title: Factors associated with the failure of clopidogrel dose-adjustment according to platelet reactivity monitoring to optimize P2Y12-ADP receptor blockade.
abstract: BACKGROUND
  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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Département de cardiologie, Hôpital Universitaire Nord, Faculté de médecine, Aix-Marseille université, Marseille, France. laurentbonello@yahoo.fr
authors.forename: Laurent
authors.initials: L
authors.lastname: Bonello
authors.forename: Laurence
authors.initials: L
authors.lastname: Camoin-Jau
authors.forename: Julien
authors.initials: J
authors.lastname: Mancini
authors.forename: Jacques
authors.initials: J
authors.lastname: Bessereau
authors.forename: Charlotte
authors.initials: C
authors.lastname: Grosdidier
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Alessi
authors.forename: Michel
authors.initials: M
authors.lastname: Ostorero
authors.forename: Françoise
authors.initials: F
authors.lastname: Dignat-George
authors.forename: Franck
authors.initials: F
authors.lastname: Paganelli
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D054058:Acute Coronary Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D043303:Aryldialkylphosphatase / Q000235:genetics; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D054796:Drug Dosage Calculations; D005260:Female; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D008875:Middle Aged; D010750:Phosphoproteins / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D011110:Polymorphism, Genetic; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058925:Receptors, Purinergic P2Y12 / Q000378:metabolism; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D000098662:Vasodilator-Stimulated Phosphoprotein; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; D013988:Ticlopidine