Treatment with 5-lipoxygenase inhibitor VIA-2291 (Atreleuton) in patients with recent acute coronary syndrome.
BACKGROUND
Production of leukotrienes by 5-lipoxygenase (5-LO) has been linked to unstable atherosclerotic plaques and cardiovascular events. VIA-2291 is a potent 5-LO inhibitor.


RESULTS
In a double-blinded study, 191 patients were randomly assigned 3 weeks after an acute coronary syndrome to receive 25, 50, or 100 mg VIA-2291 or placebo daily for 12 weeks. The primary study end point, whole blood stimulated leukotriene LTB4 at trough drug level, was reduced in all VIA-2291 groups (P<0.0001) in a dose-dependent fashion, with approximately 80% inhibition in >90% of patients in the 100-mg group. A significant reduction of urine leukotriene LTE4 was obtained in all dose groups. No serious adverse events were considered related to study drug. A subset of 93 patients who had undergone a 64-slice coronary CT examination at baseline continued on study medication for a total of 24 weeks and underwent a repeat scan. Five of these patients withdrew or were noncompliant and 28 had nonevaluable scans. Among the 60 remaining patients, new coronary plaques were observed in 5 of 18 (27.8%) placebo-treated patients and in 2 of 42 (4.8%) VIA-2291-treated patients (P=0.01). A reduction in noncalcified plaque volume at 24 weeks versus placebo was observed in VIA-2291-treated groups in the 34 of these 60 patients in whom this end point was analyzable (P<0.01).


CONCLUSIONS
VIA-2291 reduces leukotriene production at 12 weeks after an acute coronary syndrome. Preliminary data from the CT substudy suggest that such a reduction in leukotriene production may influence atherosclerosis; however, this requires confirmation in a larger study. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00358826.
Tardif
Jean-Claude
JC
Department of Medicine, Radiology, Montreal Heart Institute and Université de Montréal, Montreal, Canada.
L'allier
Philippe L
PL
Ibrahim
Reda
R
Grégoire
Jean C
JC
Nozza
Anna
A
Cossette
Mariève
M
Kouz
Simon
S
Lavoie
Marc-André
MA
Paquin
Janie
J
Brotz
Tilmann M
TM
Taub
Rebecca
R
Pressacco
Josephine
J
D054058:Acute Coronary Syndrome / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D001094:Arachidonate 5-Lipoxygenase / Q000187:drug effects / Q000378:metabolism; D015415:Biomarkers / Q000097:blood / Q000652:urine; D002097:C-Reactive Protein / Q000187:drug effects; D003287:Contrast Media; D017023:Coronary Angiography / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000627:therapeutic use; D007975:Leukotriene B4 / Q000097:blood; D017999:Leukotriene E4 / Q000652:urine; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D015588:Observer Variation; D011446:Prospective Studies; D011856:Radiographic Image Enhancement / Q000379:methods; D014057:Tomography, X-Ray Computed / Q000379:methods; D016896:Treatment Outcome; D014283:Triiodobenzoic Acids
D015415:Biomarkers; D003287:Contrast Media; D016859:Lipoxygenase Inhibitors; D014283:Triiodobenzoic Acids; D007975:Leukotriene B4; D017999:Leukotriene E4; D002097:C-Reactive Protein; D001094:Arachidonate 5-Lipoxygenase; C044834:iodixanol; C096921:atreleuton; D006918:Hydroxyurea