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Effects Of The Direct Lipoprotein-Associated Phospholipase A 2 Inhibitor Darapladib On Human Coronary Atherosclerotic Plaque

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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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 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-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.