Assessing the Impact of Intensification of Lipid Lowering Therapy With Guidelines-based Evinacumab Administration on Coronary Plaque Volumes Measured by Coronary Computed Tomography Angiography (CCTA) in Patients With Homozygous Familial Hypercholesterolemia (HoFH)

This is a multicenter, international, non-profit, observational study with retrospective and prospective data collection evaluating the real-world impact of intensified lipid-lowering therapy including Evinacumab on coronary atherosclerosis in patients with Homozygous Familial Hypercholesterolemia (HoFH).

Background and Rationale

HoFH is characterized by markedly elevated LDL-C levels due to impaired LDL receptor function, leading to accelerated and diffuse atherosclerosis and early cardiovascular morbidity and mortality. Despite aggressive combination therapy (statins, ezetimibe, PCSK9 inhibitors, lomitapide, and lipoprotein apheresis), most patients fail to reach LDL-C targets.

Evinacumab is a fully human monoclonal antibody directed against ANGPTL3 and lowers LDL-C independently of LDL receptor activity. Clinical trials have demonstrated approximately 50% LDL-C reduction in HoFH patients. However, the effect of Evinacumab on coronary plaque burden and phenotype in real-world clinical practice has not been systematically evaluated.

Coronary computed tomography angiography (CCTA) allows non-invasive quantification of total plaque burden, differentiation of calcified and non-calcified plaque, and identification of high-risk plaque features. Imaging-based plaque assessment represents a validated surrogate of atherosclerosis progression and cardiovascular risk.

Study Design

This is a non-interventional, observational study conducted in approximately 25 European centers. The study includes both retrospective data (up to 30 months prior to enrollment) and prospective follow-up (up to 24 months).

Patients are allocated to cohorts based exclusively on routine clinical care decisions:

• Intensified Treatment Group: HoFH patients who initiated Evinacumab as add-on therapy to stable background lipid-lowering treatment within 24 months before enrollment.
• Conventional Treatment Group: HoFH patients receiving standard lipid-lowering therapy without Evinacumab, either due to lack of availability or clinical decision not to initiate treatment.

No therapeutic interventions are mandated or modified by the study protocol.

Study Population

Approximately 52 patients are expected to be enrolled (approximately 35 in the intensified treatment group and 17 in the conventional treatment group). Eligible patients must have a clinical or genetic diagnosis of HoFH and available baseline and follow-up CCTA scans performed according to routine clinical practice.

Objectives

Primary Objective:

To assess whether intensification of lipid-lowering therapy including Evinacumab is associated with stabilization or regression of coronary atherosclerotic plaques compared with conventional therapy, as measured by change in percent non-calcified plaque volume (NCPV) between baseline and follow-up CCTA.

Secondary Objectives:

• To evaluate changes in total plaque volume, calcified plaque volume, and percent atheroma volume.
• To assess changes in high-risk plaque characteristics (low-attenuation plaque, positive remodeling).
• To evaluate changes in LDL-C levels between groups.

Exploratory Objectives:

• To evaluate changes in patient-reported outcomes (SAQ-7, Rose Dyspnea Scale, PHQ-2).
• To assess changes in pericoronary adipose tissue (PCAT) attenuation in RCA and LAD.
• To characterize the presence and progression of supravalvular atherosclerosis.

Imaging Analysis

CCTA scans performed in routine care will be analyzed centrally using standardized, FDA-cleared artificial intelligence-based quantitative software. Blinded core laboratory analysis will ensure consistency across sites.

Statistical Considerations

The primary endpoint is the annualized change in percent NCPV from baseline to 18-24 months. Between-group comparisons will be performed using appropriate parametric or non-parametric tests. Secondary and exploratory endpoints will be analyzed descriptively and comparatively.

Safety

As a non-interventional study, safety data will be collected from routine clinical documentation. Treatment decisions remain under the responsibility of the treating physician.

Conclusion

This study will provide real-world imaging data on the effect of intensified lipid-lowering therapy including Evinacumab on coronary plaque burden and phenotype in HoFH patients. The findings may contribute to optimizing cardiovascular risk management strategies in this high-risk population.