Alirocumab and cardiovascular outcomes in patients without a prior ischemic event

Background ODYSSEY OUTCOMES demonstrated that alirocumab reduces cardiovascular event rates after acute coronary syndrome. VESALIUS-CV recently showed that evolocumab lowers cardiovascular event rates in patients without prior myocardial infarction (MI) or stroke. Data on alirocumab effectiveness in patients without prior ischemic events are limited. Aim To evaluate 4-year absolute and relative risk reductions in major adverse cardiovascular events after initiation of alirocumab in patients with established atherosclerotic cardiovascular disease (ASCVD) without prior MI, unstable angina, or ischemic stroke. Methods OPTIMUS-EPIC (Outcomes and PrevenTIon program with PCSK9i Monoclonal antibodies in ASCVD PopUlation without prior iSchemic events) is an observational comparative-effectiveness study using the PHARMO Data Network. Using this population-based network of linked electronic healthcare databases in the Netherlands (2016-2024), adults with established ASCVD and no prior MI, unstable angina, or ischemic stroke were identified. New users of alirocumab (75 mg Q2W, 150 mg Q2W, or 300 mg Q4W) were propensity-score matched (1:3) to patients not receiving a PCSK9 inhibitor. The primary endpoint was a composite of all-cause death, MI, or ischemic stroke. Four-year cumulative incidence was evaluated using observed rates in the matched cohort and using target-trial emulation with g-computation, both under an intention-to-treat framework. The confounder set for g-computation comprised all baseline characteristics (Table). Results A total of 4,008 patients were included in the study (1,008 alirocumab users and 3,000 matched comparators). Median (IQR) age was 66 (59-72) years in the alirocumab group and 66 (59-73) years in the comparator group, and 62% of alirocumab users versus 63% of comparators were male. Baseline median (IQR) LDL-C levels were 3.4 (2.6-4.3) mmol/L in the alirocumab group and 3.3 (2.5-4.4) mmol/L in the comparator group. Use of lipid-lowering therapy, including statin+ ezetimibe combination, was high in both groups (Table). At 4 years, the observed primary endpoint rate (95%CI) was 9.5% (7.0-12.0%) with alirocumab versus 15.5% (13.8-17.0%) without a PCSK9 inhibitor, with an absolute risk reduction (ARR) of 6.0% (3.0-9.0%; p<0.001) and relative risk reduction (RRR) of 38.7% (18.7-58.7%; p<0.001); (Figure 1A). Using g-computation, the 4-year primary endpoint rate (95%CI) was 9.4% (7.6-11.5%) with alirocumab versus 15.3% (13.9-17.0%) without a PCSK9 inhibitor, with ARR of 5.9% (3.3%-8.2%; p<0.001) and RRR of 38.6% (21.0-50.7%; p<0.001); (Figure 1B). Conclusions In this population-based cohort of patients with ASCVD without prior acute ischemic events, alirocumab was associated with lower 4-year risk of all-cause death, MI, or ischemic stroke, supporting the clinical value of alirocumab in these patients and complementing recent randomized trial evidence.KM