AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
Beyond Statins: Real-World Long-Term Effectiveness of PCSK9 Inhibitors versus Ezetimibe in Atherosclerotic Cardiovascular Disease
By Gupta U, Khanal S, Mehta KA et al.
Introduction: Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of global morbidity and mortality.Although statins remain the foundation of lipid-lowering therapy, some patients need add-on agents such as ezetimibe or PCSK9 inhibitors to reach guideline LDL-C targets. However, real-world data comparing the long-term effectiveness of these two strategies are limited. Research Question: What are the long-term real-world outcomes of PCSK9 inhibitor-based versus ezetimibe-based regimens in patients with ASCVD on statin therapy? Methods Using the TriNetX Research Network, we identified patients with ASCVD on statin therapy prescribed ezetimibe (N=176,169) or a PCSK9 inhibitor (N=16,150). Propensity score matching generated two well-balanced cohorts (N=16,145 per group). Primary and secondary outcomes; all-cause mortality, all-cause readmission, myocardial infarction (MI), revascularization, major adverse cardiovascular events (MACE), ischemic stroke, and heart failure (HF) exacerbation-were analyzed over 3-year and 5-year follow-ups. Results: Baseline mean low-density lipoprotein cholesterol was higher in the PCSK9 inhibitor group than the ezetimibe group (114.2±54.5 mg/dL vs 98.9±41.1 mg/dL). The PCSK9 inhibitor regimen demonstrated a significant reduction in all-cause mortality at 3 years (OR: 0.78, p<0.001; HR: 0.785, p<0.001) and 5 years (OR: 0.777, p<0.001; HR: 0.79, p<0.001). Diminished risks of all-cause readmission were observed with PCSK9 inhibitors at 3 years (OR: 0.901, p=0.03) and 5 years (OR: 0.889, p=0.012). Conversely, the PCSK9 inhibitor cohort experienced a higher risk of MI at 5 years (OR: 1.109, p=0.002; HR: 1.101, p=0.03) and revascularization at 3 years (OR: 1.22, p=0.01; HR: 1.202, p=0.002) and 5 years (OR: 1.194, p=0.002; HR: 1.182, p=0.002). No significant differences were noted for composite MACE, ischemic stroke, or HF exacerbation. Conclusion: PCSK9 inhibitor-based regimens are associated with a significant long-term survival advantage and lower readmission rates compared to ezetimibe-based regimens in high-risk ASCVD patients. Higher risks of MI and revascularization in the PCSK9 inhibitor group likely reflect residual confounding given their higher baseline lipid levels and clinical severity. These findings support expanding intensive PCSK9 inhibitor utilization for secondary prevention.