar
  30. 30.
    Packer M, Califf RM, Konstam MA, et al., for the OVERTURE study group: Comparison of omapatrilat and enalapril in patients with chronic heart failure. The omapatrilat versus enalapril rnaodmized trial of utility in reducing events (OVERTURE). Circulation 2002, 106:r21-r27.The first large prospective, randomized trial in heart failure demonstrating that omapatrilat is as effective but not superior to an ACE inhibitor.CrossRefGoogle Scholar
  31. 31.
    Burnier M: Angiotensin II type 1 receptor blockers. Circulation 2001, 103:904–912.PubMedGoogle Scholar
  32. 32.
    Cao Z, Burrell LM, Tikkanen I, et al.: Vasopeptidase inhibition attenuates the progression of renal injury in subtotal nephrectomized rats. Kidney Int 2001, 60:715–721.PubMedCrossRefGoogle Scholar
  33. 33.
    Taal MW, Nenov VD, Wong W, et al.: Vasopeptidase inhibition affords greater renoprotection than angiotensinconverting enzyme inhibition alone. J Am Soc Nephrol 2001, 12:2051–2059.PubMedGoogle Scholar

Copyright information

© Current Science Inc. 2003

Authors and Affiliations

  • Anne Zanchi
  • Marc Maillard
  • Michel Burnier
    • 1
  1. 1.Division of Hypertension and Vascular MedicineLausanneSwitzerland

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