Stewart RA

References (2)

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 - Wallentin_2016_J.Am.Heart.Assoc_5_
Author(s) : Wallentin L , Held C , Armstrong PW , Cannon CP , Davies RY , Granger CB , Hagstrom E , Harrington RA , Hochman JS , Koenig W , Krug-Gourley S , Mohler ER, 3rd , Siegbahn A , Tarka E , Steg PG , Stewart RA , Weiss R , Ostlund O , White HD
Ref : J Am Heart Assoc , 5 : , 2016
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 micromol/min per liter (interquartile range 143.1-204.2 micromol/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: Unique identifier: NCT00799903.
ESTHER : Wallentin_2016_J.Am.Heart.Assoc_5_
PubMedSearch : Wallentin_2016_J.Am.Heart.Assoc_5_
PubMedID: 27329448

Title : Changes in lipoprotein-Associated phospholipase A2 activity predict coronary events and partly account for the treatment effect of pravastatin: results from the Long-Term Intervention with Pravastatin in Ischemic Disease study - White_2013_J.Am.Heart.Assoc_2_e000360
Author(s) : White HD , Simes J , Stewart RA , Blankenberg S , Barnes EH , Marschner IC , Thompson P , West M , Zeller T , Colquhoun DM , Nestel P , Keech AC , Sullivan DR , Hunt D , Tonkin A
Ref : J Am Heart Assoc , 2 :e000360 , 2013
Abstract : BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) levels are associated with coronary heart disease (CHD) in healthy individuals and in patients who have had ischemic events. METHODS AND RESULTS: The Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) study randomized 9014 patients with cholesterol levels of 4.0 to 7.0 mmol/L to placebo or pravastatin 3 to 36 months after myocardial infarction or unstable angina and showed a reduction in CHD and total mortality. We assessed the value of baseline and change in Lp-PLA2 activity to predict outcomes over a 6-year follow-up, the effect of pravastatin on Lp-PLA2 levels, and whether pravastatin treatment effect was related to Lp-PLA2 activity change. Lp-PLA2 was measured at randomization and 1 year, and levels were grouped as quartiles. The prespecified end point was CHD death or nonfatal myocardial infarction. Baseline Lp-PLA2 activity was positively associated with CHD events (P < 0.001) but not after adjustment for 23 baseline factors (P = 0.66). In 6518 patients who were event free at 1 year, change in Lp-PLA2 was a significant independent predictor of subsequent CHD events after adjustment for these risk factors, including LDL cholesterol and LDL cholesterol changes (P < 0.001). Pravastatin reduced Lp-PLA2 by 16% compared with placebo (P < 0.001). After adjustment for Lp-PLA2 change, the pravastatin treatment effect was reduced from 23% to 10% (P = 0.26), with 59% of the treatment effect accounted for by changes in Lp-PLA2. Similar reductions in treatment effect were seen after adjustment for LDL cholesterol change. CONCLUSION: Reduction in Lp-PLA2 activity during the first year was a highly significant predictor of CHD events, independent of change in LDL cholesterol, and may account for over half of the benefits of pravastatin in the LIPID study.
ESTHER : White_2013_J.Am.Heart.Assoc_2_e000360
PubMedSearch : White_2013_J.Am.Heart.Assoc_2_e000360
PubMedID: 24152981
Gene_locus related to this paper: human-PLA2G7