AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
Comparative Cardiovascular Outcomes Across PCSK9-Targeted Therapies: A Real-World Matched Cohort Analysis of Inclisiran, Alirocumab, and Evolocumab
By Iorfida A, Dhruva Y, Mootz N et al.
Introduction/Background: PCSK9-targeted therapies reduce LDL-C and cardiovascular events, but real-world comparative outcomes among inclisiran, alirocumab, and evolocumab remain unclear. Research Questions/Hypothesis: Does PCSK9-targeted therapy reduce AMI, MACE, and all-cause mortality compared with no PCSK9 inhibitor use, and do outcomes differ among inclisiran, alirocumab, and evolocumab? We hypothesized that PCSK9-targeted therapy would be associated with improved cardiovascular outcomes and lower mortality and that differences in mechanism of action and dosing frequency may yield different outcomes among agents. Methods/Approach: We conducted a retrospective cohort study using the TriNetX Research Analytics Network. Patients aged ≥50 years with atherosclerotic heart disease and dyslipidemia were stratified by PCSK9-targeted therapy exposure: any PCSK9 inhibitor versus none, and mutually exclusive head-to-head cohorts of inclisiran, alirocumab, and evolocumab. Outcomes included AMI, MACE (AMI, cerebral infarction, or cardiac arrest), and all-cause mortality at 1, 3, and 5 years. One-to-one propensity score matching of age, sex, BMI, blood pressure, and relevant comorbidities was performed prior to Kaplan-Meier survival analysis and multivariable Cox proportional hazards regression (p < 0.05). Results/Data: After matching, PCSK9 therapy was associated with significantly lower MACE at 1 year (HR 0.857, 95% CI 0.837-0.878), 3 years (HR 0.946, 95% CI 0.927-0.965), and 5 years (HR 0.969, 95% CI 0.950-0.989). All-cause mortality was lower at 1 year (HR 0.323, 95% CI 0.305-0.341), 3 years (HR 0.432, 95% CI 0.416-0.448), and 5 years (HR 0.467, 95% CI 0.451-0.483), though its magnitude may reflect residual confounding. AMI was lower at 1 year but not consistently thereafter. Inclisiran showed lower mortality than evolocumab (HRs 0.639, 0.670, 0.695) and alirocumab (HRs 0.386, 0.423, 0.438) across all time points, though neither reached significance. Alirocumab and evolocumab had broadly similar AMI and MACE rates, but mortality favored evolocumab at 3 years (HR 1.358, 95% CI 1.200-1.536) and 5 years (HR 1.325, 95% CI 1.193-1.470). Conclusion(s): In this real-world matched cohort analysis, PCSK9-targeted therapy was associated with lower MACE and all-cause mortality. Inclisiran demonstrated the most favorable observed profile, while evolocumab showed lower mortality than alirocumab. These findings are associative and may reflect residual confounding. Ongoing RCTs such as ORION-4 should provide prospective validation of these findings and further describe outcomes associated with inclisiran.