Pharmacogenomic polygenic response score predicts ischaemic events and cardiovascular mortality in clopidogrel-treated patients.

Abstract

AIMS:

Clopidogrel is prescribed for the prevention of atherothrombotic events. While investigations have identified genetic determinants of inter-individual variability in on-treatment platelet inhibition (e.g. CYP2C19*2), evidence that these variants have clinical utility to predict major adverse cardiovascular events (CVEs) remains controversial.

METHODS AND RESULTS:

We assessed the impact of 31 candidate gene polymorphisms on adenosine diphosphate (ADP)-stimulated platelet reactivity in 3391 clopidogrel-treated coronary artery disease patients of the International Clopidogrel Pharmacogenomics Consortium (ICPC). The influence of these polymorphisms on CVEs was tested in 2134 ICPC patients (N = 129 events) in whom clinical event data were available. Several variants were associated with on-treatment ADP-stimulated platelet reactivity (CYP2C19*2, P = 8.8 × 10-54; CES1 G143E, P = 1.3 × 10-16; CYP2C19*17, P = 9.5 × 10-10; CYP2B6 1294 + 53 C > T, P = 3.0 × 10-4; CYP2B6 516 G > T, P = 1.0 × 10-3; CYP2C9*2, P = 1.2 × 10-3; and CYP2C9*3, P = 1.5 × 10-3). While no individual variant was associated with CVEs, generation of a pharmacogenomic polygenic response score (PgxRS) revealed that patients who carried a greater number of alleles that associated with increased on-treatment platelet reactivity were more likely to experience CVEs (β = 0.17, SE 0.06, P = 0.01) and cardiovascular-related death (β = 0.43, SE 0.16, P = 0.007). Patients who carried eight or more risk alleles were significantly more likely to experience CVEs [odds ratio (OR) = 1.78, 95% confidence interval (CI) 1.14-2.76, P = 0.01] and cardiovascular death (OR = 4.39, 95% CI 1.35-14.27, P = 0.01) compared to patients who carried six or fewer of these alleles.

CONCLUSION:

Several polymorphisms impact clopidogrel response and PgxRS is a predictor of cardiovascular outcomes. Additional investigations that identify novel determinants of clopidogrel response and validating polygenic models may facilitate future precision medicine strategies.

• Authors: Joshua P Lewis, Joshua D Backman, Jean-Luc Reny, Thomas O Bergmeijer, Braxton D Mitchell, Marylyn D Ritchie, Jean-Pierre Déry, Ruth E Pakyz, Li Gong, Kathleen Ryan, Eun-Young Kim, Daniel Aradi, Israel Fernandez-Cadenas, Ming Ta Michael Lee, Ryan M Whaley, Joan Montaner, Gian Franco Gensini, John H Cleator, Kiyuk Chang, Lene Holmvang, Willibald Hochholzer, Dan M Roden, Stefan Winter, Russ B Altman, Dimitrios Alexopoulos, Ho-Sook Kim, Meinrad Gawaz, Kevin P Bliden, Marco Valgimigli, Rossella Marcucci, Gianluca Campo, Elke Schaeffeler, Nadia P Dridi, Ming-Shien Wen, Jae Gook Shin, Pierre Fontana, Betti Giusti, Tobias Geisler, Michiaki Kubo, Dietmar Trenk, Jolanta M Siller-Matula, Jurriën M Ten Berg, Paul A Gurbel, Matthias Schwab, Teri E Klein, Alan R Shuldiner, ICPC Investigators
• Journal: European heart journal. Cardiovascular pharmacotherapy (Eur Heart J Cardiovasc Pharmacother) Vol. 6 Issue 4 Pg. 203-210 (07 01 2020) ISSN: 2055-6845 [Electronic] England
• PMID: 31504375 (Publication Type: Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected].

Chemical References

• Platelet Aggregation Inhibitors
• Clopidogrel

Topics

• Aged
• Brain Ischemia (mortality, prevention & control)
• Clopidogrel (adverse effects, therapeutic use)
• Coronary Artery Disease (blood, diagnosis, mortality, therapy)
• Coronary Thrombosis (mortality, prevention & control)
• Decision Support Techniques
• Europe
• Female
• Humans
• Male
• Middle Aged
• Myocardial Infarction (mortality, prevention & control)
• Percutaneous Coronary Intervention (adverse effects, instrumentation, mortality)
• Pharmacogenomic Variants
• Platelet Aggregation (drug effects, genetics)
• Platelet Aggregation Inhibitors (adverse effects, therapeutic use)
• Polymorphism, Single Nucleotide
• Predictive Value of Tests
• Risk Assessment
• Risk Factors
• Stents
• Stroke (mortality, prevention & control)
• Treatment Outcome