Document Detail

Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque.
MedLine Citation:
PMID:  18765397     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is expressed abundantly in the necrotic core of coronary lesions, and products of its enzymatic activity may contribute to inflammation and cell death, rendering plaque vulnerable to rupture. METHODS AND RESULTS: This study compared the effects of 12 months of treatment with darapladib (an oral Lp-PLA(2) inhibitor, 160 mg daily) or placebo on coronary atheroma deformability (intravascular ultrasound palpography) and plasma high-sensitivity C-reactive protein in 330 patients with angiographically documented coronary disease. Secondary end points included changes in necrotic core size (intravascular ultrasound radiofrequency), atheroma size (intravascular ultrasound gray scale), and blood biomarkers. BACKGROUND: =0.37). In contrast, Lp-PLA(2) activity was inhibited by 59% with darapladib (P<0.001 versus placebo). After 12 months, there were no significant differences between groups in plaque deformability (P=0.22) or plasma high-sensitivity C-reactive protein (P=0.35). In the placebo-treated group, however, necrotic core volume increased significantly (4.5+/-17.9 mm(3); P=0.009), whereas darapladib halted this increase (-0.5+/-13.9 mm(3); P=0.71), resulting in a significant treatment difference of -5.2 mm(3) (P=0.012). These intraplaque compositional changes occurred without a significant treatment difference in total atheroma volume (P=0.95). CONCLUSIONS: Despite adherence to a high level of standard-of-care treatment, the necrotic core continued to expand among patients receiving placebo. In contrast, Lp-PLA(2) inhibition with darapladib prevented necrotic core expansion, a key determinant of plaque vulnerability. These findings suggest that Lp-PLA(2) inhibition may represent a novel therapeutic approach.
Patrick W Serruys; Héctor M García-García; Pawel Buszman; Paul Erne; Stefan Verheye; Michael Aschermann; Henrikus Duckers; Oyvind Bleie; Dariusz Dudek; Hans Erik Bøtker; Clemens von Birgelen; Don D'Amico; Tammy Hutchinson; Andrew Zambanini; Frits Mastik; Gerrit-Anne van Es; Antonius F W van der Steen; D Geoffrey Vince; Peter Ganz; Christian W Hamm; William Wijns; Andrew Zalewski;
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Publication Detail:
Type:  Journal Article; Multicenter Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't     Date:  2008-09-01
Journal Detail:
Title:  Circulation     Volume:  118     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2008 Sep 
Date Detail:
Created Date:  2008-09-09     Completed Date:  2008-10-17     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1172-82     Citation Subset:  AIM; IM    
Thoraxcenter, Ba583, Erasmus MC, Rotterdam, Netherlands.
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MeSH Terms
1-Alkyl-2-acetylglycerophosphocholine Esterase / antagonists & inhibitors*
Anti-Inflammatory Agents / therapeutic use*
Benzaldehydes / administration & dosage*,  therapeutic use
Cardiovascular Agents
Coronary Disease / drug therapy*,  pathology,  prevention & control
Double-Blind Method
Enzyme Inhibitors / therapeutic use
Middle Aged
Necrosis / drug therapy,  prevention & control
Oximes / administration & dosage*,  therapeutic use
Treatment Outcome
Reg. No./Substance:
0/Anti-Inflammatory Agents; 0/Benzaldehydes; 0/Cardiovascular Agents; 0/Enzyme Inhibitors; 0/Oximes; 0/darapladib; EC Esterase
Patrick W Serruys / ; Gerrit-Anne van Es / ; Christian Hamm / ; William Wijns / ; Andrew Zalewski / ; Andrew Zambanini / ; Peter Ganz / ; Charles S Abrams / ; Richard Cairns / ; Barry R Davis / ; Marian Fisher / ; James Shepherd / ; Sidney Smith / ; Georg Gaul / ; Victor Legrand / ; Stefan Verheye / ; William Wijns / ; Michael Aschermann / ; Hans Erik Bøtker / ; Raimund Erbel / ; Christian Hamm / ; Stefan Hardt / ; Helmut Kücherer / ; Volker Klauss / ; Wolfgang Koenig / ; Gert Richardt / ; Clemens von Birgelen / ; Adrianus Johannes van Boven / ; Herman Rolf Michels / ; Patrick Serruys / ; Pieter Smits / ; Oyvind Bleie / ; Pawel Buszman / ; Dariusz Dudek / ; Thierry Colman / ; Carlos Macaya / ; Paul Erne /

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