This Article  • Full text  • PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on ISI (70)  • Contact me when this article is cited  Related Content  • Related article  • Similar articles in JAMA  Topic Collections  • Cardiovascular System  • Randomized Controlled Trial  • Cardiovascular Disease/ Myocardial Infarction  • Alert me on articles by topic  Social Bookmarking   What's this?

A Randomized Trial

Hakon Hakonarson, MD, PhD; Sverrir Thorvaldsson, MSc; Anna Helgadottir, MD; Daniel Gudbjartsson, PhD; Florian Zink, PhD; Margret Andresdottir, MSc; Andrei Manolescu, PhD; David O. Arnar, MD, PhD; Karl Andersen, MD, PhD; Axel Sigurdsson, MD; Gestur Thorgeirsson, MD, MSc; Asgeir Jonsson, MD; Uggi Agnarsson, MD; Halldora Bjornsdottir, MD; Gizur Gottskalksson, MD; Atli Einarsson, MD; Hrefna Gudmundsdottir, MD, PhD; Asdis E. Adalsteinsdottir, MSc; Kolbeinn Gudmundsson, MD; Kristleifur Kristjansson, MD; Thordur Hardarson, MD, PhD; Arni Kristinsson, MD, PhD; Eric J. Topol, MD; Jeffrey Gulcher, MD, PhD; Augustine Kong, PhD; Mark Gurney, PhD; Gudmundur Thorgeirsson, MD, PhD; Kari Stefansson, MD, PhD

JAMA. 2005;293:2245-2256.

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.

Author Affiliations: Decode Genetics Inc, Reykjavik, Iceland (Drs Hakonarson, Helgadottir, Gudbjartsson, Zink, Manolescu, Gudmundsson, Kristjansson, Gulcher, Kong, Gurney, and Stefansson, Mr Thorvaldsson, and Mss Andresdottir and Adalsteinsdottir); Landspitali University Hospital, Reykjavik, Iceland (Drs Arnar, Andersen, Sigurdsson, Gestur Thorgeirsson, Jonsson, Agnarsson, Bjornsdottir, Gottskalksson, Hardarson, Kristinsson, and Gudmundur Thorgeirsson); Icelandic Heart Association, Reykjavik (Drs Einarsson and Gudmundsdottir); and Cleveland Clinic Foundation, Cleveland, Ohio (Dr Topol).

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati     What's this?

RELATED ARTICLE

Translating the Human Genome Project Into Prevention of Myocardial Infarction and Stroke—Getting Close?
Christopher J. O’Donnell
JAMA. 2005;293(18):2277-2279.
EXTRACT | FULL TEXT  

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Levels of Prostaglandin E Metabolite and Leukotriene E4 Are Increased in the Urine of Smokers: Evidence that Celecoxib Shunts Arachidonic Acid into the 5-Lipoxygenase Pathway
Duffield-Lillico et al.
Cancer Prevention Research 2009;2:322-329.
ABSTRACT | FULL TEXT  

Mechanisms of Cyclooxygenase-2 Inhibition and Cardiovascular Side Effects--The Plot Thickens
Marnett
Cancer Prevention Research 2009;2:288-290.
FULL TEXT  

JUPITER to Earth: A statin helps people with normal LDL-C and high hs-CRP, but what does it mean?
SHISHEHBOR and HAZEN
Cleveland Clinic Journal of Medicine 2009;76:37-44.
ABSTRACT | FULL TEXT  

Leukotriene B4 enhances the activity of nuclear factor-{kappa}B pathway through BLT1 and BLT2 receptors in atherosclerosis
Sanchez-Galan et al.
Cardiovasc Res 2009;81:216-225.
ABSTRACT | FULL TEXT  

Leukotriene modifiers in the treatment of cardiovascular diseases
Riccioni et al.
J. Leukoc. Biol. 2008;84:1374-1378.
ABSTRACT | FULL TEXT  

Phosphorylation of 5-Lipoxygenase at Ser523 by Protein Kinase A Determines Whether Pioglitazone and Atorvastatin Induce Proinflammatory Leukotriene B4 or Anti-Inflammatory 15-Epi-Lipoxin A4 Production
Ye et al.
J. Immunol. 2008;181:3515-3523.
ABSTRACT | FULL TEXT  

Future Use of Genomics in Coronary Artery Disease
Damani and Topol
J Am Coll Cardiol 2007;50:1933-1940.
ABSTRACT | FULL TEXT  

Leukotrienes
Peters-Golden and Henderson
NEJM 2007;357:1841-1854.
FULL TEXT  

The Effect of Montelukast and Low-Dose Theophylline on Cardiovascular Disease Risk Factors in Asthmatics
Allayee et al.
Chest 2007;132:868-874.
ABSTRACT | FULL TEXT  

Genetic Testing in Cardiovascular Disease
Robin et al.
J Am Coll Cardiol 2007;50:727-737.
ABSTRACT | FULL TEXT  

Atherosclerosis: The Path From Genomics to Therapeutics
Miller et al.
J Am Coll Cardiol 2007;49:1589-1599.
ABSTRACT | FULL TEXT  

Reports of clinical trials should begin and end with up-to-date systematic reviews of other relevant evidence: a status report
Clarke et al.
JRSM 2007;100:187-190.
ABSTRACT | FULL TEXT  

Redefining Risk in Acute Coronary Syndromes Using Molecular Medicine
Anwaruddin et al.
J Am Coll Cardiol 2007;49:279-289.
ABSTRACT | FULL TEXT  

Arachidonic Acid Metabolism as a Potential Mediator of Cardiac Fibrosis Associated with Inflammation
Levick et al.
J. Immunol. 2007;178:641-646.
ABSTRACT | FULL TEXT  

Gamma-glutamyltransferase, leukotrienes, and cardiovascular risk
Back
Eur Heart J 2007;28:269-269.
FULL TEXT  

Pharmacogenetics of Asthma
Hall
Chest 2006;130:1873-1878.
ABSTRACT | FULL TEXT  

Pharmacogenomics: Challenges and Opportunities.
Roden et al.
ANN INTERN MED 2006;145:749-757.
ABSTRACT | FULL TEXT  

Genetic susceptibility to myocardial infarction and coronary artery disease
Topol et al.
Hum Mol Genet 2006;15:R117-R123.
ABSTRACT | FULL TEXT  

The genetics of heart attack.
Topol
Heart 2006;92:855-861.
FULL TEXT  

Complex Inheritance of the 5-Lipoxygenase Locus Influencing Atherosclerosis in Mice
Ghazalpour et al.
Genetics 2006;173:943-951.
ABSTRACT | FULL TEXT  

The Genomic Basis of Myocardial Infarction
Topol
J Am Coll Cardiol 2005;46:1456-1465.
FULL TEXT  

Can Gene Modulation Reduce Biomarkers of MI Risk?
Journal Watch Cardiology 2005;2005:2-2.
FULL TEXT  

Translating the Human Genome Project Into Prevention of Myocardial Infarction and Stroke--Getting Close?
O'Donnell
JAMA 2005;293:2277-2279.
FULL TEXT