TY - JOUR
T1 - Effects of a 5-lipoxygnease-activating protein inhibitor on biomarkers associated with risk of myocardial infarction
T2 - A randomized trial
AU - Hakonarson, H
AU - Thorvaldsson, S
AU - Helgadottir, A.
AU - Gudbjartsson, Daniel
AU - Zink, Florian
AU - Andresdottir, Margret
AU - Arnar, Davíð Ottó
AU - Andersen, K
AU - Sigurdsson, A
AU - Thorgeirsson, Guðmundur
AU - Jonsson, A
AU - Agnarsson, U
AU - Bjornsdottir, H
AU - Gottskalksson, Gizur
AU - Einarsson, A.
AU - Gudmundsdottir, H
AU - Gudmundsson, K
AU - Adalsteinsdottir, Asdis E.
AU - Kristjansson, K.
AU - Hardarson, T
AU - Kristinsson, A
AU - Topol, Eric J.
AU - Gulcher, J
AU - Kong, A
AU - Gurney, Mark
AU - Thorgeirsson, G
AU - Stefansson, K.
AU - Manolescu, Andrei
PY - 2005/5/11
Y1 - 2005/5/11
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/18244403498
U2 - 10.1001/jama.293.18.2245
DO - 10.1001/jama.293.18.2245
M3 - Article
C2 - 15886380
SN - 1538-3598
VL - 293
SP - 2245
EP - 2256
JO - JAMA
JF - JAMA
IS - 18
ER -