More intensive use of cholesterol-lowering drugs to achieve more aggressive targets for low-density lipoprotein cholesterol (LDL-C) reduced the incidence of major cardiovascular events in patients with atherosclerotic cardiovascular disease (ASCVD) by one-third, according to a study presented at the American College of Cardiology’s Annual Scientific Sessions (ACC.26).
The results help fill an evidence gap in guiding the treatment of cardiac patients who face a high risk of serious cardiac events. Although guidelines have lowered the recommended LDL-C target for patients with ASCVD from <70 mg/dL to <55 mg/dL, evidence supporting this recommendation is 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 practical and clinically meaningful evidence by demonstrating that targeting LDL-C levels below 55 mg/dL significantly reduces the 3-year risk of major cardiovascular events in patients with ASCVD compared to the traditional goal of 70 mg/dL, without compromising safety. ”
Byung-kuk Kim, MD, director of the Department of Cardiac Catheterization and Interventions and professor of cardiology at Severance Hospital, Yonsei University School of Medicine, Seoul, South Korea, and lead author of the study
ASCVD is a type of heart disease that causes plaque to build up on the walls of your arteries. LDL-C contributes to plaque buildup. Treatments that reduce LDL-C can help slow the buildup of plaque on artery walls and reduce the chance that the plaque will rupture and cause serious events such as heart attack or stroke. However, most previous studies have focused on evaluating the outcomes of various LDL-C-lowering therapies, rather than assessing the optimal LDL-C levels to target, Kim said.
Researchers enrolled 3,048 patients at 17 sites in South Korea. The average age of participants was 64 years, and 21% were female. All participants had ASCVD, defined as acute coronary syndrome, stable angina with objective evidence, a procedure to open a blocked artery (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 pre-existing acute coronary syndromes, revascularization, and diabetes, the researchers said.
Half of the patients were randomly assigned to an LDL-C goal of less than 55 mg/dL and the other half to a goal of less than 70 mg/dL. At 3 years, the median LDL-C for patients in the first group was 56 mg/dL and for patients in the second group was 66 mg/dL. To achieve these LDL-C goals, treating physicians followed medical guidelines and increased the intensity of statin therapy and added other drugs, such as ezetimibe and PCSK9 inhibitors, as needed. Treatment decisions, including dose adjustments, addition of different treatments, and management of side effects, were left to the discretion of the clinician to reflect actual clinical practice.
The study’s primary endpoint was a combination of cardiovascular death, nonfatal heart attack, nonfatal stroke, revascularization, or hospitalization for unstable angina (chest pain or tightness). After 3 years, this composite endpoint occurred in 6.6% of patients assigned to an LDL-C goal of less than 55 mg/dL and 9.7% of patients assigned to a goal of less than 70 mg/dL, representing a 33% reduction in risk in favor of a more aggressive goal. This benefit was primarily driven by a reduction in nonfatal heart attacks and revascularization. Total cardiovascular death, heart attack, or stroke was also significantly lower in the more intensively targeted group (2.3% vs. 3.6%).
“The consistency across the population and across major subgroups suggests that the benefits of targeting LDL-C below 55 mg/dL are broadly applicable across the spectrum of ASCVD patients and are not limited to specific patient subsets,” Professor Kim said, noting that the study results are particularly relevant for patients in high-risk categories, where lower LDL-C targets are currently recommended.
The two study groups showed similar safety profiles, with no significant differences in the incidence of muscle symptoms, new onset diabetes, or worsening glycemic control in diabetic patients. Elevated creatinine, an indicator of worsening kidney function, was less common in the intensive target group, and the researchers said future studies could help determine whether more intensive LDL-C lowering can slow the progression of kidney disease.
The study was not blinded because treating clinicians need to know each patient’s target LDL-C level. Additionally, this trial was conducted entirely in South Korea and all participants were of East Asian origin, which may limit applicability to other countries or racial/ethnic groups where differences in cardiovascular risk or different patterns of LDL-C lowering therapy may be observed.
Kim also said that in the more intensively targeted group, 39% of patients failed to achieve the goal of LDL-C less than 55 mg/dL. During the study period, new non-statin cholesterol-lowering therapies such as inclisiran and bempedoic acid were not available in South Korea, and reimbursement policies generally limited the use of PCSK9 inhibitors. Kim said more intensive use of these non-statin therapies may have resulted in lower LDL-C levels achieved and perhaps greater clinical benefit. Additional studies may evaluate the effects of more intensive use of such treatments.
This study was funded by the Center for Cardiovascular Research under an agreement with Yuhan Corporation.
The study was published online at the same time. New England Medical Journal At the time of the presentation.
Kim will present his research, “Intensive Low-Density Lipoprotein Cholesterol Targeting in Patients with Atherosclerotic Cardiovascular Disease,” on Saturday, March 28th at 3:45pm CT / 8:45pm UTC in the main tent of the Great Hall.
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American College of Cardiology
