AIMS

Lipoprotein-associated phospholipase A (Lp-PLA), a novel biomarker for vascular inflammation, is associated with coronary endothelial dysfunction (CED) and independently predicts cardiovascular events. The current study aimed to determine whether darapladib, an orally administered Lp-PLA inhibitor, improved CED.

METHODS AND RESULTS

Fifty-four patients with CED were enrolled in a double-blinded randomized placebo-controlled trial, and were randomized to receive oral darapladib, 160mg daily, or placebo. Coronary angiography and invasive coronary endothelial function assessment were performed at baseline and post-6months of treatment. Primary endpoints were change in coronary artery diameter and coronary blood flow in response to acetylcholine. Additionally, Lp-PLA activity was measured at baseline and on follow-up to evaluate for adherence and drug effect. Fifty-four patients were randomized to placebo (n=29) and darapladib (n=25). Mean age in darapladib group was 55.2.±11.7years vs. 54.0±10.5years (p=0.11). On follow-up, there was no significant difference in the percent response to acetylcholine of coronary artery diameter in treatment vs. placebo group (+3 (IQR -9, 15) vs. +3 (-12, 19); p=0.87) or coronary blood flow (-5 (IQR -24, 54) vs. 39 (IQR -26, 67); p=0.41). There was significant reduction in Lp-PLA activity in the treatment arm vs. placebo (-76 (IQR -113, -52) vs. -7(-21, -7); p<0.001).

DISCUSSION

Lp-PLA inhibition with darapladib did not improve coronary endothelial function, despite significantly reduced Lp-PLA2 activity with darapladib. This study suggests endogenous Lp-PLA may not play a primary role in coronary endothelial function in humans. CLINICALTRIALS.

GOV IDENTIFIER

NCT01067339.