Darapladib for Preventing Ischemic Events in Stable Coronary Heart Disease

Abstract

BackgroundElevated lipoprotein-associated phospholipase A 2 activity promotes the development of vulnerable atherosclerotic plaques, and elevated plasma levels of this enzyme are associated with an increased risk of coronary events. Darapladib is a selective oral inhibitor of lipoprotein-associated phospholipase A 2 . MethodsIn a double-blind trial, we randomly assigned 15,828 patients with stable coronary heart disease to receive either once-daily darapladib (at a dose of 160 mg) or placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the components of the primary end point as well as major coronary events (death from coronary heart disease, myocardial infarction, or urgent coronary revascularization for myocardial ischemia) and total coronary events (death from coronary heart disease, myocardial infarction, hospitalization for unstable angina, or any coronary revascularization). ResultsDuring a median follow-up period of 3.7 years, the primary end point occurred in 769 of 7924 patients (9.7%) in the darapladib group and 819 of 7904 patients (10.4%) in the placebo group (hazard ratio in the darapladib group, 0.94; 95% confidence interval [CI], 0.85 to 1.03; P = 0.20). There were also no significant between-group differences in the rates of the individual components of the primary end point or in all-cause mortality. Darapladib, as compared with placebo, reduced the rate of major coronary events (9.3% vs. 10.3%; hazard ratio, 0.90; 95% CI, 0.82 to 1.00; P = 0.045) and total coronary events (14.6% vs. 16.1%; hazard ratio, 0.91; 95% CI, 0.84 to 0.98; P = 0.02). ConclusionsIn patients with stable coronary heart disease, darapladib did not significantly reduce the risk of the primary composite end point of cardiovascular death, myocardial infarction, or stroke. (Funded by GlaxoSmithKline; STABILITY ClinicalTrials.gov number, NCT00799903.)The Darapladib is a potent and reversible oral inhibitor of lipoprotein-associated phospholipase A 2 . 10 In a swine model of atherosclerosis, darapladib reduced levels of lipoprotein-associated phospholipase A 2 in plaque, reduced the necrotic core area, and inhibited the development of lesions in coronary arteries. 11 Darapladib has also been shown to reduce lipoprotein-associated phospholipase A 2 activity in human carotid plaque. 12 In the Integrated Biomarker and Imaging Study 2 (IBIS-2) involving patients with coronary heart disease, darapladib, as compared with placebo, halted the progression in the volume of the necrotic core of coronary-artery plaques (a secondary end point), as determined by intravascular ultrasonographic virtual histologic analysis during a 12-month period. 13 These findings suggest that darapladib could reduce the risk of events associated with coronary heart disease by altering the composition of atherosclerotic plaques to a less vulnerable state. 1 In the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) trial, we evaluated the clini...

Lipoprotein‐Associated Phospholipase A 2 Activity Is a Marker of Risk But Not a Useful Target for Treatment in Patients With Stable Coronary Heart Disease

“…The STABILITY trial was a prospective double‐blind randomized trial evaluating the efficacy and safety of darapladib 160 mg, a specific inhibitor of Lp‐PLA 2 , compared with placebo concerning cardiovascular outcomes in patients with stable CHD 19. In brief, the study randomized 15 828 patients from 39 countries with stable CHD, defined as prior MI, prior coronary revascularization, or multivessel CHD confirmed by coronary angiography.…”

“…Experiments in hypercholesterolemic diabetic swine17 and in an angiographic and intravascular ultrasound study in patients18 showed that darapladib prevented progression of the necrotic core, assumed to be the vulnerable component of atherosclerotic lesions. In the present STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial (ClinicalTrials.gov identifier NCT00799903), darapladib 160 mg daily did not significantly reduce the primary composite end point of cardiovascular death, myocardial infarction (MI), or stroke in patients with stable CHD (hazard ratio [HR] 0.94, 95% CI 0.85–1.03, P =0.20) but nominally reduced the rate of the secondary end point, major coronary events (coronary death, MI, or urgent coronary revascularization; HR 0.90, 95% CI 0.82–1.00, P =0.045) 19. The present predefined ancillary study evaluated the independent prognostic value of baseline Lp‐PLA 2 activity concerning cardiovascular events, the reduction of Lp‐PLA 2 activity by darapladib, and the associations between baseline and changes in Lp‐PLA 2 activity and clinical outcomes.…”

Sex Differences in Clinical Characteristics, Psychosocial Factors, and Outcomes Among Patients With Stable Coronary Heart Disease: Insights from the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) Trial

“…The design and main findings of the STABILITY trial were published previously 14. Briefly, STABILITY was a randomized, double‐blind, controlled trial that enrolled patients with a history of CHD, including previous myocardial infarction (MI), previous percutaneous coronary intervention or coronary artery bypass grafting, or multivessel coronary disease confirmed by angiography, and on statin therapy unless contraindicated or not tolerated.…”

“…The STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial compared darapladib, an oral inhibitor of lipoprotein‐associated phospholipase A 2 , with placebo in patients with high‐risk stable CHD 14. This secondary analysis was planned to describe baseline characteristics, psychosocial factors, and treatments for CHD of men and women enrolled in this contemporary trial.…”

Lowering Inflammation Level by Lp-PLA2 Inhibitor (Darapladib) in Early Atherosclerosis Development: in vivo Rat Type 2 Diabetes Mellitus Model

“…7,8,9,10 However, there are several opinions about darapladib usefulness. 11 So, this study aims to determine epression of inflammation marker of T2DM in vivo model with darapladib treatment.…”