Intensive LDL Cholesterol Targeting in Atherosclerotic Cardiovascular Disease

N Engl J Med. 2026 Apr 9;394(14):1365-1375. doi: 10.1056/NEJMoa2600283. Epub 2026 Mar 28.

Abstract

Background: Despite guideline recommendations, evidence from randomized trials evaluating the appropriate low-density lipoprotein (LDL) cholesterol target for secondary prevention in patients with atherosclerotic cardiovascular disease remains limited.

Methods: In this open-label superiority trial conducted in South Korea, we randomly assigned patients with atherosclerotic cardiovascular disease in a 1:1 ratio to a target LDL cholesterol level of less than 55 mg per deciliter (1.4 mmol per liter) (intensive-targeting group) or less than 70 mg per deciliter (1.8 mmol per liter) (conventional-targeting group). The primary end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, any revascularization, or hospitalization for unstable angina at 3 years. Safety was also assessed.

Results: Of 3048 patients who underwent randomization, 1526 were assigned to the intensive-targeting group and 1522 to the conventional-targeting group. The median follow-up was 3.0 years. The median LDL cholesterol level during the trial was 56 mg per deciliter (1.4 mmol per liter) in the intensive-targeting group and 66 mg per deciliter (1.7 mmol per liter) in the conventional-targeting group. A primary end-point event occurred in 100 patients (Kaplan-Meier estimate of cumulative incidence, 6.6%) in the intensive-targeting group and in 147 patients (Kaplan-Meier estimate of cumulative incidence, 9.7%) in the conventional-targeting group (hazard ratio, 0.67; 95% confidence interval, 0.52 to 0.86; P = 0.002). The incidence of prespecified safety end points was similar in the two trial groups, except for a lower incidence of creatinine elevation in the intensive-targeting group.

Conclusions: Among patients with atherosclerotic cardiovascular disease, targeting an LDL cholesterol level of less than 55 mg per deciliter resulted in a lower risk of cardiovascular events at 3 years than targeting a level of less than 70 mg per deciliter. (Funded by the Cardiovascular Research Center and Yuhan; Ez-PAVE ClinicalTrials.gov number, NCT04626973.).

Publication types

  • Randomized Controlled Trial
  • Multicenter Study
  • Equivalence Trial

MeSH terms

  • Aged
  • Anticholesteremic Agents* / adverse effects
  • Anticholesteremic Agents* / therapeutic use
  • Atherosclerosis* / blood
  • Atherosclerosis* / drug therapy
  • Atherosclerosis* / mortality
  • Atherosclerosis* / surgery
  • Cardiovascular Diseases* / blood
  • Cardiovascular Diseases* / epidemiology
  • Cardiovascular Diseases* / mortality
  • Cardiovascular Diseases* / prevention & control
  • Cardiovascular Surgical Procedures / statistics & numerical data
  • Cholesterol, LDL* / blood
  • Disease Progression
  • Drug Therapy, Combination / adverse effects
  • Drug Therapy, Combination / methods
  • Ezetimibe / adverse effects
  • Ezetimibe / therapeutic use
  • Female
  • Follow-Up Studies
  • Hospitalization / statistics & numerical data
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors* / adverse effects
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors* / therapeutic use
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Practice Guidelines as Topic
  • Recurrence
  • Republic of Korea / epidemiology
  • Secondary Prevention* / methods
  • Secondary Prevention* / standards
  • Treatment Outcome

Substances

  • Anticholesteremic Agents
  • Cholesterol, LDL
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Ezetimibe

Associated data

  • ClinicalTrials.gov/NCT04626973