Upfront combination lipid-lowering therapy in statin-naive acute coronary syndrome patients with high admission LDL-C: real-world support for the 2025 ESC dyslipidaemias guidelines

Abstract

The 2025 ESC/EAS Focused Update on the Management of Dyslipidaemias recommends initiating combination therapy with a high-intensity statin plus ezetimibe during the index hospitalization for acute coronary syndrome (ACS) in lipid-lowering therapy (LLT)-naive patients unlikely to achieve LDL-C goals with monotherapy. This Class IIa recommendation upgrades the previous IIb advice, targeting patients with high baseline LDL-C levels. This study aims to identify the proportion of ACS patients eligible for this upfront strategy specifically based on high admission LDL-C, and to evaluate its real-world efficacy in achieving the therapeutic target (<55 mg/dL). This is a prospective, observational, single-centre study of consecutive ACS patients from the CARTACS registry. We analyzed 923 patients admitted for ACS with confirmed coronary disease and Friedewald-calculated in-hospital LDL-C measurements between July 2023 and August 2025. "LDL-driven Predicted Monotherapy Failure" (LDL-PMF) was defined as an admission LDL-C >110 mg/dL in LLT-naive patients, representing the threshold where the expected ≈50% reduction from high-intensity statin monotherapy fails to reach the <55 mg/dL target. A binary logistic regression model was used to identify independent predictors of achieving the LDL-C target after 3 months of follow-up. A total of 444 patients (48%) were LLT-naive. Within this naive cohort, 211 (48%) met the criteria for LDL-PMF (LDL-C >110 mg/dL). In this specific subgroup, 85 (40%) received statin monotherapy, 124 (59%) received combination therapy (high-intensity statin + ezetimibe) at discharge, and 2 (1%) received alternative LLT regimens. Patients on combination therapy achieved significantly lower follow-up LDL-C levels (47 [39–62] vs. 65 [55–86] mg/dL; p < 0.001) and a higher rate of target achievement (65% vs. 27%; p < 0.001) than those on monotherapy. In the multivariable analysis (Table), ezetimibe use was the strongest independent predictor of reaching the target (OR 6.17, 95% CI: 2.78–13.71; p < 0.001). Nearly half of LLT-naive ACS patients are at high risk of monotherapy failure based on their high admission LDL-C levels. Our findings strongly support the 2025 ESC/EAS Guidelines update: in patients with LDL-PMF, adding ezetimibe to high-intensity statins at discharge significantly increases the likelihood of achieving the <55 mg/dL target compared to monotherapy.TableFigure