Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque.
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.


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.
Serruys
Patrick W
PW
Thoraxcenter, Ba583, Erasmus MC, Rotterdam, Netherlands. p.w.j.c.serruys@erasmusmc.nl
García-García
Héctor M
HM
Buszman
Pawel
P
Erne
Paul
P
Verheye
Stefan
S
Aschermann
Michael
M
Duckers
Henrikus
H
Bleie
Oyvind
O
Dudek
Dariusz
D
Bøtker
Hans Erik
HE
von Birgelen
Clemens
C
D'Amico
Don
D
Hutchinson
Tammy
T
Zambanini
Andrew
A
Mastik
Frits
F
van Es
Gerrit-Anne
GA
van der Steen
Antonius F W
AF
Vince
D Geoffrey
DG
Ganz
Peter
P
Hamm
Christian W
CW
Wijns
William
W
Zalewski
Andrew
A