An intensive targeting of low-density lipoprotein cholesterol (LDL-C) level (<55 mg/dL) reduces the risk of cardiovascular events at 3 years in patients with atherosclerotic cardiovascular disease (ASCVD) when compared with conventional targeting (<70 mg/dL), results of the Ez-PAVE trial have shown.
“The Ez-PAVE trial adds practical and clinically meaningful evidence by demonstrating that, in patients with ASCVD, targeting an LDL-C level of <55 mg/dL leads to a significantly lower 3-year risk of major cardiovascular events compared with the conventional target of 70 mg/dL, without compromising safety,” said lead study author Dr Byeong-Keuk Kim, director of the Cardiac Catheterization and Intervention Department and professor in the Division of Cardiology at Severance Hospital, Yonsei University College of Medicine in Seoul, South Korea, in a press statement.
A total of 3,048 patients with ASCVD were randomly allocated in a 1:1 ratio to a target LDL-C level of <55 mg/dL (intensive-targeting group; n=1,526) or <70 mg/dL (conventional-targeting group; n=1,522). During the trial, the median LDL-C level was 56 mg/dL in the intensive-targeting group and 66 mg/dL in the conventional-targeting group. [N Engl J Med 2026;doi:10.1056/NEJMoa2600283]
Over a median follow-up of 3 years, the primary endpoint of a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, any revascularization, or hospitalization for unstable angina at 3 years after randomization occurred in 100 patients in the intensive-targeting group and in 147 individuals in the conventional-targeting group (cumulative incidence, 6.6 percent vs 9.7 percent; hazard ratio, 0.67, 95 percent confidence interval, 0.52‒0.86; p=0.002).
With regard to safety, the incidence of new-onset diabetes (among patients without diabetes at baseline), worsening of glycaemic control (among patients with diabetes at baseline), statin-associated muscle symptoms leading to changes in therapy dose or regimen, cancer diagnosis, cataract surgery, and elevation of the aminotransferase or creatine kinase level did not differ between the two groups, except for creatinine elevation, which had a lower incidence in the intensive-targeting group.
These findings remained consistent in subgroup analyses.
“The consistency across the overall population and key subgroups suggests that the benefit of targeting LDL-C lower than 55 mg/dL is broadly applicable across the spectrum of patients with ASCVD and is not limited to specific patient subsets,” said Kim, adding that these results are vital for patients at greater risk of cardiovascular events, for whom lower LDL-C targets are currently recommended.
Challenging
In previous studies, intravascular imaging demonstrated the efficacy of a more aggressive cholesterol-lowering therapy with high-intensity statins, ezetimibe, or PCSK9 inhibitors in slowing atherosclerosis progression and promoting plaque regression. [JAMA 2004;291:1071-1080; J Am Coll Cardiol 2015;66:495-507; JAMA 2022;327:1771-1781]
However, achieving an LDL-C level of <55 mg/dL remains a challenge, highlighting the need for more rigorous efforts, such as earlier and broader use of PCSK9 inhibitors, according to Kim and colleagues.
Furthermore, real-world data show a bleaker picture, with fewer than one in four patients with ASCVD achieving an LDL-C level of <55 mg/dL, fewer than 10 percent receiving ezetimibe, and about 1 percent receiving PCSK9 inhibitors. [Eur J Prev Cardiol 2021;28:1279-1289; Am Heart J 2025;279:107-117]
“The present findings support intensifying LDL cholesterol–lowering therapy through the active use of ezetimibe and additional nonstatin agents,” said Kim and colleagues. [N Engl J Med 2015;372:2387-2397; Eur Heart J 2025;46:4359-4378; J Am Coll Cardiol 2022;80:1366-1418; N Engl J Med 2026;394:117-127]
“With the most recent guidelines endorsing a target LDL-C level of <40 mg/dL for patients at extreme risk, the proactive role of nonstatin agents, including early combination therapy with ezetimibe, warrants further dedicated investigation,” they added.