TY - JOUR
T1 - Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque
AU - Serruys, Patrick W.
AU - Garcia-Garcia, Hector M.
AU - Buszman, Pawel
AU - Erne, Paul
AU - Verheye, Stefan
AU - Aschermann, Michael
AU - Duckers, Henrikus
AU - Bleie, Oyvind
AU - Dudek, Dariusz
AU - Bøtker, Hans Erik
AU - von Birgelen, Clemens
AU - D'Amico, Don
AU - Hutchinson, Tammy
AU - Zambanini, Andrew
AU - Mastik, Frits
AU - van Es, Gerrit-Anne
AU - van der Steen, Antonius F.W.
AU - Vince, D. Geoffrey
AU - Ganz, Peter
AU - Hamm, Christian W.
AU - Wijns, William
AU - Zalewski, Andrew
PY - 2008
Y1 - 2008
N2 - 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 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 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.
AB - 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 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 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.
KW - METIS-254321
KW - Atherosclerosis
KW - Drugss
KW - Imaging
KW - Lipoprotein-associated phospholipase A2
U2 - 10.1161/CIRCULATIONAHA.108.771899
DO - 10.1161/CIRCULATIONAHA.108.771899
M3 - Article
VL - 118
SP - 1172
EP - 1182
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 11
ER -