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

BACKGROUND: Lipoprotein‐associated phospholipase A2 (Lp‐PLA(2)) 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‐PLA(2) activity to predict outcomes over a 6‐year follow‐up, the effect of pravastatin on Lp‐PLA(2) levels, and whether pravastatin treatment effect was related to Lp‐PLA(2) activity change. Lp‐PLA(2) 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‐PLA(2) 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‐PLA(2) 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‐PLA(2) by 16% compared with placebo (P<0.001). After adjustment for Lp‐PLA(2) 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‐PLA(2). Similar reductions in treatment effect were seen after adjustment for LDL cholesterol change. CONCLUSION: Reduction in Lp‐PLA(2) 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.