Long-term Effectiveness of PCSK9 Inhibitors versus Ezetimibe as Adjunctive Therapy to Statins in Patients with Atherosclerotic Cardiovascular Disease: A TriNetX Database Analysis

Purpose: Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of mortality. While statins are the cornerstone of therapy, many patients require intensification. This study compares the long-term real-world effectiveness of adding a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor versus ezetimibe to background statin therapy. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network (January 2018–January 2023). We identified adult patients with established ASCVD on statin therapy initiating either a PCSK9 inhibitor or ezetimibe. Propensity score matching (1:1) was utilized to balance baseline demographics, comorbidities, and medications, resulting in 16,145 patients per group. The primary outcome was all-cause mortality at 3 and 5 years. Secondary outcomes included myocardial infarction (MI), stroke, revascularization, and hospital readmission. Results The PCSK9 inhibitor cohort demonstrated a significant reduction in all-cause mortality compared to the ezetimibe cohort at 3 years (OR: 0.78, HR: 0.79, p < 0.001) and 5 years (OR: 0.78, HR: 0.79, p < 0.001). All-cause readmissions were also lower in the PCSK9 inhibitor group (5-year OR: 0.89, p = 0.01; HR: 0.95, p = 0.15). Conversely, rates of MI were higher in the PCSK9 inhibitor group at 5 years (OR: 1.11, p = 0.03; HR: 1.10, p = 0.03), likely reflecting channeling bias due to higher baseline risk (residual LDL-C imbalance). Conclusion In this large real-world analysis, PCSK9 inhibitor use was associated with lower all-cause mortality and fewer hospital readmissions over 5 years compared with ezetimibe, despite preferential use in a higher-risk population. These findings are observational and hypothesis-generating, highlighting the impact of treatment channeling in real-world lipid-lowering therapy and the need for further studies with cause-specific outcome adjudication.