An intensified approach to administering cholesterol-reducing pharmaceuticals, aiming for a more stringent target of low-density lipoprotein cholesterol (LDL-C), resulted in a one-third reduction in the incidence of significant cardiovascular incidents among individuals diagnosed with atherosclerotic cardiovascular disease (ASCVD). These findings were unveiled at the American College of Cardiology’s Annual Scientific Session (ACC.26).
These outcomes contribute to addressing a critical gap in evidence that informs the management of patients with cardiac conditions who face a substantial risk of severe cardiac events. While clinical guidelines have decreased the recommended LDL-C threshold for ASCVD patients from below 70 mg/dL to under 55 mg/dL, the empirical support for this revised recommendation has been somewhat limited. The recently concluded Ez-PAVE trial represents the inaugural randomized, head-to-head comparison evaluating these two distinct LDL-C targets within the ASCVD patient population.
The Ez-PAVE trial furnishes practical and clinically salient evidence by demonstrating that, in the context of ASCVD patients, targeting an LDL-C level below 55 mg/dL yields a demonstrably lower three-year risk of major cardiovascular events when contrasted with the conventional benchmark of 70 mg/dL, all without compromising patient safety.”
Byeong-Keuk Kim, MD, 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, and lead author of the study
ASCVD is a classification of heart disease characterized by the accumulation of plaque within arterial walls. LDL-C is a key contributor to this plaque buildup. Therapeutic interventions designed to lower LDL-C can effectively decelerate plaque deposition in the arteries and diminish the propensity for these plaques to rupture, thereby averting serious outcomes like myocardial infarctions and strokes. Nevertheless, the majority of prior investigations have primarily concentrated on evaluating the efficacy of various LDL-C-lowering treatments rather than establishing the optimal LDL-C level to be pursued with these therapies, as noted by Dr. Kim.
A total of 3,048 individuals were recruited for this research across 17 distinct sites in South Korea. The average age of the participants was 64 years, with 21% being female. Every participant presented with ASCVD, which was defined by conditions such as a history of acute coronary syndrome, stable angina with objective diagnostic evidence, a procedure to restore arterial patency (revascularization), stroke or transient ischemic attack, or peripheral artery disease. The study cohort, in its entirety, is representative of a high-risk to very-high-risk demographic, evidenced by the prevalent presence of prior acute coronary syndrome, revascularization procedures, and diabetes, according to the investigators.
Participants were equally divided, with half randomly assigned to pursue an LDL-C target of less than 55 mg/dL and the other half assigned to a target of less than 70 mg/dL. At the three-year mark, individuals in the former group exhibited a median LDL-C level of 56 mg/dL, while those in the latter group had a median of 66 mg/dL. To achieve these specific LDL-C objectives, the treating physicians adhered to established medical protocols, escalating the intensity of statin therapy and introducing supplementary medications such as ezetimibe and PCSK9 inhibitors as necessitated. Treatment decisions, encompassing dosage adjustments, the incorporation of diverse therapeutic agents, and the management of adverse reactions, were left to the discretion of the clinicians to accurately mirror real-world clinical practice.
The paramount objective of the investigation was a composite endpoint comprising cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke, any revascularization procedure, or hospitalization due to unstable angina (chest discomfort or tightness). Over the three-year period, this composite endpoint manifested in 6.6% of participants assigned to the less than 55 mg/dL LDL-C target group and in 9.7% of those assigned to the 70 mg/dL target group, signifying a 33% reduction in risk favoring the more ambitious target. This observed benefit was predominantly driven by a decrease in non-fatal heart attacks and revascularization procedures. The combined endpoint of cardiovascular death, heart attack, or stroke also demonstrated a statistically significant reduction in the group receiving more intensive treatment (2.3% compared to 3.6%).
“The uniform results observed across the entire patient cohort and within key subgroups underscore the widespread applicability of targeting LDL-C below 55 mg/dL for patients with ASCVD, extending beyond specific patient classifications,” Dr. Kim remarked, emphasizing that these discoveries are particularly pertinent for individuals within higher-risk categories, for whom lower LDL-C targets are currently advised.
A comparable safety profile was noted between the two study arms, with no significant disparities in the occurrence of muscular discomfort, newly diagnosed diabetes, or exacerbation of glycemic control in diabetic patients. An elevation in creatinine levels (a marker of diminished kidney function) was infrequent in the group aiming for more aggressive LDL-C reduction, leading researchers to suggest that future studies could investigate whether more intensive LDL-C lowering might contribute to a slower progression of renal disease.
The study was not conducted under double-blind conditions, as it was imperative for the treating physicians to be aware of the LDL-C target for each patient. Furthermore, the trial was exclusively conducted within South Korea, and all participants hailed from East Asia, which may limit the generalizability of the findings to other geographical regions or racial and ethnic groups that might exhibit different cardiovascular risk profiles or distinct patterns in LDL-C lowering therapy response.
Dr. Kim also pointed out that in the more intensive treatment group, 39% of patients never attained the target LDL-C level of less than 55 mg/dL. During the study’s duration, novel non-statin cholesterol-lowering medications, including inclisiran and bempedoic acid, were not accessible in South Korea, and the utilization of PCSK9 inhibitors was generally constrained due to reimbursement policies. Dr. Kim posited that a more comprehensive application of such non-statin therapies could have potentially resulted in lower achieved LDL-C levels and possibly augmented clinical benefits. Subsequent investigations could explore the impact of more aggressive utilization of these advanced therapies.
The research received funding from the Cardiovascular Research Center under an agreement with Yuhan Corporation.
This study was concurrently disseminated online in the New England Journal of Medicine concurrently with its presentation.
Dr. Kim is scheduled to present the findings of the study, titled “Intensive Low-density Lipoprotein Cholesterol Targeting in Patients with Atherosclerotic Cardiovascular Disease,” on Saturday, March 28, at 3:45 p.m. CT / 20:45 UTC, in the Main Tent, Great Hall.
