Intensive LDL Cholesterol Targeting in Atherosclerotic Cardiovascular Disease
In patients with established atherosclerotic cardiovascular disease, aiming for low-density lipoprotein cholesterol under 55 mg/dL lowered 3-year cardiovascular events versus under 70 mg/dL, with similar overall safety.
*Open-label randomized superiority trial; Level 1b (OCEBM).
*Open-label randomized superiority trial; Level 1b (OCEBM).
Citation
Lee Y-J, Lee S-J, Kim JW, et al.; Ez-PAVE Investigators. Intensive LDL Cholesterol Targeting in Atherosclerotic Cardiovascular Disease. N Engl J Med. 2026;394:1365-1375. doi:10.1056/NEJMoa2600283.
Background
Guidelines recommend very low “bad” cholesterol goals for secondary prevention, but direct randomized evidence comparing specific targets has been limited. This trial tested whether a stricter target improves outcomes in people with known atherosclerotic cardiovascular disease.
Patients
3048 adults (19–80 years) in South Korea with documented atherosclerotic cardiovascular disease (e.g., prior heart attack or unstable angina, stable angina with testing, prior artery revascularization, stroke or transient ischemic attack, or peripheral artery disease). Key exclusion: low-density lipoprotein cholesterol <70 mg/dL while not taking a statin.
Intervention
Treat-to-target low-density lipoprotein cholesterol <55 mg/dL using statins and other lipid-lowering medicines as needed.
Control
Treat-to-target low-density lipoprotein cholesterol <70 mg/dL.
Outcome
Primary: composite of cardiovascular death, nonfatal heart attack, nonfatal stroke, any revascularization, or hospitalization for unstable angina. Safety outcomes included diabetes-related measures and lab abnormalities.
Follow-up Period
Median 3.0 years.
Results
| Outcome (3-year cumulative incidence) | <55 mg/dL target | <70 mg/dL target | Hazard ratio (95% confidence interval) | NNT |
|---|---|---|---|---|
| Primary composite (primary) | 6.6% | 9.7% | 0.67 (0.52 to 0.86) | 33 |
| Nonfatal heart attack | 0.8% | 1.7% | 0.46 (0.23 to 0.91) | 112 |
| Any revascularization | 4.8% | 7.5% | 0.63 (0.47 to 0.84) | 38 |
Analyses were intention-to-treat. Prespecified safety outcomes were similar overall; creatinine elevation occurred less often with the <55 mg/dL target (1.2% vs 2.7%).
Limitations
Open-label design may have influenced decisions about revascularization (part of the primary composite). Event rates were lower than expected, and 39% of the intensive-target group did not reach the <55 mg/dL goal by 3 years. Conducted only in East Asian patients; longer-term results are unknown. Absolute benefit was modest (NNT 33 over 3 years).
Funding
Cardiovascular Research Center (South Korea) and Yuhan; funders reported no trial role.
Clinical Application
For secondary prevention, consider treating to low-density lipoprotein cholesterol <55 mg/dL using combination therapy when needed, balancing cost, access, and patient tolerance.
Discussion
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In this open-label randomized superiority trial, intensive LDL targeting <55 mg/dL versus <70 mg/dL reduced the 3-year composite cardiovascular outcome (6.6% vs 9.7%; HR 0.67). How should the unblinded design, composite outcome, and South Korean population affect validity, applicability, and practice change? In this randomized trial, the primary outcome occurred in 6.6% of the intensive-targeting group and 9.7% of the conventional-targeting group, with HR 0.67. Which interpretation best distinguishes the absolute and relative treatment effects?