PCSK9-Targeting Therapies and Mortality: A Systematic Review and Meta-Analysis of Randomized Trials

AIMS: To evaluate the association of PCSK9-targeting therapies with mortality and cardiovascular events in stable or clinically stabilized randomized trial populations. METHODS: We systematically reviewed randomized trials comparing alirocumab, evolocumab or inclisiran with placebo or active control. The review was registered in PROSPERO (CRD420261395609). Treatment effects were pooled as incidence rate ratios (IRRs) using random-effects models. The primary outcome was all-cause mortality. Prespecified subgroup analyses were based on trial-level known atherosclerosis status, as defined by enrollment criteria. RESULTS: Thirty-two trials enrolled 77,178 participants. Individual atherosclerosis status could not be determined beyond trial-level eligibility criteria. Mortality estimates were predominantly informed by large cardiovascular outcome trials. All-cause mortality was lower with PCSK9-targeting therapy (IRR 0.88, 95% CI 0.82-0.95). Estimates favored PCSK9-targeting treatment in both trials requiring known atherosclerosis for enrollment (IRR 0.90, 95% CI 0.83-0.98) and trials without such an enrollment requirement (IRR 0.78, 95% CI 0.62-0.97; interaction p = 0.21). PCSK9-targeting treatment additionally reduced myocardial infarction, stroke, and coronary revascularization rates. Leave-one-out estimates remained directionally consistent. CONCLUSION: PCSK9-targeting therapies were associated with lower all-cause mortality and fewer ischemic events across trial populations. The predominant contribution of large cardiovascular outcome trials enrolling populations with known atherosclerosis and using PCSK9 antibodies limits the ability to infer a survival benefit in populations not selected on the basis of atherosclerosis status and across individual therapies, particularly inclisiran.