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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, Michael H. Davidson, MD, FACC, 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
Baylor College of Medicine and Methodist DeBakey Heart Center, Houston, Texas
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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