Factors associated with the failure of clopidogrel dose-adjustment according to platelet reactivity monitoring to optimize P2Y12-ADP receptor blockade

Thromb Res. 2012 Jul;130(1):70-4. doi: 10.1016/j.thromres.2011.12.038. Epub 2012 Jan 27.

Abstract

Introduction: Inter-individual variability in clopidogrel responsiveness is dependent on genetic polymorphisms. We aimed to investigate the impact of 3 genetic polymorphisms involved in clopidogrel metabolism on a strategy of dose-adjustment according to platelet reactivity (PR) monitoring.

Material and methods: [corrected] This prospective multicenter study enrolled 498 ACS patients undergoing PCI. PR was measured using the Vasodilator-Stimulated Phosphoprotein index (VASP) and a cut-off value of ≥50% defined high on-treatment platelet reactivity (HTPR). Genetic polymorphisms of cytochrome (CYP) 2C19, Paraxonase-1 (PON1) and ABCB1 were determined by allele specific PCR. Dose-adjustment was performed using up-to 3 additional loading doses (LD) of 600mg clopidogrel in order to obtain a VASP <50% in patients with HTPR following the first LD.

Results: CYP 2C19 2*polymorphism (p=0.02), but neither PON1 (p=0.8) nor ABCB1 genotype (p=0.9), was significantly associated with HTPR. The dose-adjustment strategy failed in 11% of patients. ABCB1 polymorphism was significantly associated with a failed dose-adjustment (FDA) (p=0.04). No relation was found between the other genotypes and the efficacy of LD adjustment. In multivariate analysis, BMI and ABCB1 polymorphism were the only factors significantly associated with FDA (p=0.005 and p=0.04 respectively).

Conclusion: While CYP 2C19 2* is associated with HTPR after 600mg of clopidogrel, ABCB1 is responsible for the failure of a strategy of loading dose-adjustment according to PR monitoring. These findings may help to define a therapeutic strategy to optimize anti-platelet therapy in ACS patients undergoing PCI.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • Acute Coronary Syndrome / drug therapy*
  • Acute Coronary Syndrome / genetics
  • Acute Coronary Syndrome / metabolism
  • Aged
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Aryldialkylphosphatase / genetics
  • Blood Platelets / drug effects*
  • Blood Platelets / metabolism
  • Cell Adhesion Molecules / metabolism
  • Clopidogrel
  • Cytochrome P-450 CYP2C19
  • Drug Dosage Calculations
  • Female
  • Humans
  • Male
  • Microfilament Proteins / metabolism
  • Middle Aged
  • Phosphoproteins / metabolism
  • Platelet Aggregation Inhibitors / administration & dosage*
  • Platelet Aggregation Inhibitors / metabolism
  • Platelet Aggregation Inhibitors / pharmacology
  • Polymorphism, Genetic*
  • Purinergic P2Y Receptor Antagonists / administration & dosage*
  • Purinergic P2Y Receptor Antagonists / metabolism
  • Purinergic P2Y Receptor Antagonists / pharmacology
  • Receptors, Purinergic P2 / metabolism
  • Receptors, Purinergic P2Y12 / metabolism
  • Ticlopidine / administration & dosage
  • Ticlopidine / analogs & derivatives*
  • Ticlopidine / metabolism
  • Ticlopidine / pharmacology

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Cell Adhesion Molecules
  • Microfilament Proteins
  • Phosphoproteins
  • Platelet Aggregation Inhibitors
  • Purinergic P2Y Receptor Antagonists
  • Receptors, Purinergic P2
  • Receptors, Purinergic P2Y12
  • vasodilator-stimulated phosphoprotein
  • Clopidogrel
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP2C19
  • Aryldialkylphosphatase
  • PON1 protein, human
  • Ticlopidine