Intensive Lipid-lowering for Plaque and Major Adverse Cardiovascular Events in Low to Intermediate 10-year ASCVD Risk Population

Study Overview
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Brief Summary
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Current guidelines recommend moderate-intensity lipid-lowering therapy (goal for LDL-C <2.6 mmol/L or 30%-50% reduction from baseline) for patients with intermediate 10-year ASCVD risk. In these patients, early coronary atherosclerotic plaques (luminal stenosis<50%) detected by coronary CT angiography are common, but further interventions are lacking. This study aims to analyze whether intensive lipid-lowering therapy (goal for LDL-C <1.8 mmol/L or ≥50% reduction from baseline) could delay the progression of coronary atherosclerotic lesions and reduce the adverse cardiovascular events in these target patients.

Detailed Description
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Both American (2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease) and European (2019 ESC/EAS Guidelines for the management of dyslipidemias) guidelines currently recommended moderate-intensity lipid-lowering (goal for LDL-C <2.6 mmol/L or 30%-50% reduction from baseline) for primary prevention in the population at intermediate (or borderline) 10-year ASCVD risk, but the residual risk in this group of the population remains to be explored, especially in a subset with only nonobstructive atherosclerotic plaques(luminal stenosis<50%) detected by CCTA, for whom further risk stratification and precise interventions for primary prevention are lacking. CCTA could show accurate images of patients' early coronary atherosclerotic lesions, and provides a wealth of image-based anatomical and functional information including plaque burden (total plaque volume, calcification score, segment involvement score, etc.), plaque composition, high-risk plaque characteristics, luminal stenosis, and CT-FFR. With this complete imaging information on CCTA, there is an urgent need to investigate primary prevention strategies and the evidence-based rationale for performing precise risk stratification in low to intermediate risk populations with nonobstructive coronary atherosclerotic lesions using CCTA. A prospective, randomized, open-label, blinded endpoint analysis (PROBE) will be conducted in the population at clinical low to intermediate 10-year ASCVD risk with nonobstructive coronary atherosclerotic lesions, predominantly non-calcified plaques detected by CCTA. And the purpose of this study is to demonstrate that intensive lipid-lowering could slow down plaque progression and reduce the incidence of MACE in the target population, which provides an evidence-based rationale for further risk re-stratification. Enrolled people will be randomized into the intervention group (goal for LDL-C <1.8 mmol/L or ≥50% reduction from baseline) and control group (goal for LDL-C <2.6 mmol/L or 30%-50% reduction from baseline).

Official Title
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Effects of Intensive Lipid-lowering on Coronary Atherosclerotic Plaque Phenotype and Major Adverse Cardiovascular Events in Adults With Low to Intermediate 10-year ASCVD Risk: a Prospective, Randomized, Open-label, Blinded Endpoint Analysis(PROBE)

Conditions
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Coronary Artery Disease Progression

Intervention / Treatment
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* Drug: Intensive lipid-lowering control
* Drug: Moderate-intensity lipid-lowering control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 40-75 years Low to Intermediate 10-year atherosclerotic cardiovascular disease (ASCVD) risk by using pooled cohort equations (PCE). Coronary CT angiography shows atherosclerotic plaque in the main coronary vessels (>2mm diameter) with luminal stenosis <50% Exclusion Criteria: Combination with serious cardiovascular diseases, including Heart failure (ejection fraction <30%) Arrhythmias (persistent atrial flutter/atrial fibrillation, second-degree or third-degree atrioventricular block) Hemodynamically important valvular disease Hemodynamically important congenital heart disease Stroke Myocardial infarction, coronary revascularization, or severe/unstable angina before or within 1 month of screening Active liver disease or hepatic dysfunction (defined as alanine aminotransferase or aspartate aminotransferase> 3 times the upper limit of normal) Unexplained creatine phosphokinase> 6 times the upper limit of normal Nephrotic syndrome Diabetes mellitus Uncontrollable hypertension Uncontrollable hypothyroidism Hypersensitivity to statins Any planned surgical procedure for the treatment of atherosclerosis Gastrointestinal diseases affecting drug absorption or history of gastrointestinal surgery Survival-limiting diseases Concurrent long-term immunosuppressive therapy Participation in another clinical trial concurrently or within 30 days before screening Pregnant or breastfeeding Other unsuitable situations deemed by physicians

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: intensive lipid-lowering group<br>Goal for LDL-C <1.8 mmol/L or ≥50% reduction from baseline. | Drug: Intensive lipid-lowering control<br>* The initial recommended therapy is 10-20mg atorvastatin plus Ezetimibe, and the type and dosage of drugs can be adjusted according to the situation.<br>* Other names: Lower goal for reducing LDL-C;|
| Active Comparator: moderate-intensity lipid-lowering group<br>Goal for LDL-C <2.6 mmol/L or 30%-50% reduction from baseline. | Drug: Moderate-intensity lipid-lowering control<br>* The initial recommended therapy is 10-20mg atorvastatin, and the type and dosage of drugs can be adjusted according to the situation.<br>* Other names: Standard goal for reducing LDL-C;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major Adverse Cardiovascular Events (MACE) | Composite of all-cause death, non-fatal MI, non-fatal stroke, any revascularization, and hospitalization for angina | Within 3 years after the enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in coronary total plaque volume(mm³) on CCTA | Total plaque volume(mm³) is defined as the sum of all plaque volumes for coronary arteries. | Within 3 years after the enrollment | 
| Change in coronary plaque burden(%) on CCTA | Plaque burden(%)=(plaque area/vessel area)×100% | Within 3 years after the enrollment | 
| Changes in coronary plaque compositions(mm³, %) on CCTA | Plaque compositions include lipid(<30 HU), fibrous(30-150HU), and calcified plaque(>350HU). | Within 3 years after the enrollment | 
| Changes in coronary high-risk plaque characteristics on CCTA | High-risk plaque characteristics are defined as positive remodeling(remodeling index, >1.1), low CT attenuation (mean CT number <30 HU), spotty calcification(punctate calcium within a plaque measuring less than 3 mm in all dimensions), or napkin-ring sign (a ringlike peripheral higher attenuation with central low CT attenuation). | Within 3 years after the enrollment | 
| Change in coronary artery calcium score (CACS) on CT | CACS is a quantification of all coronary calcification by the scoring algorithm proposed by Agatston et al. | Within 3 years after the enrollment |