Vasopeptidase inhibition with omapatrilat in chronic heart failure: acute and long-term hemodynamic and neurohumoral effects.
OBJECTIVE
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.
McClean
Dougal R
DR
Christchurch Hospital, Christchurch, New Zealand.
Ikram
Hamid
H
Mehta
Sukh
S
Heywood
J Thomas
JT
Rousseau
Michel F
MF
Niederman
Alan L
AL
Sequeira
Rafael F
RF
Fleck
Eckart
E
Singh
Steven N
SN
Coutu
Benoit
B
Hanrath
Peter
P
Komajda
Michel
M
Bryson
Catherine C
CC
Qian
Chunlin
C
Hanyok
James J
JJ
D000368:Aged; D009320:Atrial Natriuretic Factor / Q000097:blood; D004311:Double-Blind Method; D006333:Heart Failure / Q000188:drug therapy*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood; D018377:Neurotransmitter Agents / Q000097:blood; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage / Q000627:therapeutic use*; D013841:Thiazepines / Q000008:administration & dosage / Q000627:therapeutic use*; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects
D018377:Neurotransmitter Agents; D011480:Protease Inhibitors; D011725:Pyridines; D013841:Thiazepines; D020097:Natriuretic Peptide, Brain; C106266:omapatrilat; D009320:Atrial Natriuretic Factor