Effects of a 5-lipoxygenase-activating protein inhibitor on biomarkers associated with risk of myocardial infarction: a randomized trial
2005
ContextMyocardial 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.ObjectiveTo determine the effect of an inhibitor of FLAP on levels of biomarkers
associated with MI risk.Design, Setting, and PatientsA 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.InterventionsPatients 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 MeasuresChanges in levels of biomarkers associated with risk of MI.ResultsIn 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.ConclusionIn 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.
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