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CLINICAL STUDY

Vasopeptidase inhibition with omapatrilat in chronic heart failure: acute and long-term hemodynamic and neurohumoral effects

Dougal R. McClean, MD^*, Hamid Ikram, MD, PhD^*,*, Sukh Mehta, MD, J. Thomas Heywood, MD, Michel F. Rousseau, MD, Alan L. Niederman, MD^||, Rafael F. Sequeira, MD^¶, Eckart Fleck, MD^#, Steven N. Singh, MD^**, Benoit Coutu, MD, Peter Hanrath, MD, Michel Komajda, MD, Catherine C. Bryson^||||, Chunlin Qian, PhD^||||, James J. Hanyok, PharmD^|||| Omapatrilat Hemodynamic Study Group

^* Christchurch Hospital, Christchurch, New Zealand
San Bernadino, California, USA
Jerry L. Pettis Veterans Administration Medical Center, Loma Linda, California, USA
Cliniques Universitaires Saint-Luc, Brussels, Belgium
^|| Greater Fort Lauderdale Heart Group Research, Fort Lauderdale, Florida, USA
^¶ University of Miami/Jackson Memorial Medical Center, Miami, Florida, USA
^# Deutsches Herzzentrum Berlin, Berlin, Germany
^** Veterans Administration Medical Center, Washington, DC, USA
Pavillon Hopital Notre-Dame, Montreal, Canada
Medizinische Fakultat der RWTH, Aachen, Germany
Hôpital Pitiê-Salpetrire, Paris, France
^|||| Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey, USA

Manuscript received May 17, 2001; revised manuscript received March 4, 2002, accepted March 15, 2002.

^* Reprint requests and correspondence: Professor Hamid Ikram, Department of Cardiology, Christchurch Hospital, Private Bag 4710, Christchurch, New Zealand.
Hamid.Ikram{at}cdhb.govt.nz

OBJECTIVES: We investigated the acute and long-term hemodynamic and neurohumoral effects of the vasopeptidase inhibitor omapatrilat in human heart failure.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibition constitutes a major advance in the treatment of chronic heart failure (CHF). Simultaneous inhibition of both neutral endopeptidase and ACE with omapatrilat may represent a new treatment strategy in CHF.

METHODS: Three hundred and sixty-nine patients with symptomatic heart failure were randomized to double-blind treatment with omapatrilat (first 190 patients: 2.5 mg, 5 mg or 10 mg; last 179 patients: 2.5 mg, 20 mg or 40 mg once daily) for 12 weeks.

RESULTS: Acutely, the 10 mg, 20 mg and 40 mg doses of omapatrilat produced greater reductions in pulmonary capillary wedge pressure (PCWP), systolic blood pressure (SBP) and systemic vascular resistance compared with 2.5 mg. Higher doses were associated with greater increases in vasodilator and natriuretic peptides, in addition to ACE inhibition. After 12 weeks, omapatrilat 20 mg and 40 mg showed greater falls from baseline in PCWP (40 mg: 0 h to 12 h average change –7.3 ± 0.8 mm Hg) and SBP (40 mg: –11.7 ± 1.7 mm Hg) than 2.5 mg (both p < 0.01 vs. 2.5 mg). The incidence of adverse experiences and patient withdrawal were similar in all groups.

CONCLUSIONS: In CHF, the acute hemodynamic benefit seen with higher doses of omapatrilat was associated with increases in plasma vasodilator and natriuretic peptide levels in addition to ACE inhibition. After 12 weeks, the hemodynamic benefit was maintained. Omapatrilat may be a promising new agent in CHF.

Abbreviations and Acronyms   ACE   angiotensin-converting enzyme   ADM   adrenomedullin   ANP   atrial natriuretic peptide   BNP   brain natriuretic peptide   cGMP   cyclic 3",5"-guanosine monophosphate   CHF   chronic heart failure   CI   cardiac index   ET-1   endothelin-1   NEP   neutral endopeptidase   PCWP   pulmonary capillary wedge pressure   SBP   systolic blood pressure   SVR   systemic vascular resistance

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