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

Int J Cardiol. 2018 Feb 15:253:7-13. doi: 10.1016/j.ijcard.2017.09.171.

Abstract

Aims: Lipoprotein-associated phospholipase A2 (Lp-PLA2), 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-PLA2 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-PLA2 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-PLA2 activity in the treatment arm vs. placebo (-76 (IQR -113, -52) vs. -7(-21, -7); p<0.001).

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

Gov identifier: NCT01067339.

Keywords: Endothelial function; Inflammation; Lipoprotein-associated phospholipase A2.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / antagonists & inhibitors*
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / physiology
  • Adult
  • Aged
  • Benzaldehydes / administration & dosage*
  • Blood Flow Velocity / drug effects
  • Blood Flow Velocity / physiology
  • Coronary Angiography / methods
  • Coronary Artery Disease / diagnostic imaging
  • Coronary Artery Disease / drug therapy*
  • Coronary Artery Disease / physiopathology
  • Coronary Vessels / diagnostic imaging
  • Coronary Vessels / drug effects*
  • Coronary Vessels / physiology
  • Double-Blind Method
  • Endothelium, Vascular / diagnostic imaging
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / physiology
  • Female
  • Follow-Up Studies
  • Humans
  • Male
  • Middle Aged
  • Oximes / administration & dosage*
  • Phospholipase A2 Inhibitors / administration & dosage*
  • Prospective Studies

Substances

  • Benzaldehydes
  • Oximes
  • Phospholipase A2 Inhibitors
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • PLA2G7 protein, human
  • darapladib

Associated data

  • ClinicalTrials.gov/NCT01067339