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Cited by 169Lipoproteins and Cardiovascular HealthAtherosclerosis and Cardiovascular DiseasesLipid metabolism and disorders

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)

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Cho, Leslie, Nicholls, Stephen J., Nordestgaard, Børge G., Landmesser, Ulf, Tsimikas, Sotirios, Blaha, Michael J., Leitersdorf, Eran, Lincoff, A. Michael +6 more·2025·American Heart Journal
DOI 10.1016/j.ahj.2025.03.019
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Abstract

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: NCT04023552.

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Authors
Cho, L., Nicholls, S. J., Nordestgaard, B. G., Landmesser, U., Tsimikas, S., Blaha, M. J., Leitersdorf, E., Lincoff, A. M., Lesogor, A., Manning, B., Kozlovski, P., Cao, H., Wang, J., & Nissen, S. E.
Affiliations
  • Cleveland Clinic (US)
  • Monash University (AU)
  • University of Copenhagen (DK)
  • Deutsches Herzzentrum der Charité (DE)
  • University of California San Diego (US)
  • Johns Hopkins University (US)
  • Hebrew University of Jerusalem (IL)
  • Novartis (Switzerland) (CH)
  • Novartis (United States) (US)
ORCID
Venue
American Heart Journal
Publisher
Elsevier BV
Published
2025-09
Volume
287
Pages
1-9
ISSN
0002-8703 (ISSN-L)
DOI
10.1016/j.ahj.2025.03.019
OpenAlex
W4409133212
Semantic Scholar
f7419eb775679c32ad6cad7beff226bd47b960b7
Cited by
169
References
29
Citations by year
2026: 126 · 2025: 43
FWCI
145.97
Type
journal article
Language
en
Open access
Licence
Locations
  • American Heart Journal (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
Funders
Novartis
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Keywords
lipoprotein(a), pelacarsen, antisense oligonucleotides, Lp(a) lowering, major adverse cardiovascular events, atherosclerotic cardiovascular disease, established cardiovascular disease, cardiovascular mortality, myocardial infarction, stroke, coronary revascularization, apolipoprotein(a)
MeSH terms
Cardiovascular Diseases, Double-Blind Method, Female, Humans, Male, Middle Aged, Oligonucleotides, Randomized Controlled Trials as Topic, Oligonucleotides, Antisense, Lipoprotein(a)

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