Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque

Patrick W. Serruys, Hector M. Garcia-Garcia, 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. HammWilliam Wijns, Andrew Zalewski

    Research output: Contribution to journalArticleAcademicpeer-review

    448 Citations (Scopus)

    Abstract

    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-PLA2 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 therapy was comparable between groups, with no difference in low-density lipoprotein cholesterol at 12 months (placebo, 88±34 mg/dL; darapladib, 84±31 mg/dL; P=0.37). In contrast, Lp-PLA2 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 mm3P=0.009), whereas darapladib halted this increase (−0.5±13.9 mm3P=0.71), resulting in a significant treatment difference of −5.2 mm3 (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.

    Original languageEnglish
    Pages (from-to)1172-1182
    Number of pages11
    JournalCirculation
    Volume118
    Issue number11
    DOIs
    Publication statusPublished - 2008

    Keywords

    • METIS-254321
    • Atherosclerosis
    • Drugss
    • Imaging
    • Lipoprotein-associated phospholipase A2

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