Lipoprotein-associated phospholipase A₂ activity is a marker of risk but not a useful target for treatment in patients with stable coronary heart disease

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 lmol/min per liter (interquartile range 143.1-204.2 lmol/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.