Lp(a)HORIZON试验的设计和基本原理：评估Pelacarsen降低脂蛋白(a)对CVD和Lp(a)升高患者主要心血管事件的影响。

IF 3.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

American heart journal Pub Date : 2025-04-02 DOI:10.1016/j.ahj.2025.03.019

Leslie Cho MD , Stephen J. Nicholls MBBS, PhD , Børge G. Nordestgaard MD, DMSc , Ulf Landmesser MD , Sotirios Tsimikas MD , Michael J. Blaha MD, MPH , Eran Leitersdorf MD , A. Michael Lincoff MD , Anastasia Lesogor MD , Brian Manning Pharm D , Plamen Kozlovski MD , Hui Cao MD , Jing Wang MD, PhD , Steven E. Nissen MD

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引用次数: 0

摘要

背景：脂蛋白（a），简称 Lp（a），由与脂蛋白（a）共价结合的脂蛋白 B-100 组成，是动脉粥样硬化性心血管疾病（CVD）和钙化性主动脉瓣狭窄的一个独立的、由基因决定的致病危险因素。全球 20% 以上的心血管疾病患者脂蛋白（a）升高。目前还没有获得批准的降低脂蛋白（a）水平的药物治疗方法，也没有随机试验证明降低脂蛋白（a）可降低心血管疾病风险：Lp(a) HORIZON是一项3期、随机、安慰剂对照、双盲、平行组、多国试验，在8323名已确诊心血管疾病且Lp(a)水平升高≥70 mg/dL（约149 nmol/L）的患者中进行，测试反义寡核苷酸（ASO）pelacarsen对主要不良心血管事件（MACE）发生率的影响。已确诊的心血管疾病定义为心肌梗塞（MI）、缺血性中风或有症状的外周动脉疾病。最短随访时间为 2.5 年。研究将在累计发生 993 例 CEC 证实的原发性心血管事件后结束。根据目前的事件累积趋势，预计整个研究持续时间约为 6 年。患者按 1:1 的比例随机接受每月皮下 (SQ) 注射佩拉卡森 80 毫克或匹配的安慰剂，同时接受心血管疾病的优化标准治疗。主要终点是心血管死亡、非致命性心肌梗死、非致命性中风或需要住院的紧急冠状动脉血运重建的复合终点。该终点将在总体人群和筛查时脂蛋白（a）≥ 90 mg/dL（约 192 nmol/L）的亚人群中进行评估，设计的多重对照将在总体人群和亚人群中测试主要终点：Lp(a) HORIZON 将确定佩拉卡森对 Lp(a) 升高和已确诊心血管疾病患者的心血管发病率和死亡率的影响。

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Design and Rationale of Lp(a)HORIZON Trial: Assessing the Effect of Lipoprotein(a) Lowering With Pelacarsen on Major Cardiovascular Events in Patients With CVD and Elevated Lp(a)

Background

Lipoprotein(a), abbreviated Lp(a), consists of apolipoprotein B-100 covalently bound to apolipoprotein(a), and represents an independent, genetically-determined, causal risk factor for atherosclerotic cardiovascular disease (CVD) and calcific aortic stenosis. More than 20% of the world CVD population has elevated Lp(a). Currently there are no approved pharmacologic treatments to lower Lp(a) levels, and no randomized trials have demonstrated that lowering Lp(a) reduces CVD risk.

Study Design

Lp(a) HORIZON is a phase 3, randomized, placebo-controlled, double-blind, parallel-group, multinational trial in 8,323 patients with established CVD and elevated Lp(a) levels of ≥70 mg/dL (approximately 149 nmol/L), testing the effect of pelacarsen, an antisense oligonucleotide (ASO) on the incidence of major adverse cardiovascular events (MACE). Established CVD is defined as history of myocardial infarction (MI), ischemic stroke or symptomatic peripheral artery disease. The minimum follow-up is required to be 2.5 years. The study will end when 993 CEC confirmed primary CV events have accumulated. Based on the current event accrual trend, the overal study duration is anticipated to be approximately 6 years. Patients were randomized in a 1:1 ratio to receive either monthly subcutaneous (SQ) injections of pelacarsen 80 mg or matching placebo on a background of optimized standard of care therapy for CVD. The primary endpoint is a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or urgent coronary revascularization requiring hospitalization. This endpoint will be evaluated in the overall population and in a subpopulation of Lp(a) ≥90 mg/dL (approximately 192 nmol/L) at screening, with multiplicity control designed to test the primary endpoint in both the overall population and the subpopulation.

Conclusion

Lp(a) HORIZON will determine the effect of pelacarsen on cardiovascular morbidity and mortality in patients with elevated Lp(a) and established CVD.

Trial Registration

NCT 04023552.

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来源期刊

American heart journal 医学-心血管系统

CiteScore

8.20

自引率

2.10%

发文量

214

审稿时长

38 days

期刊介绍： The American Heart Journal will consider for publication suitable articles on topics pertaining to the broad discipline of cardiovascular disease. Our goal is to provide the reader primary investigation, scholarly review, and opinion concerning the practice of cardiovascular medicine. We especially encourage submission of 3 types of reports that are not frequently seen in cardiovascular journals: negative clinical studies, reports on study designs, and studies involving the organization of medical care. The Journal does not accept individual case reports or original articles involving bench laboratory or animal research.