Benefit of upfront combination lipid-lowering therapy in statin-naïve acute coronary syndrome patients with intermediate admission LDL-C and Lp(a)-driven predicted monotherapy failure

Background The 2025 ESC/EAS Focused Update on the Management of Dyslipidaemias recommends upfront combination therapy (high-intensity statin + ezetimibe) during index hospitalization for acute coronary syndrome (ACS) in lipid-lowering therapy (LLT)-naïve patients unlikely to achieve LDL-C goals with monotherapy. Elevated lipoprotein(a) [Lp(a)] contributes a fixed cholesterol fraction that is largely unresponsive to statins. Consequently, in patients with intermediate admission LDL-C, high Lp(a) levels could identify a subgroup with a low probability of achieving therapeutic targets with statin monotherapy. Purpose To identify the proportion of LLT-naïve ACS patients eligible for upfront combination therapy due to Lp(a)-driven predicted monotherapy failure (Lp(a)-PMF), and to evaluate the real-world benefit of this strategy in achieving the absolute therapeutic target (LDL-C <55 mg/dL). Methods This prospective, single-centre study analysed 649 consecutive ACS patients from the CARTACS registry (July 2023–August 2025) with measured Lp(a) and estimated LDL-C at admission. We estimated Lp(a)-cholesterol [Lp(a)-C] using the Rosenson equation (Lp(a) nmol/L × 0.077). In LLT-naïve patients with intermediate admission LDL-C (55–110 mg/dL), Lp(a)-PMF was defined as [Admission LDL-C + Lp(a)-C] >110 mg/dL, representing the threshold at which an expected ~50% LDL-C reduction with high-intensity statin monotherapy would fail to achieve the <55 mg/dL target. Given that guideline targets are dual (≥50% reduction and <55 mg/dL), we prioritized the absolute goal, as the fixed Lp(a)-cholesterol fraction is largely unresponsive to statins and may limit the achievable relative LDL-C reduction despite adequate response of the modifiable LDL fraction. We compared 3-month absolute target attainment (<55 mg/dL) between upfront combination therapy and statin monotherapy according to Lp(a)-PMF status. Results Of 649 ACS patients, 314 (48%) were LLT-naïve; 116 had intermediate admission LDL-C (55–110 mg/dL). Among them, 23 (20%) met criteria for Lp(a)-PMF, while 93 (80%) did not (figure 1). In the Lp(a)-PMF subgroup, upfront combination therapy (n=7) showed higher target attainment than statin monotherapy (85.7% vs. 31.3%; p=0.027) despite similar baseline levels of LDL-C and Lp(a) (both p>0.4). Conversely, without Lp(a)-PMF, statin monotherapy (n=76) achieved the target in 60.5%, with a non-significant increase with upfront ezetimibe (n=17; 76.5%; p=0.273; Figure 2). Conclusions One in five LLT-naïve ACS patients with intermediate admission LDL-C have a high predicted risk of statin monotherapy failure based on their Lp(a) burden. Integrating Lp(a) concentration with LDL-C may help identify patients who derive greater benefit from upfront combination therapy versus statin monotherapy.