Target-Oriented Strategy of Ultra-Low LDL-C (<1.0 vs. 1.0-1.39 mmol/L) in Extreme-High-Risk ASCVD Patients: Clinical Benefit, Safety and Cost-Effectiveness Assessment (TARGET-EXTREME)

Target-Oriented Strategy of Ultra-Low LDL-C Goal in Extreme-High-Risk ASCVD Patients (<1.0 vs. 1.0-1.39 mmol/L): Clinical Benefit, Safety and Cost-Effectiveness Assessment- A Multicenter, Prospective, Randomized, Open-Label, Blinded-Endpoint Adaptive Trial

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

Study Overview

• Status: Not yet recruiting
• Conditions: Atherosclerotic Cardiovascular Disease (ASCVD)
• Intervention / Treatment: Drug: Lipid-lowering therapy targeting LDL-C <1.0 mmol/L; Drug: Lipid-lowering therapy targeting LDL-C 1.0-1.39 mmol/L

• Study Type: Interventional
• Enrollment (Estimated): 6000
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Hai Gao, MD; Phone Number: +86 13901015971; Email: gaohai1221@mail.ccmu.edu.cn

Study Locations

• China
  • Beijing Municipality
    • Beijing, Beijing Municipality, China, 100029
      • Beijing AnZhen Hospital, Capital Medical University
      • Contact: Hai Gao, MD; Phone Number: +86 13901015971; Email: gaohai1221@mail.ccmu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Aged 18-80 years, any sex.
2. 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).
3. LDL-C ≥1.0 mmol/L after ≥4-week maximum-tolerated statin plus ezetimibe therapy, confirmed by central laboratory.
4. Able to complete follow-up and examinations; no severe hepatic/renal dysfunction.
5. Voluntary participation with written informed consent.

Exclusion Criteria:

1. Hypersensitivity or intolerance to statins, ezetimibe, or PCSK9 inhibitors.
2. Hemorrhagic stroke, active bleeding, severe trauma or major surgery within 6 months before enrollment.
3. Malignancy (expected survival <3 years), severe liver/kidney disease, or autoimmune disease.
4. Cognitive impairment (MoCA <20) or psychiatric disorders precluding assessment cooperation.
5. Pregnant, breastfeeding, or planning pregnancy during the trial.
6. Participation in other clinical trials or use of other lipid-lowering drugs within 3 months.
7. Poor compliance or other conditions judged by investigators to interfere with the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ultra-low LDL-C target group; Participants receive statin-ezetimibe-based lipid-lowering therapy with mandatory titration algorithm, adding PCSK9 inhibitor sequentially to achieve LDL-C <1.0 mmol/L.	Drug: Lipid-lowering therapy targeting LDL-C <1.0 mmol/L; Statin-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.
Active Comparator: Moderate-low LDL-C target group; Participants maintain statin-ezetimibe therapy; dose reduction is enforced if LDL-C <1.0 mmol/L to keep level within 1.0-1.39 mmol/L.	Drug: Lipid-lowering therapy targeting LDL-C 1.0-1.39 mmol/L; Standard 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major Adverse Cardiovascular Events-4 (MACE-4)	Composite endpoint including cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, and urgent coronary revascularization.	Median 2 years, up to 5 years from randomization

Secondary Outcome Measures

Outcome Measure	Time Frame
All-cause mortality	Median 2 years, up to 5 years post-randomization
Major Adverse Cardiovascular Events-3 (MACE-3)	Median 2 years, up to 5 years post-randomization
individual components of MACE-4	Median 2 years, up to 5 years post-randomization
LDL-C target achievement rate	Median 2 years, up to 5 years post-randomization

Collaborators and Investigators

• Sponsor: Beijing Anzhen Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2027
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): December 31, 2031

Study Registration Dates

• First Submitted: May 23, 2026
• First Submitted That Met QC Criteria: May 23, 2026
• First Posted (Actual): May 29, 2026

Study Record Updates

• Last Update Posted (Actual): May 29, 2026
• Last Update Submitted That Met QC Criteria: May 23, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Extreme-high-risk ASCVD, LDL-C target, Ultra-low LDL-C, Lipid-lowering therapy
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis
• Other Study ID Numbers: LIPID-2026-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No