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J Am Coll Cardiol, 2008; 51:1632-1641, doi:10.1016/j.jacc.2007.11.079
© 2008 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: CLINICAL TRIAL

The Effect of Darapladib on Plasma Lipoprotein-Associated Phospholipase A2 Activity and Cardiovascular Biomarkers in Patients With Stable Coronary Heart Disease or Coronary Heart Disease Risk Equivalent

The Results of a Multicenter, Randomized, Double-Blind, Placebo-Controlled Study

Emile R. Mohler, III, MD, FACC*,*, Christie M. Ballantyne, MD, FACC{dagger}, Michael H. Davidson, MD, FACC{ddagger}, Markolf Hanefeld, MD, PhD§, Luis M. Ruilope, MD, PhD||, Joel L. Johnson, PharmD, Andrew Zalewski, MD,# for the Darapladib Investigators

* University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
{dagger} Baylor College of Medicine and Methodist DeBakey Heart Center, Houston, Texas
{ddagger} Radiant Research, Rush University Medical Center, Chicago, Illinois
§ Center for Clinical Studies, Dresden, Germany
|| Hospital 12 de Octubre, Madrid, Spain
GlaxoSmithKline, Philadelphia, Pennsylvania, and Research Triangle Park, North Carolina
# Thomas Jefferson University, Philadelphia, Pennsylvania.

Manuscript received September 26, 2007; revised manuscript received November 7, 2007, accepted November 21, 2007.

* Reprint requests and correspondence: Dr. Emile R. Mohler, III, Hospital of the University of Pennsylvania, 4th Floor Penn Tower Building, 3400 Spruce Street, Philadelphia, Pennsylvania 19104. (Email: mohlere{at}uphs.upenn.edu).

Objectives: This study examined the effects of darapladib, a selective lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor, on biomarkers of cardiovascular (CV) risk.

Background: Elevated Lp-PLA2 levels are associated with an increased risk of CV events.

Methods: Coronary heart disease (CHD) and CHD-risk equivalent patients (n = 959) receiving atorvastatin (20 or 80 mg) were randomized to oral darapladib 40 mg, 80 mg, 160 mg, or placebo once daily for 12 weeks. Blood samples were analyzed for Lp-PLA2 activity and other biomarkers.

Results: Baseline low-density lipoprotein cholesterol (LDL-C) was 67 ± 22 mg/dl. Plasma Lp-PLA2 was higher in older patients (≥75 years), in men, in those taking atorvastatin 20 mg, at LDL-C ≥70 mg/dl or high-density lipoprotein cholesterol (HDL-C) <40 mg/dl, or in those with documented vascular disease (multivariate regression; p < 0.01). Darapladib 40, 80, and 160 mg inhibited Lp-PLA2 activity by approximately 43%, 55%, and 66% compared with placebo (p < 0.001 weeks 4 and 12). Sustained dose-dependent inhibition was noted overall in both atorvastatin groups and at different baseline LDL-C (≥70 vs. <70 mg/dl) and HDL-C (<40 vs. ≥40 mg/dl). At 12 weeks, darapladib 160 mg decreased interleukin (IL)-6 by 12.3% (95% confidence interval [CI] –22% to –1%; p = 0.028) and high-sensitivity C-reactive protein (hs-CRP) by 13.0% (95% CI –28% to +5%; p = 0.15) compared with placebo. The Lp-PLA2 inhibition produced no detrimental effects on platelet biomarkers (P-selectin, CD40 ligand, urinary 11-dehydrothromboxane B2). No major safety concerns were noted.

Conclusions: Darapladib produced sustained inhibition of plasma Lp-PLA2 activity in patients receiving intensive atorvastatin therapy. Changes in IL-6 and hs-CRP after 12 weeks of darapladib 160 mg suggest a possible reduction in inflammatory burden. Further studies will determine whether Lp-PLA2 inhibition is associated with favorable effects on CV events. (SB-480848 in Subjects With Coronary Heart Disease; NCT00269048 [ClinicalTrials.gov] )

Abbreviations and Acronyms
  CHD = coronary heart disease
  CI = confidence interval
  CV = cardiovascular
  HDL-C = high-density lipoprotein cholesterol
  hs-CRP = high-sensitivity C-reactive protein
  IL = interleukin
  LDL-C = low-density lipoprotein cholesterol
  Lp-PLA2 = lipoprotein-associated phospholipase A2
  PAF-AH = platelet-activating factor-acetylhydrolase


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