Key Points
• In the randomized EZ-PAVE trial, an LDL C target of <55 mg/dL significantly reduced the 3-year risk of major cardiovascular events compared with a target of <70 mg/dL in patients with ASCVD.
• The primary composite endpoint occurred in 6.6% of patients in the intensive targeting group versus 9.7% in the conventional targeting group, yielding a hazard ratio of 0.67 with P = 0.002.
• More intensive LDL C lowering was not associated with major safety concerns, with similar rates of most prespecified safety endpoints between groups.
The Ez-PAVE trial was presented at ACC 2026 with simultaneous publication in New England Journal of Medicine. It was an investigator initiated, multicenter, randomized, open label superiority trial conducted across 17 sites in South Korea. A total of 3,048 patients with documented ASCVD underwent 1 to 1 randomization to either 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). Lipid lowering therapy was adjusted to achieve assigned LDL C goals, with statin up titration and ezetimibe recommendation before PCSK9 inhibitor use. The primary endpoint was a 3-year composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, any revascularization, or hospitalization for unstable angina.
The two groups were well balanced at baseline. Median LDL C levels were 77 mg/dL in the intensive targeting group and 75 mg/dL in the conventional group, while diabetes was present in 39.6% of patients in both groups. During follow up, LDL C separation between treatment arms was achieved early and remained consistent. By 36 months, median LDL C was 52 mg/dL in the intensive group and 66 mg/dL in the conventional group. At the same time point, 60.8% of patients in the intensive group had achieved LDL C <55 mg/dL compared with 24.2% in the conventional group.
At 3 years, the primary endpoint occurred in 6.6% of patients assigned to intensive targeting versus 9.7% of those assigned to conventional targeting, corresponding to a 33% relative risk reduction with a hazard ratio of 0.67 and a 95% confidence interval of 0.52 to 0.86. The difference was statistically significant by log rank testing (P = 0.002). Several secondary outcomes also favored intensive LDL C lowering. Nonfatal myocardial infarction occurred in 0.8% of the intensive group compared with 1.7% of the conventional group. Any revascularization occurred in 4.8% versus 7.5%, respectively. In addition, the composite of cardiovascular death, nonfatal MI, or nonfatal stroke was lower with intensive targeting, occurring in 2.3% versus 3.6% of patients.
With respect to safety, the investigators reported no major safety penalty associated with the lower LDL C goal. Rates of new onset diabetes, worsening glycemic control, statin associated muscle symptoms, cancer diagnosis, cataract surgery, aminotransferase elevation, and creatine kinase elevation were similar between groups. Creatinine elevation greater than 1.5 times baseline was less frequent in the intensive targeting arm, occurring in 1.2% of patients compared with 2.7% in the conventional arm.
The investigators noted several limitations, including the open label design, lower than expected event rates, incomplete LDL C target attainment in a substantial proportion of intensively treated patients, limited use of PCSK9 inhibitors, lack of newer non statin therapies during the study period, and enrollment limited to East Asian patients. Even so, Ez-PAVE offers timely randomized support for more aggressive LDL C lowering in secondary prevention and reinforces contemporary guideline recommendations favoring lower LDL C thresholds in patients with ASCVD.