Effect of Darapladib Treatment on Endarterectomy Carotid Plaque Lipoprotein-Associated Phospholipase A2 Activity: A Randomized, Controlled Trial

BackgroundThe 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.MethodsPatients 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.ResultsDarapladib 40 mg and 80 mg reduced plasma lipoprotein-associated phospholipase A2 activity by 52% and 81%, respectively, versus placebo (both P2 activity were also observed compared with placebo (PP = 0.053 vs placebo). In a post-hoc analysis, plaque caspase-3 (PPConclusionsShort-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 InformationName of Registry 1: ClinicalTrials.govRegistry Number 1: NCT01916720Trial URL in Registry Database 1: www.clinicaltrials.gov/ct2/show/NCT01916720Name of Registry 2: GSK Clinical Study RegisterRegistry Number 2∶480848/010Trial URL in Registry Database 2: www.gsk-clinicalstudyregister.com/result_detail.jsp?protocolId=480848%2F010&studyId=74F5DB65-4661-4FA8-91D4-EBF78D769F24&compound=darapladib&type=Compound&letterrange=A-F