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The Effects of the Direct Lipoprotein-Associated Phospholipase A2 Inhibitor Darapladib on Human Coronary Athlerosclerotic Plaque

03.09.2008
ESC Congress 2008 - Hot Line III

Lp-PLA2 inhibition with darapladib prevented necrotic core expansion, a key determinant of plaque vulnerability

A twelve month study of treatment with darapladib concluded that, Lp-PLA2 inhibition with darapladib prevented necrotic core expansion, a key determinant of plaque vulnerability. These findings suggest that Lp-PLA2 inhibition may represent a novel therapeutic approach. In contrast, despite adherence to a high level of standard of care treatment, necrotic core continued to expand among patients receiving a placebo.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) 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.

This study compared the effects of 12 months of treatment with darapladib (oral Lp-PLA2 inhibitor, 160 mg daily) or placebo on coronary atheroma deformability (IVUS-palpography) and plasma hs-CRP in 330 patients with angiographically documented coronary disease. Secondary end points included changes in necrotic core size (IVUS-radiofrequency), atheroma size (IVUS-greyscale), and blood biomarkers.

Background therapy was comparable between groups, with no difference in LDL-cholesterol at 12 months (placebo: 88±34 and 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 hsCRP (p=0.35).

In the placebo-treated group, however, necrotic core volume increased significantly (4.5±17.9 mm3, p=0.009), whereas darapladib halted this increase (-0.5±13.9 mm3, p=0.71), resulting in a significant treatment difference of -5.2 mm3 (p=0.012). These intra-plaque compositional changes occurred without a significant treatment difference in total atheroma volume (p=0.95).

Jacqueline Partarrieu | alfa
Further information:
http://www.escardio.org

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