Treatment with 5-lipoxygenase inhibitor VIA-2291 (Atreleuton) in patients with recent acute coronary syndrome.

Abstract

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.

METHODS AND 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.

• Authors: Jean-Claude Tardif, Philippe L L'allier, Reda Ibrahim, Jean C Grégoire, Anna Nozza, Mariève Cossette, Simon Kouz, Marc-André Lavoie, Janie Paquin, Tilmann M Brotz, Rebecca Taub, Josephine Pressacco
• Journal: Circulation. Cardiovascular imaging (Circ Cardiovasc Imaging) Vol. 3 Issue 3 Pg. 298-307 (May 2010) ISSN: 1942-0080 [Electronic] United States
• PMID: 20190281 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Contrast Media
• Lipoxygenase Inhibitors
• Triiodobenzoic Acids
• Leukotriene B4
• Leukotriene E4
• C-Reactive Protein
• Arachidonate 5-Lipoxygenase
• iodixanol
• atreleuton
• Hydroxyurea

Topics

• Acute Coronary Syndrome (diagnostic imaging, drug therapy, metabolism)
• Adult
• Aged
• Aged, 80 and over
• Analysis of Variance
• Arachidonate 5-Lipoxygenase (drug effects, metabolism)
• Biomarkers (blood, urine)
• C-Reactive Protein (drug effects)
• Contrast Media
• Coronary Angiography (methods)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Female
• Humans
• Hydroxyurea (analogs & derivatives, therapeutic use)
• Leukotriene B4 (blood)
• Leukotriene E4 (urine)
• Lipoxygenase Inhibitors (therapeutic use)
• Male
• Middle Aged
• Observer Variation
• Prospective Studies
• Radiographic Image Enhancement (methods)
• Tomography, X-Ray Computed (methods)
• Treatment Outcome
• Triiodobenzoic Acids