Low-density lipoprotein cholesterol (LDL-C) is a well-established, modifiable causal factor in atherosclerotic cardiovascular disease (ASCVD), and effective lipid-lowering treatment (LLT) remains central to secondary prevention strategies, particularly after acute coronary syndromes (ACS). According to the 2019 Europea Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines [1] and a recent guideline Focus Update [2], very high-risk patients, i.e. those with established ASCVD, should achieve LDL-C <55 mg/dL, along with a ≥50% reduction from baseline. For selected individuals at extreme cardiovascular risk—including those with polivascular disease, early recurrent events (< 2years), diabetes with organ damage, or familial hypercholesterolaemia—an LDL-C goal of <40 mg/dL has been recommended. According to the international guidelines, LLT should be a step-by-step process, with high intensity statin therapy representing the first step in patients with ASCVD, followed by combination therapy with ezetimibe, bempedoic acid, proprotein convertase subtilisin/kexin type 9 serine protease inhibitors (PCSK9i) or inclisiran, a PCSK9 silencing RNA messenger drugs.

Despite the intensive approach suggested by literature, real world data obtained after the publication of 2019 ESC/EAS guideline showed that only a minority of patients with ASCVD are at LDL-C target. The multinational DA VINCI study reported that only ∼18% of very-high-risk patients were at LDL-C < 55 mg/dL according to the 2019 ESC/EAS recommendations [3],[4]. Similar findings emerged from SANTORINI, where just 20–22% of high or very high risk patients were at target despite widespread statin use [5],[6]. The global INTERASPIRE study confirmed these gaps, with only 16.6% of coronary heart disease patients achieving LDL-C < 55 mg/dL one year after hospitalization, with a marked sex disparity (12% in women vs. 18% in men) [7]. Nationally, the Italian BRING-UP Prevention registry reported a higher but still suboptimal attainment rate of 32.6%, despite greater use of statins and ezetimibe, while PCSK9i and inclisiran remained under-utilized [8]. Complementing these findings, the ITACARE-P (Italian Alliance for Cardiovasculare Rehabilitation and Prevention) registry [9] offers a detailed picture of lipid management in Italian patients with ASCVD referred to structured cardiovascular rehabilitation and secondary prevention programs. In this cohort, 43% of very-high-risk patients achieved LDL-C < 55 mg/dL, whereas only 18% of those at extreme risk—defined by multiple recurrent events within 2 years—reached LDL-C < 40 mg/dL, despite >90% being on statins, 61% on ezetimibe, and 8% on PCSK9i. Among patients not at target, LLT was left unchanged in 51%, and even among those whose treatment was modified/intensified, only 42% were estimated to have received an adjustment sufficient to reach guideline-recommended LDL-C goals [9]. These data highlight a consistent treatment gap in the management of very high-risk patients across care settings, as a consequence of clinical inertia, and underscore the need for structured, decision-guided therapeutic strategies in clinical practice.

The present study aims to further characterize real-world LLT patterns within the cohort enrolled in the ITACARE-P registry, by performing a Monte Carlo simulation of stepwise LLT intensification among patients not at LDL-C goal. This approach was designed to estimate how adherence to evidence-based recommendations could translate into improved LDL-C target attainment in routine clinical practice. Building on the results of this simulation, we propose a pragmatic treatment algorithm that could be readily implemented in cardiovascular rehabilitation programs and secondary prevention outpatient clinics, with the ultimate goal of reducing clinical inertia and maximizing achievement of guideline-recommended LDL-C targets.