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

Eur Heart J Cardiovasc Pharmacother. 2020 Jul 1;6(4):203-210. doi: 10.1093/ehjcvp/pvz045.

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.

Keywords: Clopidogrel; Pharmacogenetics; Platelet aggregation.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Platelet Aggregation Inhibitors
  • Clopidogrel