Statin-free PCSK9 inhibitor therapy versus high-intensity atorvastatin for primary prevention: a target trial emulation study

Background Proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors reduce cardiovascular events in secondary prevention. However, real-world evidence comparing statin-free PCSK9 inhibitor therapy with high-intensity statins in primary prevention remains limited. Purpose To evaluate the comparative effectiveness of statin-free PCSK9 inhibitor therapy versus high-intensity atorvastatin for cardiovascular outcomes in individuals without established atherosclerotic cardiovascular disease (ASCVD). Methods We conducted a target trial emulation study using the TriNetX global federated electronic health record network. Adults aged >40 years with dyslipidaemia and no prior ASCVD, heart failure, or cancer (2013–2024) were included. Patients initiating PCSK9 inhibitor monotherapy were compared with those initiating high-intensity atorvastatin (40–80 mg). A 3-month washout period was applied. One-to-one propensity score matching balanced demographics, comorbidities, lipid levels, and concomitant medications. The primary outcome was major adverse cardiovascular events (MACE: all-cause mortality, acute coronary syndrome, stroke, or heart failure) at 1 year. Cox proportional hazards models were used under an intention-to-treat framework. Results Among 308,286 eligible patients, 5,715 received PCSK9 inhibitors and 302,571 received atorvastatin. After matching, 5,570 patients were included in each group. At 1 year, MACE occurred in 2.9% of the PCSK9 group versus 4.2% of the atorvastatin group (hazard ratio [HR] 0.71; 95% confidence interval [CI] 0.58–0.86), corresponding to a number needed to treat of 82. PCSK9 inhibitors were associated with lower risks of all-cause mortality (HR 0.51; 95% CI 0.31–0.86), ischaemic stroke (HR 0.63; 95% CI 0.41–0.97), and all-cause hospitalisation (HR 0.84; 95% CI 0.77–0.92). Results were consistent across multiple sensitivity analyses and prespecified subgroups, with greater benefit observed in patients with baseline LDL cholesterol ≥190 mg/dL. No association was observed in falsification analyses. Conclusions In this large real-world target trial emulation, statin-free PCSK9 inhibitor therapy was associated with significantly lower cardiovascular event rates compared with high-intensity atorvastatin in individuals without prior ASCVD. These findings suggest potential applicability of PCSK9 inhibitors for primary prevention in clinical scenarios where patients are unable to tolerate statins or require alternative lipid-lowering strategies.