The goal of this clinical trial is to learn whether an ultra-low LDL-C target (\<1.0 mmol/L) can improve clinical outcomes compared with a moderately low LDL-C target (1.0-1.39 mmol/L) in Chinese patients with extreme-high-risk atherosclerotic cardiovascular disease (ASCVD). It also aims to evaluate long-term safety and cost-effectiveness, and explore potential benefit subgroups and underlying mechanisms. The main questions it aims to answer are:
Does an LDL-C target \<1.0 mmol/L reduce major adverse cardiovascular events (MACE-4: cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, urgent coronary revascularization) compared with a target of 1.0-1.39 mmol/L?What are the long-term safety risks including cognitive decline, hemorrhagic stroke, new-onset diabetes, new malignancies and severe adverse drug reactions under different LDL-C targets?Researchers will compare participants receiving an LDL-C target \<1.0 mmol/L with those receiving a target of 1.0-1.39 mmol/L to see if the ultra-low LDL-C strategy provides better clinical benefit with acceptable safety and economic value.
Participants will:
Receive lipid-lowering therapy following a mandatory titration-maintenance-off-target correction algorithm according to their assigned LDL-C target Undergo routine follow-up every 3 months, cognitive assessment every 6 months, and comprehensive annual re-examinations for a median of 2 years and up to 5 years Have centralized blinded lipid testing and endpoint adjudication by an independent Clinical Event Committee
Aged 18-80 years, any sex.
Diagnosed with ultra-high-risk ASCVD per 2023 Chinese Lipid Guidelines: either ≥2 major ASCVD events within 24 months, or 1 major ASCVD event plus ≥2 high-risk factors (diabetes, multi-vessel disease, premature CHD family history, elevated Lp(a), hypertension).
LDL-C ≥1.0 mmol/L after ≥4-week maximum-tolerated statin plus ezetimibe therapy, confirmed by central laboratory.
Able to complete follow-up and examinations; no severe hepatic/renal dysfunction.
Hypersensitivity or intolerance to statins, ezetimibe, or PCSK9 inhibitors.
Hemorrhagic stroke, active bleeding, severe trauma or major surgery within 6 months before enrollment.
Malignancy (expected survival <3 years), severe liver/kidney disease, or autoimmune disease.
Cognitive impairment (MoCA <20) or psychiatric disorders precluding assessment cooperation.
Parallel
Lipid-lowering therapy targeting LDL-C <1.0 mmol/L
DrugStatin-ezetimibe-based lipid-lowering therapy with mandatory titration-maintenance-off-target correction algorithm. PCSK9 inhibitor is sequentially added and dose-adjusted based on centralized blinded lipid test results to achieve LDL-C level \<1.0 mmol/L.
Lipid-lowering therapy targeting LDL-C 1.0-1.39 mmol/L
DrugStandard statin-ezetimibe lipid-lowering therapy. Mandatory dose reduction (discontinue ezetimibe → halve statin → discontinue statin) will be performed if LDL-C drops below 1.0 mmol/L, to maintain LDL-C within 1.0-1.39 mmol/L.
Major Adverse Cardiovascular Events-4 (MACE-4)
Composite endpoint including cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, and urgent coronary revascularization.
All-cause mortality
Major Adverse Cardiovascular Events-3 (MACE-3)
individual components of MACE-4
LDL-C target achievement rate
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