Effects of the Direct Lipoprotein-Associated Phospholipase A2 Inhibitor Darapladib on Human Coronary Atherosclerotic Plaque Export

@article{citeulike:3817846, abstract = {Background-- 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. 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-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. 10.1161/CIRCULATIONAHA.108.771899}, author = {Serruys, Patrick W. and Garcia-Garcia, Hector M. and Buszman, Pawel and Erne, Paul and Verheye, Stefan and Aschermann, Michael and Duckers, Henrikus and Bleie, Oyvind and Dudek, Dariusz and Botker, Hans E. and von Birgelen, Clemens and D'Amico, Don and Hutchinson, Tammy and Zambanini, Andrew and Mastik, Frits and van Es, Gerrit-Anne and van der Steen, Antonius F. and Vince, Geoffrey D. and Ganz, Peter and Hamm, Christian W. and Wijns, William and Zalewski, Andrew and For}, citeulike-article-id = {3817846}, citeulike-linkout-0 = {http://dx.doi.org/10.1161/CIRCULATIONAHA.108.771899}, citeulike-linkout-1 = {http://circ.ahajournals.org/cgi/content/abstract/118/11/1172}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/18765397}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=18765397}, day = {9}, doi = {10.1161/CIRCULATIONAHA.108.771899}, journal = {Circulation}, keywords = {a2, core, darapladib, lipoprotein-associated, necrotic, phospholipase}, month = {September}, number = {11}, pages = {1172--1182}, posted-at = {2008-12-22 16:52:54}, priority = {2}, title = {Effects of the Direct Lipoprotein-Associated Phospholipase A2 Inhibitor Darapladib on Human Coronary Atherosclerotic Plaque}, url = {http://dx.doi.org/10.1161/CIRCULATIONAHA.108.771899}, volume = {118}, year = {2008} }

TY - JOUR ID - citeulike:3817846 L3 - citeulike-article-id:3817846 N2 - Background-- 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. 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-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. 10.1161/CIRCULATIONAHA.108.771899 IS - 11 JF - Circulation EP - 1182 TI - Effects of the Direct Lipoprotein-Associated Phospholipase A2 Inhibitor Darapladib on Human Coronary Atherosclerotic Plaque VL - 118 SP - 1172 KW - a2 KW - core KW - darapladib KW - lipoprotein-associated KW - necrotic KW - phospholipase AU - Serruys, Patrick AU - Garcia-Garcia, Hector AU - Buszman, Pawel AU - Erne, Paul AU - Verheye, Stefan AU - Aschermann, Michael AU - Duckers, Henrikus AU - Bleie, Oyvind AU - Dudek, Dariusz AU - Botker, Hans 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 AU - Vince, Geoffrey AU - Ganz, Peter AU - Hamm, Christian AU - Wijns, William AU - Zalewski, Andrew AU - For PY - 2008/09/09/ UR - http://dx.doi.org/10.1161/CIRCULATIONAHA.108.771899 ER -