Wallentin, LLWallentinHeld, CCHeldArmstrong, PWPWArmstrongCannon, CPCPCannonDavies, RYRYDaviesGranger, CBCBGrangerHagström, EEHagströmHarrington, RARAHarringtonHochman, JSJSHochmanKoenig, WWKoenigKrug-Gourley, SSKrug-GourleyMohler, ERERMohlerSiegbahn, AASiegbahnTarka, EETarkaSteg, PGPGStegStewart, RARAStewartWeiss, RRWeissÖstlund, OOÖstlundWhite, HDHDWhiteSTABILITY Investigators2016-10-052016-06-212016-10-052016-06-21Journal of the American Heart Association, 2016, 5 (6)2047-9980http://hdl.handle.net/10044/1/41105BACKGROUND: We evaluated lipoprotein-associated phospholipase A2 (Lp-PLA2) activity in patients with stable coronary heart disease before and during treatment with darapladib, a selective Lp-PLA2 inhibitor, in relation to outcomes and the effects of darapladib in the STABILITY trial. METHODS AND RESULTS: Plasma Lp-PLA2 activity was determined at baseline (n=14 500); at 1 month (n=13 709); serially (n=100) at 3, 6, and 18 months; and at the end of treatment. Adjusted Cox regression models evaluated associations between Lp-PLA2 activity levels and outcomes. At baseline, the median Lp-PLA2 level was 172.4 μmol/min per liter (interquartile range 143.1-204.2 μmol/min per liter). Comparing the highest and lowest Lp-PLA2 quartile groups, the hazard ratios were 1.50 (95% CI 1.23-1.82) for the primary composite end point (cardiovascular death, myocardial infarction, or stroke), 1.95 (95% CI 1.29-2.93) for hospitalization for heart failure, 1.42 (1.07-1.89) for cardiovascular death, and 1.37 (1.03-1.81) for myocardial infarction after adjustment for baseline characteristics, standard laboratory variables, and other prognostic biomarkers. Treatment with darapladib led to a ≈65% persistent reduction in median Lp-PLA2 activity. There were no associations between on-treatment Lp-PLA2 activity or changes of Lp-PLA2 activity and outcomes, and there were no significant interactions between baseline and on-treatment Lp-PLA2 activity or changes in Lp-PLA2 activity levels and the effects of darapladib on outcomes. CONCLUSIONS: Although high Lp-PLA2 activity was associated with increased risk of cardiovascular events, pharmacological lowering of Lp-PLA2 activity by ≈65% did not significantly reduce cardiovascular events in patients with stable coronary heart disease, regardless of the baseline level or the magnitude of change of Lp-PLA2 activity. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00799903.© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.atherosclerosiscoronary diseaseinflammationlipoproteinmyocardial infarctionJournal Articlehttps://www.dx.doi.org/10.1161/JAHA.116.0034072047-9980