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J Am Heart Assoc. 2016 Jun 21;5(6). pii: e003407. doi: 10.1161/JAHA.116.003407.

Lipoprotein-Associated Phospholipase A2 Activity Is a Marker of Risk But Not a Useful Target for Treatment in Patients With Stable Coronary Heart Disease.

Author information

1
Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden Uppsala Clinical Research Center (UCR), Uppsala University, Uppsala, Sweden lars.wallentin@ucr.uu.se.
2
Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden Uppsala Clinical Research Center (UCR), Uppsala University, Uppsala, Sweden.
3
Canadian VIGOUR Centre, University of Alberta, Edmonton, Canada.
4
Cardiovascular Division, Brigham and Women's Hospital, Boston, MA Harvard Clinical Research Institute, Boston, MA.
5
Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, King of Prussia, PA.
6
Medical Center, Duke University, Durham, NC.
7
Department of Medicine, Stanford University, Stanford, CA.
8
Department of Medicine, NYU Langone Medical Center, New York, NY.
9
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.
10
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
11
Uppsala Clinical Research Center (UCR), Uppsala University, Uppsala, Sweden Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden.
12
Former Employee of Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, King of Prussia, PA.
13
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.
14
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand University of Auckland, New Zealand.
15
Maine Research Associates, Auburn, ME.
16
Uppsala Clinical Research Center (UCR), Uppsala University, Uppsala, Sweden.

Abstract

BACKGROUND:

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.

KEYWORDS:

atherosclerosis; coronary disease; inflammation; lipoprotein; myocardial infarction

PMID:
27329448
PMCID:
PMC4937279
DOI:
10.1161/JAHA.116.003407
[Indexed for MEDLINE]
Free PMC Article

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