The clinical, cardiac, renal, arterial and neurohormonal effects of omapatrilat, a vasopeptidase inhibitor, in patients with chronic heart failure.
OBJECTIVE
We sought to examine the effects of long-term vasopeptidase inhibition in patients with heart failure.


BACKGROUND
The long-term effects of omapatrilat, an agent that inhibits both neutral endopeptidase and angiotensin-converting enzyme, on clinical status, neurohormonal indexes and left ventricular function in patients with chronic heart failure (CHF) have not been previously documented.


METHODS
Forty-eight patients in New York Heart Association functional class II or III, with left ventricular ejection fraction (LVEF)< or =40% and in sinus rhythm were randomized to a dose-ranging pilot study of omapatrilat for 12 weeks. Measurements were performed at baseline and 12 weeks.


RESULTS
There was an improvement in functional status, as reported by the patient (p<0.001) and physician (p<0.001) at 12 weeks. Dose-dependent improvements in LVEF (p<0.001) and LV end-systolic wall stress (sigma) (p<0.05) were seen, together with a reduction in systolic blood pressure (p<0.05). There was evidence of a natriuretic effect (p<0.001), and total blood volume decreased (p<0.05). Omapatrilat induced an increase in postdose plasma atrial natriuretic peptide levels (p<0.01) in the high dose groups, with a reduction in predose plasma brain natriuretic peptide (p<0.001) and epinephrine (p<0.01) levels after 12 weeks of therapy. Omapatrilat was well tolerated.


CONCLUSIONS
The sustained hemodynamic, neurohumoral and renal effects of omapatrilat, together with improved functional status, suggest that vasopeptidase inhibition has potential as a new therapeutic modality for the treatment of CHF.
Department of Cardiology, Christchurch Hospital, Christchurch, New Zealand.
D R
DR
McClean
H
H
Ikram
A H
AH
Garlick
A M
AM
Richards
M G
MG
Nicholls
I G
IG
Crozier
D000368:Aged; D000369:Aged, 80 and over; D009320:Atrial Natriuretic Factor / Q000097:blood; D001810:Blood Volume / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004837:Epinephrine / Q000097:blood; D005260:Female; D006333:Heart Failure / Q000188:drug therapy*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects*; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D013841:Thiazepines / Q000494:pharmacology* / Q000627:therapeutic use; D016277:Ventricular Function, Left / Q000187:drug effects*
D011725:Pyridines; D013841:Thiazepines; D020097:Natriuretic Peptide, Brain; C106266:omapatrilat; D009320:Atrial Natriuretic Factor; D008666:Metalloendopeptidases; D004837:Epinephrine