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Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque.
Circulation. 2008 Sep 09; 118(11):1172-82.Circ

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-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

=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.

Authors+Show Affiliations

Thoraxcenter, Ba583, Erasmus MC, Rotterdam, Netherlands. p.w.j.c.serruys@erasmusmc.nlNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18765397

Citation

Serruys, Patrick W., et al. "Effects of the Direct Lipoprotein-associated Phospholipase A(2) Inhibitor Darapladib On Human Coronary Atherosclerotic Plaque." Circulation, vol. 118, no. 11, 2008, pp. 1172-82.
Serruys PW, García-García HM, Buszman P, et al. Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque. Circulation. 2008;118(11):1172-82.
Serruys, P. W., García-García, H. M., Buszman, P., Erne, P., Verheye, S., Aschermann, M., Duckers, H., Bleie, O., Dudek, D., Bøtker, H. E., von Birgelen, C., D'Amico, D., Hutchinson, T., Zambanini, A., Mastik, F., van Es, G. A., van der Steen, A. F., Vince, D. G., Ganz, P., ... Zalewski, A. (2008). Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque. Circulation, 118(11), 1172-82. https://doi.org/10.1161/CIRCULATIONAHA.108.771899
Serruys PW, et al. Effects of the Direct Lipoprotein-associated Phospholipase A(2) Inhibitor Darapladib On Human Coronary Atherosclerotic Plaque. Circulation. 2008 Sep 9;118(11):1172-82. PubMed PMID: 18765397.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque. AU - Serruys,Patrick W, AU - García-García,Héctor 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, AU - ,, Y1 - 2008/09/01/ PY - 2008/9/4/pubmed PY - 2008/10/18/medline PY - 2008/9/4/entrez SP - 1172 EP - 82 JF - Circulation JO - Circulation VL - 118 IS - 11 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-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: =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. SN - 1524-4539 UR - https://www.unboundmedicine.com/medline/citation/18765397/Effects_of_the_direct_lipoprotein_associated_phospholipase_A_2__inhibitor_darapladib_on_human_coronary_atherosclerotic_plaque_ L2 - http://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.108.771899?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -