title: Lipoprotein-Associated Phospholipase A2 Activity Is a Marker of Risk But Not a Useful Target for Treatment in Patients With Stable Coronary Heart Disease.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  URL: https://www.clinicaltrials.gov. Unique identifier: NCT00799903.
authors.affiliation: Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden Uppsala Clinical Research Center (UCR), Uppsala University, Uppsala, Sweden lars.wallentin@ucr.uu.se.
authors.forename: Lars
authors.initials: L
authors.lastname: Wallentin
authors.affiliation: Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden Uppsala Clinical Research Center (UCR), Uppsala University, Uppsala, Sweden.
authors.forename: Claes
authors.initials: C
authors.lastname: Held
authors.affiliation: Canadian VIGOUR Centre, University of Alberta, Edmonton, Canada.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Armstrong
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, MA Harvard Clinical Research Institute, Boston, MA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Cannon
authors.affiliation: Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, King of Prussia, PA.
authors.forename: Richard Y
authors.initials: RY
authors.lastname: Davies
authors.affiliation: Medical Center, Duke University, Durham, NC.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Granger
authors.affiliation: Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden Uppsala Clinical Research Center (UCR), Uppsala University, Uppsala, Sweden.
authors.forename: Emil
authors.initials: E
authors.lastname: Hagström
authors.affiliation: Department of Medicine, Stanford University, Stanford, CA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harrington
authors.affiliation: Department of Medicine, NYU Langone Medical Center, New York, NY.
authors.forename: Judith S
authors.initials: JS
authors.lastname: Hochman
authors.affiliation: Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany Deutsches Herzzentrum München, Technische Universität München, Munich, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Koenig
authors.affiliation: Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, King of Prussia, PA.
authors.forename: Sue
authors.initials: S
authors.lastname: Krug-Gourley
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Emile R
authors.initials: ER
authors.lastname: Mohler
authors.affiliation: Uppsala Clinical Research Center (UCR), Uppsala University, Uppsala, Sweden Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden.
authors.forename: Agneta
authors.initials: A
authors.lastname: Siegbahn
authors.affiliation: Former Employee of Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, King of Prussia, PA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tarka
authors.affiliation: FACT (French Alliance for Cardiovascular Trials), Paris, France DHU FIRE, Université Paris-Diderot, Sorbonne Paris-Cité, Paris, France Hôpital Bichat, INSERUM U-1148, Paris, France NHLI, ICMS, Imperial College, Royal Brompton Hospital, London, UK.
authors.forename: Philippe Gabriel
authors.initials: PG
authors.lastname: Steg
authors.affiliation: Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand University of Auckland, New Zealand.
authors.forename: Ralph A H
authors.initials: RA
authors.lastname: Stewart
authors.affiliation: Maine Research Associates, Auburn, ME.
authors.forename: Robert
authors.initials: R
authors.lastname: Weiss
authors.affiliation: Uppsala Clinical Research Center (UCR), Uppsala University, Uppsala, Sweden.
authors.forename: Ollie
authors.initials: O
authors.lastname: Östlund
authors.affiliation: Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand University of Auckland, New Zealand.
authors.forename: Harvey D
authors.initials: HD
authors.lastname: White
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000378:metabolism*; D000368:Aged; D001547:Benzaldehydes / Q000008:administration & dosage / Q000009:adverse effects; D015415:Biomarkers / Q000378:metabolism; D003327:Coronary Disease / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000209:etiology / Q000401:mortality; D010091:Oximes / Q000008:administration & dosage / Q000009:adverse effects; D064801:Phospholipase A2 Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D011446:Prospective Studies; D020521:Stroke / Q000209:etiology / Q000401:mortality; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
chemical_list: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D001547:Benzaldehydes; D015415:Biomarkers; D010091:Oximes; D064801:Phospholipase A2 Inhibitors; C529040:darapladib; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
keywords: atherosclerosis; coronary disease; inflammation; lipoprotein; myocardial infarction