darapladib and Necrosis

Lipoprotein-associated phospholipase A2 (Lp-PLA2) may play a role in plaque progression and vulnerability. We aimed to define plaque characteristics on multimodality intravascular imaging in patients with coronary endothelial dysfunction in response to long-term inhibition of Lp-PLA2 by darapladib.. This is a double-blinded, randomized study screening 70 patients, and enrolling 54 patients with suspected ischemia, without obstructive disease on angiography and with coronary endothelial dysfunction by invasive assessment. Patients were randomized to receive darapladib or placebo for 6 months. Forty patients underwent multimodality intravascular imaging at baseline and after 6 months of therapy. Several parameters of plaque vulnerability were measured, including maximum value of lipid core burden index for any of the 4-mm segment (maxLCBI4 mm) by near-infrared spectroscopy. Microchannels and macrophages were assessed using optical coherence tomography and necrotic core volume by virtual histology intravascular ultrasound.. There was no significant difference in maxLCBI4 mm [64.56 (7.74, 128.56) vs. 22.43 (0, 75.63), P=0.522] or in macrophage images angle [-9.5° (-25.53°, 12.68°) vs. -16.7° (-28.6°, -4.8°), P=0.489] between groups. There was a trend toward shorter microchannel length in the darapladib arm [0, (-4.4, 0.2) mm vs. 0.8 (-0.15, 1.9) mm, P=0.08]. Percentage of necrotic core volume was not significantly different.. Thus, long-term inhibition of endogenous Lp-PLA2 activity with darapladib was not associated with a change in plaque progression and vulnerability indices after 6 months of therapy, and the endogenous Lp-PLA2 pathway may not play a direct role in the progression of early atherosclerosis in humans.

Topics: Adult; Aged; Benzaldehydes; Coronary Angiography; Coronary Artery Disease; Coronary Vessels; Disease Progression; Double-Blind Method; Female; Humans; Male; Middle Aged; Minnesota; Multimodal Imaging; Necrosis; Oximes; Phospholipase A2 Inhibitors; Plaque, Atherosclerotic; Predictive Value of Tests; Spectroscopy, Near-Infrared; Time Factors; Tomography, Optical Coherence; Treatment Outcome; Ultrasonography, Interventional

We explored the impact of patient demographics, anthropometric measurements, cardiovascular risk factors, and soluble biomarkers on necrotic core and atheroma size in patients with coronary disease. The IBIS-2 trial enrolled 330 patients. In the multivariate analysis, at baseline, creatinine had a positive, whereas baseline mean lumen diameter and myeloperoxidase had a negative, independent association with percentage of necrotic core (PNC); while age, glomerular filtration rate <60, HbA1c, previous PCI or CABG and baseline % diameter stenosis were positively, and acute coronary syndromes (ACS) were negatively associated with baseline percentage atheroma volume (PAV). The variables associated with a decrease in PNC from baseline were darapladib, ACS and a large content of NC at baseline, while variables associated with an increase in PNC were previous stroke and % diameter stenosis at baseline. Those variables associated with a decrease in PAV from baseline were waist circumference, statin use, CD40L and baseline PAV, while the only variable associated with an increase in PAV was baseline diastolic blood pressure. Treatment with darapladib was associated with a decrease in necrotic core, but was not associated with a decrease in percentage atheroma volume. On the contrary, statin use was only associated with a decrease in percentage atheroma volume.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Acute Coronary Syndrome; Aged; Benzaldehydes; Biomarkers; C-Reactive Protein; CD40 Ligand; Coronary Artery Disease; Coronary Vessels; Creatinine; Double-Blind Method; Enzyme Inhibitors; Europe; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intercellular Adhesion Molecule-1; Interleukin-6; Male; Matrix Metalloproteinase 9; Middle Aged; Multivariate Analysis; Necrosis; Oximes; Peroxidase; Plaque, Atherosclerotic; Predictive Value of Tests; Risk Assessment; Risk Factors; Ultrasonography, Interventional

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.. 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.. =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).. 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.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Aged; Anti-Inflammatory Agents; Benzaldehydes; Cardiovascular Agents; Coronary Disease; Double-Blind Method; Enzyme Inhibitors; Female; Humans; Male; Middle Aged; Necrosis; Oximes; Treatment Outcome