Patients With High Genome-Wide Polygenic Risk Scores for Coronary Artery Disease May Receive Greater Clinical Benefit From Alirocumab Treatment in the ODYSSEY OUTCOMES Trial

Background: Alirocumab, an antibody that blocks PCSK9 (proprotein convertase subtilisin/kexin type 9), was associated with reduced major adverse cardiovascular events (MACE) and death in the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatme...

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Autores: Damask, A, Steg, PG, Schwartz, GG, Szarek, M, Hagstrom, E, Badimon, L, Chapman, MJ, Boileau, C, Tsimikas, S, Ginsberg, HN, Banerjee, P, Manvelian, G, Pordy, R, Hess, S, Overton, JD, Lotta, LA, Yancopoulos, GD, Abecasis, GR, Baras, A, Paulding, C
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Recursos:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p2043
Acesso em linha:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=2043
Access Level:acceso abierto
Palavra-chave:cardiovascular disease
genetics
genomics
polygenic inheritance
pharmacogenomics
proprotein convertase
subtilisin-kexin type 9
risk factors
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spelling Patients With High Genome-Wide Polygenic Risk Scores for Coronary Artery Disease May Receive Greater Clinical Benefit From Alirocumab Treatment in the ODYSSEY OUTCOMES TrialDamask, ASteg, PGSchwartz, GGSzarek, MHagstrom, EBadimon, LChapman, MJBoileau, CTsimikas, SGinsberg, HNBanerjee, PManvelian, GPordy, RHess, SOverton, JDLotta, LAYancopoulos, GDAbecasis, GRBaras, APaulding, Ccardiovascular diseasegeneticsgenomicspolygenic inheritancepharmacogenomicsproprotein convertasesubtilisin-kexin type 9risk factorsBackground: Alirocumab, an antibody that blocks PCSK9 (proprotein convertase subtilisin/kexin type 9), was associated with reduced major adverse cardiovascular events (MACE) and death in the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab). In this study, higher baseline levels of low-density lipoprotein cholesterol (LDL-C) predicted greater benefit from alirocumab treatment. Recent studies indicate high polygenic risk scores (PRS) for coronary artery disease (CAD) identify individuals at higher risk who derive increased benefit from statins. We performed post hoc analyses to determine whether high PRS for CAD identifies higher-risk individuals, independent of baseline LDL-C and other known risk factors, who might derive greater benefit from alirocumab treatment. Methods: ODYSSEY OUTCOMES was a randomized, double-blind, placebo-controlled trial comparing alirocumab or placebo in 18 924 patients with acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin treatment. The primary endpoint (MACE) comprised death of CAD, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization. A genome-wide PRS for CAD comprising 6 579 025 genetic variants was evaluated in 11 953 patients with available DNA samples. Analysis of MACE risk was performed in placebo-treated patients, whereas treatment benefit analysis was performed in all patients. Results: The incidence of MACE in the placebo group was related to PRS for CAD: 17.0% for high PRS patients (>90th percentile) and 11.4% for lower PRS patients (<= 90th percentile; P<0.001); this PRS relationship was not explained by baseline LDL-C or other established risk factors. Both the absolute and relative reduction of MACE by alirocumab compared with placebo was greater in high versus low PRS patients. There was an absolute reduction by alirocumab in high versus low PRS groups of 6.0% and 1.5%, respectively, and a relative risk reduction by alirocumab of 37% in the high PRS group (hazard ratio, 0.63 [95% CI, 0.46-0.86]; P=0.004) versus a 13% reduction in the low PRS group (hazard ratio, 0.87 [95% CI, 0.78-0.98]; P=0.022; interaction P=0.04). Conclusions: A high PRS for CAD is associated with elevated risk for recurrent MACE after acute coronary syndrome and a larger absolute and relative risk reduction with alirocumab treatment, providing an independent tool for risk stratification and precision medicine.LIPPINCOTT WILLIAMS & WILKINS2020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=2043CIRCULATIONISSN: 00097322ISSNe: 15244539reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pauinstname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)Inglésinfo:eu-repo/semantics/openAccessoai:iibsantpau.fundanetsuite.com:p20432026-06-14T12:41:47Z
dc.title.none.fl_str_mv Patients With High Genome-Wide Polygenic Risk Scores for Coronary Artery Disease May Receive Greater Clinical Benefit From Alirocumab Treatment in the ODYSSEY OUTCOMES Trial
title Patients With High Genome-Wide Polygenic Risk Scores for Coronary Artery Disease May Receive Greater Clinical Benefit From Alirocumab Treatment in the ODYSSEY OUTCOMES Trial
spellingShingle Patients With High Genome-Wide Polygenic Risk Scores for Coronary Artery Disease May Receive Greater Clinical Benefit From Alirocumab Treatment in the ODYSSEY OUTCOMES Trial
Damask, A
cardiovascular disease
genetics
genomics
polygenic inheritance
pharmacogenomics
proprotein convertase
subtilisin-kexin type 9
risk factors
title_short Patients With High Genome-Wide Polygenic Risk Scores for Coronary Artery Disease May Receive Greater Clinical Benefit From Alirocumab Treatment in the ODYSSEY OUTCOMES Trial
title_full Patients With High Genome-Wide Polygenic Risk Scores for Coronary Artery Disease May Receive Greater Clinical Benefit From Alirocumab Treatment in the ODYSSEY OUTCOMES Trial
title_fullStr Patients With High Genome-Wide Polygenic Risk Scores for Coronary Artery Disease May Receive Greater Clinical Benefit From Alirocumab Treatment in the ODYSSEY OUTCOMES Trial
title_full_unstemmed Patients With High Genome-Wide Polygenic Risk Scores for Coronary Artery Disease May Receive Greater Clinical Benefit From Alirocumab Treatment in the ODYSSEY OUTCOMES Trial
title_sort Patients With High Genome-Wide Polygenic Risk Scores for Coronary Artery Disease May Receive Greater Clinical Benefit From Alirocumab Treatment in the ODYSSEY OUTCOMES Trial
dc.creator.none.fl_str_mv Damask, A
Steg, PG
Schwartz, GG
Szarek, M
Hagstrom, E
Badimon, L
Chapman, MJ
Boileau, C
Tsimikas, S
Ginsberg, HN
Banerjee, P
Manvelian, G
Pordy, R
Hess, S
Overton, JD
Lotta, LA
Yancopoulos, GD
Abecasis, GR
Baras, A
Paulding, C
author Damask, A
author_facet Damask, A
Steg, PG
Schwartz, GG
Szarek, M
Hagstrom, E
Badimon, L
Chapman, MJ
Boileau, C
Tsimikas, S
Ginsberg, HN
Banerjee, P
Manvelian, G
Pordy, R
Hess, S
Overton, JD
Lotta, LA
Yancopoulos, GD
Abecasis, GR
Baras, A
Paulding, C
author_role author
author2 Steg, PG
Schwartz, GG
Szarek, M
Hagstrom, E
Badimon, L
Chapman, MJ
Boileau, C
Tsimikas, S
Ginsberg, HN
Banerjee, P
Manvelian, G
Pordy, R
Hess, S
Overton, JD
Lotta, LA
Yancopoulos, GD
Abecasis, GR
Baras, A
Paulding, C
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv cardiovascular disease
genetics
genomics
polygenic inheritance
pharmacogenomics
proprotein convertase
subtilisin-kexin type 9
risk factors
topic cardiovascular disease
genetics
genomics
polygenic inheritance
pharmacogenomics
proprotein convertase
subtilisin-kexin type 9
risk factors
description Background: Alirocumab, an antibody that blocks PCSK9 (proprotein convertase subtilisin/kexin type 9), was associated with reduced major adverse cardiovascular events (MACE) and death in the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab). In this study, higher baseline levels of low-density lipoprotein cholesterol (LDL-C) predicted greater benefit from alirocumab treatment. Recent studies indicate high polygenic risk scores (PRS) for coronary artery disease (CAD) identify individuals at higher risk who derive increased benefit from statins. We performed post hoc analyses to determine whether high PRS for CAD identifies higher-risk individuals, independent of baseline LDL-C and other known risk factors, who might derive greater benefit from alirocumab treatment. Methods: ODYSSEY OUTCOMES was a randomized, double-blind, placebo-controlled trial comparing alirocumab or placebo in 18 924 patients with acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin treatment. The primary endpoint (MACE) comprised death of CAD, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization. A genome-wide PRS for CAD comprising 6 579 025 genetic variants was evaluated in 11 953 patients with available DNA samples. Analysis of MACE risk was performed in placebo-treated patients, whereas treatment benefit analysis was performed in all patients. Results: The incidence of MACE in the placebo group was related to PRS for CAD: 17.0% for high PRS patients (>90th percentile) and 11.4% for lower PRS patients (<= 90th percentile; P<0.001); this PRS relationship was not explained by baseline LDL-C or other established risk factors. Both the absolute and relative reduction of MACE by alirocumab compared with placebo was greater in high versus low PRS patients. There was an absolute reduction by alirocumab in high versus low PRS groups of 6.0% and 1.5%, respectively, and a relative risk reduction by alirocumab of 37% in the high PRS group (hazard ratio, 0.63 [95% CI, 0.46-0.86]; P=0.004) versus a 13% reduction in the low PRS group (hazard ratio, 0.87 [95% CI, 0.78-0.98]; P=0.022; interaction P=0.04). Conclusions: A high PRS for CAD is associated with elevated risk for recurrent MACE after acute coronary syndrome and a larger absolute and relative risk reduction with alirocumab treatment, providing an independent tool for risk stratification and precision medicine.
publishDate 2020
dc.date.none.fl_str_mv 2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=2043
url https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=2043
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv LIPPINCOTT WILLIAMS & WILKINS
publisher.none.fl_str_mv LIPPINCOTT WILLIAMS & WILKINS
dc.source.none.fl_str_mv CIRCULATION
ISSN: 00097322
ISSNe: 15244539
reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
instname_str Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
reponame_str r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
collection r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
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repository.mail.fl_str_mv
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score 15.812429

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