title: High on-treatment platelet reactivity by ADP and increased risk of MACE in good clopidogrel metabolizers.
abstract: High on-treatment platelet reactivity (HPR) by ADP, which primarily reflects the effect of thienopyridines, has been found to be an independent predictor of ischemic events in patients with acute coronary syndrome (ACS) on dual antiplatelet therapy. CYP2C19*2 is associated with HPR by ADP. The aim of our study was to evaluate if high on-clopidogrel platelet reactivity (HPR) by ADP is associated with an increased risk of major adverse coronary events (MACE) after ACS independent of CYP2C19*2 allele, i.e. whether genotyping patients for CYP2C19*2 polymorphism is sufficient to identify those to be switched to novel antiplatelets. A total of 1187 patients were included (CYP2C19 *1/*1 n = 892; *1/*2 n = 264; *2/*2 n = 31); 76 MACE (CV death and non-fatal MI) were recorded in non-carriers of CYP2C19*2 (8.5%) and 39 in carriers of CYP2C19*2 (13.2%). At the landmark analysis in the first 6 months, HPR by ADP and CYP2C19*2 allele were both significantly and independently associated with MACE [HPR by ADP: HR = 2.0 (95% CI 1.2-3.4), p = 0.01; CYP2C19*2 allele: HR = 2.3 (95% CI 1.3-3.9), p = 0.003]. At the land mark analysis from 7 to 12 months, only HPR by ADP remained significantly associated with the risk of MACE [HPR by ADP: HR = 2.7 (95% CI 1.4-5.3), p = 0.003; CYP2C19*2: HR = 0.8 (95% CI 0.2-1.1), p = ns]. CYP2C19*2 allele and HPR by ADP are both independently associated with an increased risk of MACE in the first 6 months after ACS. HPR by ADP is associated with an increased risk until 12 months of follow-up. Therefore, both phenotype and genotype are clinically relevant for the evaluation of the antiplatelet effect of clopidogrel and for the prognostic stratification of ACS patients.
authors.affiliation: Department of Medical and Surgical Critical Care, Centre for the Study at Molecular and Clinical Level of Chronic, Degenerative and Neoplastic Diseases to Develop Novel Therapies, University of Florence, Viale Morgagni 85, Florence, Italy. rossella.marcucci@unifi.it
authors.forename: Rossella
authors.initials: R
authors.lastname: Marcucci
authors.forename: Betti
authors.initials: B
authors.lastname: Giusti
authors.forename: Rita
authors.initials: R
authors.lastname: Paniccia
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Gori
authors.forename: Claudia
authors.initials: C
authors.lastname: Saracini
authors.forename: Serafina
authors.initials: S
authors.lastname: Valente
authors.forename: Cristina
authors.initials: C
authors.lastname: Giglioli
authors.forename: Guido
authors.initials: G
authors.lastname: Parodi
authors.forename: David
authors.initials: D
authors.lastname: Antoniucci
authors.forename: Gian Franco
authors.initials: GF
authors.lastname: Gensini
authors.forename: Rosanna
authors.initials: R
authors.lastname: Abbate
mesh_terms: D054058:Acute Coronary Syndrome / Q000097:blood* / Q000150:complications / Q000235:genetics / Q000401:mortality; D000244:Adenosine Diphosphate / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000097:blood / Q000235:genetics*; D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D006493:Heparin / Q000494:pharmacology / Q000627:therapeutic use; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood* / Q000209:etiology / Q000235:genetics / Q000401:mortality; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D012306:Risk; D015996:Survival Rate; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D010975:Platelet Aggregation Inhibitors; D000244:Adenosine Diphosphate; D006493:Heparin; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine