View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Journal of the American College of Cardiology Vol. 39, No. 12, 2002 © 2002 by the American College of Cardiology Foundation ISSN 0735-1097/02/$22.00 Published by Elsevier Science Inc. PII S0735-1097(02)01881-8 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,࿣࿣ for the Omapatrilat Hemodynamic Study Group Christchurch, New Zealand; San Bernadino and Loma Linda, California; Brussels, Belgium; Fort Lauderdale and Miami, Florida; Berlin and Aachen, Germany; Washington, DC; Montreal, Canada; Paris, France; and Princeton, New Jersey 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 endopep- tidase 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:0hto12haverage change Ϫ7.3 Ϯ 0.8 mm Hg) and SBP (40 mg: Ϫ11.7 Ϯ 1.7 mm Hg) than 2.5 mg (both p Ͻ 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. (J Am Coll Cardiol 2002;39:2034–41) © 2002 by the American College of Cardiology Foundation Angiotensin-converting enzyme (ACE) inhibition consti- in CHF (4,5). However, their therapeutic usefulness is tutes a major advance in the treatment of chronic heart limited by a short half-life, due to rapid degradation by failure (CHF), with symptomatic improvement and some neutral endopeptidase (NEP) (6). Other NEP substrates survival gains (1). However, despite the first line use of include bradykinin (7) and adrenomedullin (ADM) (8). ACE inhibitors and, more recently, beta-adrenergic block- Omapatrilat is the first of a new class of drugs known as ing agents, the prognosis of CHF remains poor (1,2). vasopeptidase inhibitors, which simultaneously inhibit both The natriuretic peptides are counter-regulatory to the NEP and ACE, resulting in increased levels of natriuretic renin-angiotensin system, causing vasodilation, diuresis and peptides and bradykinin, with a reduction in angiotensin II natriuresis (3–5). Augmentation of their levels with exog- (9,10). In patients with heart failure, omapatrilat therapy for enously administered atrial natriuretic peptide (ANP) and 24 weeks showed a similar increase in week 12 exercise brain natriuretic peptide (BNP) has resulted in a reduction tolerance but conferred more benefit than lisinopril in the in filling pressures, natriuresis and diuresis in acute studies composite of death, hospital admission or discontinuation of study treatment for worsening heart failure (11). From the *Christchurch Hospital, Christchurch, New Zealand; †San Bernadino, The purpose of this multicenter study was to evaluate the California; ‡Jerry L. Pettis Veterans Administration Medical Center, Loma Linda, hemodynamic and neurohumoral effects, safety and tolera- California; §Cliniques Universitaires Saint-Luc, Brussels, Belgium; ࿣Greater Fort bility of increasing doses of omapatrilat after a single oral Lauderdale Heart Group Research, Fort Lauderdale, Florida; ¶University of Miami/ Jackson Memorial Medical Center, Miami, Florida; #Deutsches Herzzentrum Berlin, dose and after 12 weeks of once-daily oral therapy in Berlin, Germany; **Veterans Administration Medical Center, Washington, DC; patients with symptomatic heart failure. ††Pavillon Hopital Notre-Dame, Montreal, Canada; ‡‡Medizinische Fakultat der RWTH, Aachen, Germany; §§Hoˆpital Pitieˆ-Salpetri⌸re, Paris, France; and ࿣࿣Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey. Supported by a project grant from Bristol-Myers Squibb Pharmaceutical Research METHODS Institute, Princeton, New Jersey. Manuscript received May 17, 2001; revised manuscript received March 4, 2002, Study design. Patients with stable symptomatic heart fail- accepted March 15, 2002. ure (New York Heart Association functional class II to IV), JACC Vol. 39, No. 12, 2002 McClean et al. 2035 June 19, 2002:2034–41 Hemodynamic Effects of Omapatrilat in Heart Failure Subjects were continued for 12 weeks on double-blind Abbreviations and Acronyms study drug. All other medications (except ACE inhibitors or ACE ϭ angiotensin-converting enzyme angiotensin II receptor antagonists) were restarted and ADM ϭ adrenomedullin continued throughout the 12 weeks. Outpatient evaluations ϭ ANP atrial natriuretic peptide were performed at weeks 1, 2, 4, 6 and 8. Up to four BNP ϭ brain natriuretic peptide cGMP ϭ cyclic 3Ј,5Ј-guanosine monophosphate supplemental doses of diuretics were permitted for worsen- CHF ϭ chronic heart failure ing heart failure, with no supplemental doses permitted CI ϭ cardiac index within 72 h before hemodynamic measurements. Patients ET-1 ϭ endothelin-1 were withdrawn from the study if an increase in the daily ϭ NEP neutral endopeptidase maintenance dose of diuretic or other heart failure medica- PCWP ϭ pulmonary capillary wedge pressure ϭ tion was required. The diuretic dose could be decreased to SBP systolic blood pressure Ͼ ␮ SVR ϭ systemic vascular resistance correct serum creatinine 3.0 mg/dl (265 mol/l) or to correct symptomatic hypotension. After 12 weeks, patients underwent a second right heart left ventricular ejection fraction Յ40% and in sinus rhythm catheterization. On the morning of the next day, the study were eligible for enrollment in this multicenter double- medication was administered after two consecutive predose blind, randomized study. The protocol was approved by recordings showed Յ10% variability in PCWP and CI; local ethical committees, and all patients gave written, repeat measurements were performed over a similar 24-h informed consent. period as on day 1. All other medications were withheld Studies in normal human volunteers have shown evidence during the 24-h period. of significant ACE inhibition with 2.5 mg to 75 mg doses Methodology. Hemodynamic assessment was performed of omapatrilat (12,13), while dose-related NEP inhibition, the day after placement of a balloon-tipped thermodilution as measured by changes in urinary ANP and urinary cyclic catheter in the pulmonary artery. Pulmonary arterial pres- 3Ј,5Ј-guanosine monophosphate (cGMP), was shown from sures and electrocardiogram were measured continuously, the 7.5-mg to the 75-mg dose (12). In contrast, the 2.5-mg cardiac output was measured by the thermodilution tech- omapatrilat dose, although showing selective ACE inhibi- nique, and arterial blood pressures by brachial sphygmoma- tion, did not change urinary ANP and cGMP. Since ethical nometry. All measurements were performed in triplicate in considerations excluded a placebo control, the 2.5-mg dose the semisupine position. Cardiac index and systemic vascu- was used as an active control. lar resistance (SVR) were calculated using standard formulas The study was conducted in two sequential, separate (14). Physician and subject assessments of the change in panels. In panel I, patients were randomized to omapatrilat functional status were performed at three months or on 2.5 mg, 5 mg or 10 mg once daily. In panel II, patients were withdrawal from study using a global assessment scale: randomized to omapatrilat 2.5 mg, 20 mg or 40 mg once improved (greatly, moderately or slightly), unchanged or daily. An analysis of safety data from the completed panel I worsened. Subjects participating in the neurohormonal was performed before panel II started. Patients who were in substudy had venous blood drawn during both hemody- panel I were not eligible for panel II. namic monitoring periods (day 1 and week 12), predose and After enrollment, there was a 2- to 14-day single-blind at 3 h, 12 h and 24 h after dose. placebo lead-in period, where patients were stabilized on Measurement of plasma ANP, BNP, cGMP, ADM, diuretics and concomitant cardiac medications, with doses aldosterone, endothelin-1 (ET-1), renin and ACE activity remaining stable for Ն2 days before right heart catheteriza- was performed by radioimmunoassay,