Proprotein convertase subtilisin/kexin type 9 levels and the risk of cardiovascular events in statin-treated patients with cardiovascular disease

Abstract Background Previous studies have not found a consistent association between circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and the risk of cardiovascular events. Although PCSK9 is cleaved by furin and becomes biologically inactive, previous studies have employed measurement methods which cannot distinguish furin-cleaved and uncleaved form of PCSK9. Methods This study is a prespecified sub-study of the REAL-CAD study which is a prospective, multicenter, randomized trial to compare high- versus low-dose statin in patients with stable coronary artery disease (CAD). The substudy primary endpoint was a composite of major adverse cerebrovascular and cardiovascular events (MACCE) defined as a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergency hospitalization. In a case-cohort study, sub-cohort was randomly selected samples from the total cohort as tripling the number of cases with MACCE. Serum mature (uncleaved) and furin-cleaved PCSK9 levels obtained at 6 months after randomization were measured among participants who subsequently developed MACCE and among randomly selected participants. Their relationships with cardiovascular events were assessed according to the quartiles. Cox proportional hazards model was used to calculate hazard ratios (HRs) with 95% confidence intervals (CI). Results From 1,478 patients in the sub-cohort, the Cox proportional hazards models with a pseudolikelihood method for case-cohort design revealed that the risk of primary endpoint in patients in the highest quartile of mature PCSK9 concentrations was similar to the lowest quartile (HR 0.809; 95%CI, 0.541-1.209). Similarly, HRs for the highest to lowest quartiles of furin-cleaved PCSK9s was 0.948 [95%CI, 0.645-1.392] (P=0.784). As compared to the lowest quartile, both serum mature and furin-cleaved PCSK9 levels did not predict the cardiovascular events. Conclusions Serum mature and furin-cleaved PCSK9 levels did not provide useful information in the assessment of future cardiovascular events in statin-treated patients with stable CAD.Study FlowThe weighted Kaplan-Meier cueves