News:Darapladib A Direct Lipoprotein Associated Phospholipase A2 Inhibitor Reduces Necrotic Core but not Plaque Deformability

September 2, 2008 By Vijayalakshmi Kunadian MBBS MD MRCP [mailto:vkunadian@perfuse.org]

The results of IBIS-2 (Integrated Biomarker and Imaging Study) were presented by Dr. William Wijns of Belgium at the European Society of Cardiology Congress 2008 in Munich, Germany today with commentary by Dr. Filippo Crea of Italy and published ahead of print in Circulation.

Lipoprotein-associated Phospholipase A2 (LP-PLA2) is a novel biomarker that is demonstrated to be associated with an increased risk of cardiovascular events. LP-PLA2 produced by macrophages, T cells and mast cells is involved in atherogenesis. LP-PLA2 is bound to atherogenic lipoproteins and is found in large amounts in human atherosclerotic lesions. Darapladib, a selective inhibitor of LP-PLA2 causes a reduction in interleukin-6 and serum high sensitive-CRP levels 12 weeks following the administration of the drug (160 mg once daily orally).

Investigators from Belgium exlpored this drug further to determine its effects on coronary atheroma deformability and plasma high sensitive-CRP levels. This study consisted of 330 patients with coronary artery disease documented on coronary angiography and were randomized to receive darapladib (160 mg once daily per oral administration) or placebo with follow-up at 12 months. The primary endpoint of this trial consisted of plaque deformability identified on Intravascular Ultrasound (IVUS) palpography and serum high sensitive CRP levels. The secondary endpoints consisted of changes in necrotic core size measured using IVUS radiofrequency, atheroma size measured using IVUS grey scale and other serum biomarkers.

There was no difference in the background medical therapy between the two groups. At 12 month follow-up, there was no difference in the serum LDL cholesterol levels between the placebo and darapladib groups (88±34 vs. 84±31 mg/Dl, p=0.37). However, darapladib caused a significant reduction in the LP-PLA2 activity compared with placebo (59% reduction, p=0.001).

There was no improvement in the primary endpoint (plaque deformability and serum hs-CRP levels) using darapladib compared with placebo (p=0.22 and p=0.35 respectively). However at 12 month follow-up, there was a benefit in the secondary endpoint with darapladib which caused a significant reduction in the necrotic core volume (-0.5±13.9 mm3, p=0.71) compared with placebo which significantly increased the necrotic core volume (4.5±17.9 mm3, p=0.009). There was significant treatment difference between the two groups in the necrotic core volume of -5.2 mm3 (p=0.012). The changes in the composition within the plaque did not translate into significant treatment difference in the total atheroma volume on IVUS (P=0.95).

The investigators of this trial concluded that although darapladib did reduce the necrotic core volume, it did not result in significant benefits in the primary endpoints. In his commentary, Dr Filippo Crea suggested that although this study is extremely innovative “further studies using validated surrogate end-points are appropriate before considering large trials with clinical end-points”. Dr. Crea also indicated that the other strengths of this study include the fact that it has robust design consisting of core lab analysis of both imaging and biomarkers and also the fact that the investigators of this study had large experience in this field. He noted that the limitations of this study included the fact that the investigators utilized palpography and virtual histology rather than considering validated surrogate end-points such as carotid IMT, FMD or coronary plaque volume.

Reference

 * 1) http://circ.ahajournals.org/cgi/reprint/CIRCULATIONAHA.108.771899v1