PCSK9 inhibitor treatment and outcomes in patients with atherosclerotic cardiovascular disease but without prior ischaemic events: an observational study

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BACKGROUND AND AIMS: Low-density lipoprotein cholesterol (LDL-C)-lowering therapies are proven effective in atherosclerotic cardiovascular disease (ASCVD), but real-world evidence for proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) monoclonal antibodies (mAb) remains limited. This study evaluated their impact in patients with ASCVD without prior ischaemic events. METHODS: Patients initiating PCSK9i mAb from January 2016 to December 2022 were identified in the Optum Research Database. A 1:2 propensity score-matched comparator cohort of PCSK9i non-initiators was developed. The primary endpoint was a composite of non-fatal myocardial infarction, non-fatal ischaemic stroke, or all-cause mortality. Key outcomes from the parametric G-formula were 5-year event rates, relative risk reduction (RRR) and absolute risk reduction (ARR), with intention-to-treat (ITT) analysis. Additional outcomes for PCSK9i mAb initiators included absolute and percent LDL-C reduction from baseline. RESULTS: Overall, 19 670 patients met selection criteria (6545 PCSK9i mAb initiators; 13 125 non-initiators). Baseline characteristics were well-balanced. Under ITT, estimated 5-year event rates were 17.5% [95% confidence interval (CI) 15.5%, 19.5%] with PCSK9i mAb vs 25.4% (95% CI 23.6%, 27.1%) without PCSK9i, yielding a RRR of 30.9% and ARR of 7.8%. Individual endpoints showed RRRs of 28.3% for myocardial infarction (P < .0001), 26.4% for ischaemic stroke (P = .02), and 28.5% for all-cause mortality (P < .0001). Among initiators, mean baseline and follow-up LDL-C were 117.8 and 54.7 mg/dL (on-treatment analysis), respectively, representing an absolute reduction of 63.1 mg/dL and percent reduction of 53.6%. CONCLUSIONS: In ASCVD patients without prior events in clinical practice, PCSK9i mAb treatment was associated with lower ischaemic event and mortality rates.