Effects of a 5-lipoxygenase-activating protein inhibitor on biomarkers associated with risk of myocardial infarction: a randomized trial

• Published in: JAMA
• 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
• Other Authors: Decode Genetics Inc, Reykjavik, Iceland. [e-mail]
• Format: Article in Journal/Newspaper
• Language: English
• Published: American Medical Association 2009
• Subjects: Aged; Biological Markers; Carrier Proteins; Coronary Artery Disease; Cross-Over Studies; Epoxide Hydrolases; Female; Humans; Leukotriene B4; Leukotriene E4; Lipoxygenase Inhibitors; Male; Membrane Proteins; Middle Aged; Myocardial Infarction; Peroxidase; Polymorphism; Single Nucleotide; Prospective Studies; Quinolines; Risk Factors; Iceland
• Online Access: http://hdl.handle.net/2336/53793; https://doi.org/10.1001/jama.293.18.2245

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field 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 ...