Intensive LDL-C Lowering Below 55 mg/dL versus Conventional Targets in Established ASCVD

Background: Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of death worldwide, and low-density lipoprotein cholesterol (LDL-C) is its most modifiable risk factor. International guidelines recommend targeting LDL-C below 55 mg/dL in patients with established ASCVD; however, until the recent Ez-PAVE trial, no randomized controlled trial (RCT) had directly compared the clinical outcomes of targeting LDL-C <55 mg/dL versus <70 mg/dL in a head-to-head design. Objectives: To determine whether intensive LDL-C lowering strategies achieving target levels <55 mg/dL reduce the incidence of major adverse cardiovascular events (MACE) compared with standard or moderate strategies achieving LDL-C ~70 mg/dL in patients with established ASCVD. Methods: We systematically searched PubMed/MEDLINE, EMBASE, Cochrane CENTRAL, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform from inception through April 2026, without language restriction. We included RCTs enrolling adults with established ASCVD that compared intensive LDL-C lowering strategies (target or achieved LDL-C <55-60 mg/dL) versus standard strategies (target or achieved LDL-C ~70 mg/dL) and reported clinical cardiovascular outcomes. Two reviewers had screened independently, extracted data, and assessed the risk of bias using RoB 2.0. The primary outcome is MACE. Secondary outcomes include cardiovascular mortality, all-cause mortality, non-fatal MI, non-fatal stroke, revascularization, and adverse events. A random-effects model has been used. Heterogeneity is assessed using I 2 . Results: Five eligible RCTs were identified: IMPROVE-IT (n=18,144), FOURIER (n=27,564), ODYSSEY OUTCOMES (n=18,924), RACING (n=3,780), and Ez-PAVE (n=3,048), encompassing a total of 71,460 patients with established ASCVD. Intensive LDL-C lowering significantly reduced the primary endpoint of MACE (HR 0.87 [95% CI: 0.80-0.94]; P=0.0008; I 2 =69%), coronary revascularization (HR 0.86 [0.77-0.97]; P=0.01; I 2 =74%), non-fatal MI (HR 0.81 [0.72-0.91]; P=0.0004; I 2 =67%), and non-fatal stroke (HR 0.77 [0.69-0.86]; P<0.00001; I 2 =0%). Cardiovascular mortality (HR 0.98 [0.90-1.07]; P=0.64; I 2 =0%) and all-cause mortality (HR 0.93 [0.83-1.05]; P=0.24; I 2 =58%) were not significantly different between groups. The most recently completed trial, Ez-PAVE, achieving the lowest mean LDL-C (~38 mg/dL), showed the largest point estimate of benefit across all ischemic endpoints. Safety profiles were broadly acceptable across all trials. Conclusions: This meta-analysis provides the most comprehensive and updated synthesis of evidence supporting intensive LDL-C lowering in ASCVD. These findings support current guideline recommendations to target LDL-C below 55 mg/dL and reinforce the idea that lower levels are beneficial in secondary prevention.