PCSK9 Inhibitors and Risk of Aortic Stenosis in Atherosclerotic Cardiovascular Disease

Abstract

Background Atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis (AS) share lipid-related mechanisms. Although statins have not slowed established AS progression in randomized trials, whether proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9is) are associated with lower incident AS risk remains uncertain. Objectives The objective of the study was to assess the association between PCSK9is use and incident AS in statin-treated patients with ASCVD. Methods Using TriNetX, we conducted a retrospective new-user cohort study of adults aged ≥60 years with ASCVD receiving statins from January 1, 2015, to August 31, 2025. PCSK9is were compared with statin-only users after 1:1 propensity score matching. The primary outcome was new-onset AS within 5 years; secondary outcomes included all-cause mortality, heart failure exacerbation (HFE), and aortic valve replacement. Results After 1:1 matching, 22,924 patients remained in each group. PCSK9is use was associated with a lower risk of AS (HR: 0.87; 95% CI: 0.78-0.97; P = 0.012), all-cause mortality, and HFE. Aortic valve replacement reduction was not significant. Subgroup analyses showed statistically significant interaction was observed only for chronic kidney disease and heart failure. Conclusions In statin-treated patients with ASCVD, PCSK9i use was associated with a modestly lower 5-year incidence of new-onset AS. Large mortality and HFE associations may reflect residual confounding and treatment-selection bias. These findings are hypothesis-generating.