Chronic inhibition of lipoprotein-associated phospholipase A2 does not improve coronary endothelial function: A prospective, randomized-controlled trial

Aims: Lipoprotein-associated phospholipase A(2) (LP-PLA(2)), 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(2) 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, 160 mg daily, or placebo. Coronary angiography and invasive coronary endothelial function assessment were performed at baseline and post-6 months of treatment. Primary endpoints were change in coronary artery diameter and coronary blood flow in response to acetylcholine. Additionally, Lp-PLA(2) 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. +/- 11.7 years vs. 54.0 +/- 10.5 years (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(2) activity in the treatment arm vs. placebo (-76 (IQR-113,-52) vs. -7(-21, -7); p< 0.001). Discussion: Lp-PLA(2) inhibition with darapladib did not improve coronary endothelial function, despite significantly reduced Lp-PLA(2) activity with darapladib. This study suggests endogenous Lp-PLA(2) may not play a primary role in coronary endothelial function in humans. Ctinicahriak.gov Identifier: NCT01067339 (c) 2017 Elsevier B.V. All rights reserved.