Effect of darapladib treatment on endarterectomy carotid plaque lipoprotein-associated phospholipase A2 activity: a randomized, controlled trial

Abstract

Background: The aim of this study was to assess the effects of darapladib, a selective oral investigational lipoprotein-associated phospholipase A2 inhibitor, on both plasma and plaque lipoprotein-associated phospholipase A2 activity.

Methods: Patients undergoing elective carotid endarterectomy were randomized to darapladib 40 mg (n = 34), 80 mg (n = 34), or placebo (n = 34) for 14 days, followed by carotid endarterectomy 24 hours after the last dose of study medication.

Results: Darapladib 40 mg and 80 mg reduced plasma lipoprotein-associated phospholipase A2 activity by 52% and 81%, respectively, versus placebo (both P<0.001). Significant reductions in plaque lipoprotein-associated phospholipase A2 activity were also observed compared with placebo (P<0.0001), which equated to a 52% and 80% decrease compared with placebo. No significant differences were observed between groups in plaque lysophosphatidylcholine content or other biomarkers, although a dose-dependent decrease in plaque matrix metalloproteinase-9 mRNA expression was observed with darapladib 80 mg (P = 0.053 vs placebo). In a post-hoc analysis, plaque caspase-3 (P<0.001) and caspase-8 (P<0.05) activity were found to be significantly lower in the darapladib 80-mg group versus placebo. No major safety concerns were identified in the study.

Conclusions: Short-term treatment (14 ± 4 days) with darapladib produced a robust, dose-dependent reduction in plasma lipoprotein-associated phospholipase A2 activity. More importantly, darapladib demonstrated placebo-corrected reductions in carotid plaque lipoprotein-associated phospholipase A2 activity of similar magnitude. Darapladib was generally well tolerated and no safety concerns were identified. Additional studies of longer duration are needed to explore whether these pharmacodynamic effects are associated with improved clinical outcomes, as might be hypothesized.

Trial registration: ClinicalTrials.gov NCT01916720.

Figure 1. Disposition of patients throughout the carotid endarterectomy study.

Figure 2. Effect of darapladib treatment (14±4 days) on plaque and plasma lipoprotein-associated phospholipase A₂ activity.

Vertical bars for plaque and plasma data points represent 97.5% and 95% confidence intervals (CI), respectively. Baseline plasma Lp-PLA₂ activity levels are provided in Table 1. At Day 15, plasma Lp-PLA₂ activity levels (mean ± SD) for placebo, 40 mg darapladib, and 80 mg darapladib were 141.4±39.3, 63.4±28.3, and 27.0±11.4 nmol/min/ml, respectively. At Day 15, plaque Lp-PLA₂ activity levels (mean ± SEM) for placebo, 40 mg darapladib, and 80 mg darapladib were 0.94±0.14, 0.26±0.13, and 0.11±0.14 nmol/min/mg protein, respectively.

Figure 3. Analysis of plaque lysophosphatidylcholine (lysoPC) content following treatment (14±4 days) with darapladib.

Data represent mean ± standard deviation.

Figure 4. The influence of darapladib treatment (14±4 days) on the expression (mRNA) of several plaque biomarkers.

Vertical bars represent 95% confidence intervals (CI). CD40L, CD40 ligand; MMP, matrix metalloproteinase; PAI, plasminogen activator inhibitor; ICAM, intercellular adhesion molecule; IL, interleukin; Lp-PLA, lipoprotein-associated phospholipase A₂.

Figure 5. The influence of darapladib treatment (14±4 days) on plaque (A) caspase-3 activity and (B) caspase-8 activity (mean ± SEM).

P values represent comparisons of darapladib 80 mg with placebo. AU, activity units.