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Inclisiran and cardiovascular events: a patient-level analysis of phase III trials

BACKGROUND: Inclisiran, an siRNA administered twice-yearly, significantly reduced LDL cholesterol (LDL-C) in Phase III trials. Whether lowering LDL-C with inclisiran translates into a lower risk of cardiovascular (CV) events is not yet established. METHODS AND RESULTS: Patient-level, pooled analysis...

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Autores principales: Ray, Kausik K, Raal, Frederick J, Kallend, David G, Jaros, Mark J, Koenig, Wolfgang, Leiter, Lawrence A, Landmesser, Ulf, Schwartz, Gregory G, Lawrence, David, Friedman, Andrew, Garcia Conde, Lorena, Wright, R Scott
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9825807/
https://www.ncbi.nlm.nih.gov/pubmed/36331326
http://dx.doi.org/10.1093/eurheartj/ehac594
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author Ray, Kausik K
Raal, Frederick J
Kallend, David G
Jaros, Mark J
Koenig, Wolfgang
Leiter, Lawrence A
Landmesser, Ulf
Schwartz, Gregory G
Lawrence, David
Friedman, Andrew
Garcia Conde, Lorena
Wright, R Scott
author_facet Ray, Kausik K
Raal, Frederick J
Kallend, David G
Jaros, Mark J
Koenig, Wolfgang
Leiter, Lawrence A
Landmesser, Ulf
Schwartz, Gregory G
Lawrence, David
Friedman, Andrew
Garcia Conde, Lorena
Wright, R Scott
author_sort Ray, Kausik K
collection PubMed
description BACKGROUND: Inclisiran, an siRNA administered twice-yearly, significantly reduced LDL cholesterol (LDL-C) in Phase III trials. Whether lowering LDL-C with inclisiran translates into a lower risk of cardiovascular (CV) events is not yet established. METHODS AND RESULTS: Patient-level, pooled analysis of ORION-9, −10 and −11, included patients with heterozygous familial hypercholesterolaemia, atherosclerotic CV disease (ASCVD), or ASCVD risk equivalent on maximally tolerated statin-therapy, randomized 1:1 to receive 284 mg inclisiran or placebo on Days 1, 90, and 6-monthly thereafter for 18 months. Prespecified exploratory endpoint of major cardiovascular events (MACEs) included non-adjudicated CV death, cardiac arrest, non-fatal myocardial infarction (MI), and fatal and non-fatal stroke, evaluated as part of safety assessments using a standard Medical Dictionary for Regulatory Activities basket. Although not prespecified, total fatal and non-fatal MI, and stroke were also evaluated. Mean LDL-C at baseline was 2.88 mmol/L. At Day 90, the placebo-corrected percentage reduction in LDL-C with inclisiran was 50.6%, corresponding to an absolute reduction of 1.37 mmol/L (both P < 0.0001). Among 3655 patients over 18 months, 303 (8.3%) experienced MACE, including 74 (2.0%) fatal and non-fatal MIs, and 28 (0.8%) fatal and non-fatal strokes. Inclisiran significantly reduced composite MACE [OR (95% CI): 0.74 (0.58–0.94)], but not fatal and non-fatal MIs [OR (95% CI): 0.80 (0.50–1.27)] or fatal and non-fatal stroke [OR (95% CI): 0.86 (0.41–1.81)]. CONCLUSION: This analysis offers early insights into the potential CV benefits of lowering LDL-C with inclisiran and suggests potential benefits for MACE reduction. These findings await confirmation in the larger CV outcomes trials of longer duration.
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spelling pubmed-98258072023-01-10 Inclisiran and cardiovascular events: a patient-level analysis of phase III trials Ray, Kausik K Raal, Frederick J Kallend, David G Jaros, Mark J Koenig, Wolfgang Leiter, Lawrence A Landmesser, Ulf Schwartz, Gregory G Lawrence, David Friedman, Andrew Garcia Conde, Lorena Wright, R Scott Eur Heart J Fast Track Clinical Research BACKGROUND: Inclisiran, an siRNA administered twice-yearly, significantly reduced LDL cholesterol (LDL-C) in Phase III trials. Whether lowering LDL-C with inclisiran translates into a lower risk of cardiovascular (CV) events is not yet established. METHODS AND RESULTS: Patient-level, pooled analysis of ORION-9, −10 and −11, included patients with heterozygous familial hypercholesterolaemia, atherosclerotic CV disease (ASCVD), or ASCVD risk equivalent on maximally tolerated statin-therapy, randomized 1:1 to receive 284 mg inclisiran or placebo on Days 1, 90, and 6-monthly thereafter for 18 months. Prespecified exploratory endpoint of major cardiovascular events (MACEs) included non-adjudicated CV death, cardiac arrest, non-fatal myocardial infarction (MI), and fatal and non-fatal stroke, evaluated as part of safety assessments using a standard Medical Dictionary for Regulatory Activities basket. Although not prespecified, total fatal and non-fatal MI, and stroke were also evaluated. Mean LDL-C at baseline was 2.88 mmol/L. At Day 90, the placebo-corrected percentage reduction in LDL-C with inclisiran was 50.6%, corresponding to an absolute reduction of 1.37 mmol/L (both P < 0.0001). Among 3655 patients over 18 months, 303 (8.3%) experienced MACE, including 74 (2.0%) fatal and non-fatal MIs, and 28 (0.8%) fatal and non-fatal strokes. Inclisiran significantly reduced composite MACE [OR (95% CI): 0.74 (0.58–0.94)], but not fatal and non-fatal MIs [OR (95% CI): 0.80 (0.50–1.27)] or fatal and non-fatal stroke [OR (95% CI): 0.86 (0.41–1.81)]. CONCLUSION: This analysis offers early insights into the potential CV benefits of lowering LDL-C with inclisiran and suggests potential benefits for MACE reduction. These findings await confirmation in the larger CV outcomes trials of longer duration. Oxford University Press 2022-11-04 /pmc/articles/PMC9825807/ /pubmed/36331326 http://dx.doi.org/10.1093/eurheartj/ehac594 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Fast Track Clinical Research
Ray, Kausik K
Raal, Frederick J
Kallend, David G
Jaros, Mark J
Koenig, Wolfgang
Leiter, Lawrence A
Landmesser, Ulf
Schwartz, Gregory G
Lawrence, David
Friedman, Andrew
Garcia Conde, Lorena
Wright, R Scott
Inclisiran and cardiovascular events: a patient-level analysis of phase III trials
title Inclisiran and cardiovascular events: a patient-level analysis of phase III trials
title_full Inclisiran and cardiovascular events: a patient-level analysis of phase III trials
title_fullStr Inclisiran and cardiovascular events: a patient-level analysis of phase III trials
title_full_unstemmed Inclisiran and cardiovascular events: a patient-level analysis of phase III trials
title_short Inclisiran and cardiovascular events: a patient-level analysis of phase III trials
title_sort inclisiran and cardiovascular events: a patient-level analysis of phase iii trials
topic Fast Track Clinical Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9825807/
https://www.ncbi.nlm.nih.gov/pubmed/36331326
http://dx.doi.org/10.1093/eurheartj/ehac594
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