More intensive use of cholesterol-lowering drugs to achieve a more aggressive target for low-density lipoprotein cholesterol (LDL-C) reduced the rate of major cardiovascular events by one-third among patients with atherosclerotic cardiovascular disease (ASCVD).
The results help fill an evidence gap in guiding treatment for patients with heart disease who are at high risk of major cardiac events. Although guidelines have lowered the recommended LDL-C goal for patients with ASCVD from less than 70 mg/dL to less than 55 mg/dL, evidence supporting this recommendation was limited. The new trial, called Ez-PAVE, is the first randomized, head-to-head comparison of these two LDL-C targets in patients with ASCVD.
The Ez-PAVE trial adds practically and clinically relevant evidence by demonstrating that, in patients with ASCVD, targeting an LDL-C level of less than 55 mg/dL results in a significantly lower three-year risk of major CVD compared with the conventional target of 70 mg/dL, without compromising safety.
Byeong-Keuk Kim, MD, director of the Division of Cardiac Catheterization and Intervention and professor in the Department of Cardiology at Severance Hospital, Yonsei University College of Medicine in Seoul, South Korea, and lead author of the study
ASCVD is a type of heart disease in which plaque builds up in the artery walls. LDL-C contributes to plaque build-up. Treatments that lower LDL-C can help slow the buildup of plaque in artery walls and reduce the chance that the plaques will break and cause serious events, such as heart attacks and strokes. However, most previous studies have focused on evaluating outcomes from various LDL-C-lowering therapies rather than evaluating the optimal LDL-C level to target with those therapies, Kim said.
The researchers enrolled 3,048 patients at 17 sites in South Korea. Participants were 64 years old, on average, and 21% were women. All participants had ASCVD, defined as having a previous acute coronary syndrome, stable angina with objective evidence, a procedure to open blocked arteries (revascularization), stroke or transient ischemic attack, or peripheral artery disease. Overall, the study cohort reflects a high- to very-high-risk population based on the high prevalence of prior acute coronary syndrome, revascularization and diabetes, according to the researchers.
Half of the patients were randomly assigned to an LDL-C goal of less than 55 mg/dL and half to a goal of less than 70 mg/dL. At three years, patients in the first group had a median LDL-C of 56 mg/dL and those in the second group had a median of 66 mg/dL. To achieve these LDL-C goals, treating physicians followed medical guidelines by increasing the intensity of statin therapy and adding other medications such as ezetimibe and PCSK9 inhibitors when needed. Treatment decisions, including dose adjustments, addition of different therapies, and management of adverse events, were left to the discretion of the clinician to reflect real-world clinical practice.
The study’s primary endpoint was a composite of cardiovascular death, nonfatal heart attack, nonfatal stroke, any revascularization, or hospitalization for unstable angina (chest pain or tightness). At three years this composite endpoint occurred in 6.6% of those assigned to an LDL-C goal of less than 55 mg/dL and in 9.7% of those assigned to a target of 70 mg/dL, a 33% reduction in risk in favor of the more aggressive target. This benefit came mainly from a reduction in nonfatal heart attacks and revascularization. The composite of cardiovascular death, heart attack, or stroke was also significantly lower in the more intensive target group (2.3% vs. 3.6%).
“The consistency in the overall population and in key subgroups suggests that the benefit of targeting LDL-C lower than 55 mg/dL applies broadly across the spectrum of patients with ASCVD and is not limited to specific patient subsets,” Kim said, noting that the findings are particularly relevant for patients in higher-risk categories, for whom lower LDL targets are recommended.
The two study groups showed a similar safety profile, with no significant differences in the incidence of muscle symptoms, new-onset diabetes, or worsening glycemic control among people with diabetes. An increase in creatinine (a marker of worsening kidney function) was less common in the intensively targeted group, and the researchers said future studies could help clarify whether more intensive LDL-C lowering could slow the progression of kidney disease.
The study was not blinded because treating clinicians needed to know which LDL-C level to target for each patient. In addition, the trial was conducted entirely in South Korea and all participants were from East Asia, potentially limiting applicability to other countries or racial and ethnic groups that may see different differences in cardiovascular risk or different patterns of LDL-C-lowering treatment.
Kim also said that in the more intensive targeting group, 39% of patients never reached the goal below 55 mg/dL LDL-C. During the study period, newer non-statin cholesterol-lowering therapies, including inclisiran and bempedoic acid, were not available in South Korea, and the use of PCSK9 inhibitors was generally limited due to reimbursement policies. Kim said that more intensive use of such non-statin therapies may have resulted in lower achieved LDL-C levels and possibly greater clinical benefit. Additional studies could evaluate the effects of more intensive use of such treatments.
The study was funded by the Cardiovascular Research Center under contract to Yuhan Corporation.
This study was simultaneously published online at New England Journal of Medicine at the time of presentation.
Kim will present the study, “Intensive Low-density Lipoprotein Cholesterol Targeting in Patients with Atherosclerotic Cardiovascular Disease,” on Saturday, March 28, at 3:45 p.m. CT / 8:45 PM UTC on the Main Stage, Great Hall.
