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Clustering of ABCB1 and CYP2C19 Genetic Variants Predicts Risk of Major Bleeding and Thrombotic Events in Elderly Patients with Acute Coronary Syndrome Receiving Dual Antiplatelet Therapy with Aspirin and Clopidogrel

OBJECTIVE: The clinical efficacy of clopidogrel in secondary prevention of vascular events is hampered by marked inter-patient variability in drug response, which partially depends on genetic make-up. The aim of this pilot prospective study was to evaluate 12-month cardiovascular outcomes in elderly...

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Autores principales: Galeazzi, Roberta, Olivieri, Fabiola, Spazzafumo, Liana, Rose, Giuseppina, Montesanto, Alberto, Giovagnetti, Simona, Cecchini, Sara, Malatesta, Gelsomina, Di Pillo, Raffaele, Antonicelli, Roberto
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061429/
https://www.ncbi.nlm.nih.gov/pubmed/29936693
http://dx.doi.org/10.1007/s40266-018-0555-1
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author Galeazzi, Roberta
Olivieri, Fabiola
Spazzafumo, Liana
Rose, Giuseppina
Montesanto, Alberto
Giovagnetti, Simona
Cecchini, Sara
Malatesta, Gelsomina
Di Pillo, Raffaele
Antonicelli, Roberto
author_facet Galeazzi, Roberta
Olivieri, Fabiola
Spazzafumo, Liana
Rose, Giuseppina
Montesanto, Alberto
Giovagnetti, Simona
Cecchini, Sara
Malatesta, Gelsomina
Di Pillo, Raffaele
Antonicelli, Roberto
author_sort Galeazzi, Roberta
collection PubMed
description OBJECTIVE: The clinical efficacy of clopidogrel in secondary prevention of vascular events is hampered by marked inter-patient variability in drug response, which partially depends on genetic make-up. The aim of this pilot prospective study was to evaluate 12-month cardiovascular outcomes in elderly patients with acute coronary syndrome (ACS) receiving dual antiplatelet therapy (aspirin and clopidogrel) according to the clustering of CYP2C19 and ABCB1 genetic variants. METHODS: Participants were 100 consecutive ACS patients who were genotyped for CYP2C19 (G681A and C-806T) and ABCB1 (C3435T) polymorphisms, which affect clopidogrel metabolism and bioavailability, using PCR-restriction fragment length polymorphism. They were then grouped as poor, extensive and ultra-rapid metabolisers based on the combination of CYP2C19 loss-of-function (CYP2C19*2) and gain-of-function (CYP2C19*17) alleles and ABCB1 alleles. The predictive value of each phenotype for acute vascular events was estimated based on 12-month cardiovascular outcomes. RESULTS: The poor metabolisers were at an increased risk of thrombotic events (OR 1.26; 95% CI 1.099–1.45; χ(2) = 5.676; p = 0.027), whereas the ultra-rapid metabolisers had a 1.31-fold increased risk of bleeding events compared with the poor and extensive metabolisers (OR 1.31; 95% CI 1.033–1.67; χ(2) = 5.676; p = 0.048). Logistic regression model, including age, sex, BMI and smoking habit, confirmed the differential risk of major events in low and ultra-rapid metabolisers. CONCLUSIONS: Our findings suggest that ACS patients classified as ‘poor or ultra-rapid’ metabolisers based on CYP2C19 and ABCB1 genotypes should receive alternative antiplatelet therapies to clopidogrel. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40266-018-0555-1) contains supplementary material, which is available to authorized users.
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spelling pubmed-60614292018-08-09 Clustering of ABCB1 and CYP2C19 Genetic Variants Predicts Risk of Major Bleeding and Thrombotic Events in Elderly Patients with Acute Coronary Syndrome Receiving Dual Antiplatelet Therapy with Aspirin and Clopidogrel Galeazzi, Roberta Olivieri, Fabiola Spazzafumo, Liana Rose, Giuseppina Montesanto, Alberto Giovagnetti, Simona Cecchini, Sara Malatesta, Gelsomina Di Pillo, Raffaele Antonicelli, Roberto Drugs Aging Original Research Article OBJECTIVE: The clinical efficacy of clopidogrel in secondary prevention of vascular events is hampered by marked inter-patient variability in drug response, which partially depends on genetic make-up. The aim of this pilot prospective study was to evaluate 12-month cardiovascular outcomes in elderly patients with acute coronary syndrome (ACS) receiving dual antiplatelet therapy (aspirin and clopidogrel) according to the clustering of CYP2C19 and ABCB1 genetic variants. METHODS: Participants were 100 consecutive ACS patients who were genotyped for CYP2C19 (G681A and C-806T) and ABCB1 (C3435T) polymorphisms, which affect clopidogrel metabolism and bioavailability, using PCR-restriction fragment length polymorphism. They were then grouped as poor, extensive and ultra-rapid metabolisers based on the combination of CYP2C19 loss-of-function (CYP2C19*2) and gain-of-function (CYP2C19*17) alleles and ABCB1 alleles. The predictive value of each phenotype for acute vascular events was estimated based on 12-month cardiovascular outcomes. RESULTS: The poor metabolisers were at an increased risk of thrombotic events (OR 1.26; 95% CI 1.099–1.45; χ(2) = 5.676; p = 0.027), whereas the ultra-rapid metabolisers had a 1.31-fold increased risk of bleeding events compared with the poor and extensive metabolisers (OR 1.31; 95% CI 1.033–1.67; χ(2) = 5.676; p = 0.048). Logistic regression model, including age, sex, BMI and smoking habit, confirmed the differential risk of major events in low and ultra-rapid metabolisers. CONCLUSIONS: Our findings suggest that ACS patients classified as ‘poor or ultra-rapid’ metabolisers based on CYP2C19 and ABCB1 genotypes should receive alternative antiplatelet therapies to clopidogrel. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40266-018-0555-1) contains supplementary material, which is available to authorized users. Springer International Publishing 2018-06-23 2018 /pmc/articles/PMC6061429/ /pubmed/29936693 http://dx.doi.org/10.1007/s40266-018-0555-1 Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Research Article
Galeazzi, Roberta
Olivieri, Fabiola
Spazzafumo, Liana
Rose, Giuseppina
Montesanto, Alberto
Giovagnetti, Simona
Cecchini, Sara
Malatesta, Gelsomina
Di Pillo, Raffaele
Antonicelli, Roberto
Clustering of ABCB1 and CYP2C19 Genetic Variants Predicts Risk of Major Bleeding and Thrombotic Events in Elderly Patients with Acute Coronary Syndrome Receiving Dual Antiplatelet Therapy with Aspirin and Clopidogrel
title Clustering of ABCB1 and CYP2C19 Genetic Variants Predicts Risk of Major Bleeding and Thrombotic Events in Elderly Patients with Acute Coronary Syndrome Receiving Dual Antiplatelet Therapy with Aspirin and Clopidogrel
title_full Clustering of ABCB1 and CYP2C19 Genetic Variants Predicts Risk of Major Bleeding and Thrombotic Events in Elderly Patients with Acute Coronary Syndrome Receiving Dual Antiplatelet Therapy with Aspirin and Clopidogrel
title_fullStr Clustering of ABCB1 and CYP2C19 Genetic Variants Predicts Risk of Major Bleeding and Thrombotic Events in Elderly Patients with Acute Coronary Syndrome Receiving Dual Antiplatelet Therapy with Aspirin and Clopidogrel
title_full_unstemmed Clustering of ABCB1 and CYP2C19 Genetic Variants Predicts Risk of Major Bleeding and Thrombotic Events in Elderly Patients with Acute Coronary Syndrome Receiving Dual Antiplatelet Therapy with Aspirin and Clopidogrel
title_short Clustering of ABCB1 and CYP2C19 Genetic Variants Predicts Risk of Major Bleeding and Thrombotic Events in Elderly Patients with Acute Coronary Syndrome Receiving Dual Antiplatelet Therapy with Aspirin and Clopidogrel
title_sort clustering of abcb1 and cyp2c19 genetic variants predicts risk of major bleeding and thrombotic events in elderly patients with acute coronary syndrome receiving dual antiplatelet therapy with aspirin and clopidogrel
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061429/
https://www.ncbi.nlm.nih.gov/pubmed/29936693
http://dx.doi.org/10.1007/s40266-018-0555-1
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