Effects of a 5-Lipoxygenase–Activating Protein Inhibitor on Biomarkers Associated With Risk of Myocardial Infarction: A Randomized Trial

• Published in: JAMA : the journal of the American Medical Association 2005-05, Vol.293 (18), p.2245-2256
• Main Authors: Hakonarson, Hakon, Thorvaldsson, Sverrir, Helgadottir, Anna, Gudbjartsson, Daniel, Zink, Florian, Andresdottir, Margret, Manolescu, Andrei, Arnar, David O, Andersen, Karl, Sigurdsson, Axel, Thorgeirsson, Gestur, Jonsson, Asgeir, Agnarsson, Uggi, Bjornsdottir, Halldora, Gottskalksson, Gizur, Einarsson, Atli, Gudmundsdottir, Hrefna, Adalsteinsdottir, Asdis E, Gudmundsson, Kolbeinn, Kristjansson, Kristleifur, Hardarson, Thordur, Kristinsson, Arni, Topol, Eric J, Gulcher, Jeffrey, Kong, Augustine, Gurney, Mark, Thorgeirsson, Gudmundur, Stefansson, Kari
• Format: Article
• Language: English
• Subjects: 5-Lipoxygenase-Activating Proteins; Aged; Biological and medical sciences; Biomarkers - metabolism; Cardiology. Vascular system; Carrier Proteins - antagonists & inhibitors; Carrier Proteins - genetics; Coronary Artery Disease - drug therapy; Coronary Artery Disease - genetics; Coronary Artery Disease - metabolism; Coronary heart disease; Cross-Over Studies; Epoxide Hydrolases - genetics; Female; General aspects; Heart; Heart attacks; Humans; Inhibitor drugs; Leukotriene B4 - metabolism; Leukotriene E4 - metabolism; Lipoxygenase Inhibitors - therapeutic use; Male; Medical sciences; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - genetics; Middle Aged; Myocardial Infarction - genetics; Myocardial Infarction - metabolism; Myocardial Infarction - prevention & control; Myocarditis. Cardiomyopathies; Peroxidase - metabolism; Polymorphism, Single Nucleotide; Prospective Studies; Proteins; Quinolines - therapeutic use; Risk Factors
• ISSN: 0098-7484; 1538-3598
• DOI: 10.1001/jama.293.18.2245

CONTEXT Myocardial infarction (MI) is the leading cause of death in the world. Variants in the 5-lipoxygenase–activating protein (FLAP) gene are associated with risk of MI. OBJECTIVE To determine the effect of an inhibitor of FLAP on levels of biomarkers associated with MI risk. DESIGN, SETTING, AND PATIENTS A randomized, prospective, placebo-controlled, crossover trial of an inhibitor of FLAP (DG-031) in MI patients who carry at-risk variants in the FLAP gene or in the leukotriene A4 hydrolase gene. Of 268 patients screened, 191 were carriers of at-risk variants in FLAP (87%) or leukotriene A4 hydrolase (13%). Individuals were enrolled in April 2004 and were followed up by designated cardiologists from a university hospital in Iceland until September 2004. INTERVENTIONS Patients were first randomized to receive 250 mg/d of DG-031, 500 mg/d of DG-031, 750 mg/d of DG-031, or placebo. After a 2-week washout period, patients received DG-031 if they had received placebo first or placebo if they had received DG-031 first. Treatment periods lasted for 4 weeks. MAIN OUTCOME MEASURES Changes in levels of biomarkers associated with risk of MI. RESULTS In response to 750 mg/d of DG-031, production of leukotriene B4 was significantly reduced by 26% (95% confidence interval [CI], 10%-39%; P = .003) and myeloperoxidase was significantly reduced by 12% (95% CI, 2%-21%; P = .02). The higher 2 doses of DG-031 produced a nonsignificant reduction in C-reactive protein (16%; 95% CI, −2% to 31%; P = .07) at 2 weeks. However, there was a more pronounced reduction (25%; 95% CI, 5%-40%; P = .02) in C-reactive protein at the end of the washout period that persisted for another 4 weeks thereafter. The FLAP inhibitor DG-031 was well tolerated and was not associated with any serious adverse events. CONCLUSION In patients with specific at-risk variants of 2 genes in the leukotriene pathway, DG-031 led to significant and dose-dependent suppression of biomarkers that are associated with increased risk of MI events.