title: Patients with poor responsiveness to thienopyridine treatment or with diabetes have lower levels of circulating active metabolite, but their platelets respond normally to active metabolite added ex vivo.
abstract: OBJECTIVE
  We evaluated the prevalence and mechanism of poor responsiveness to clopidogrel and prasugrel in coronary artery disease patients with and without diabetes.
  
  
  BACKGROUND
  Low platelet inhibition by clopidogrel is associated with ischemic clinical events. A higher 600-mg loading dose (LD) has been advocated to increase responsiveness to clopidogrel.
  
  
  METHODS
  In this study, 110 aspirin-treated patients were randomized to double-blind treatment with clopidogrel 600 mg LD/75 mg maintenance dose (MD) for 28 days or prasugrel 60 mg LD/10 mg MD for 28 days. Pharmacodynamic (PD) response was evaluated by light transmission aggregometry and vasodilator-stimulated phosphoprotein phosphorylation. The PD poor responsiveness was defined with 4 definitions previously associated with worse clinical outcomes. Active metabolites (AM) of clopidogrel and prasugrel were measured. Clopidogrel AM was added ex vivo.
  
  
  RESULTS
  The proportion of patients with poor responsiveness was greater in the clopidogrel group for all definitions at all time points from 1 h to 29 days. Poor responders had significantly lower plasma AM levels compared with responders. Patients with diabetes were over-represented in the poor-responder groups and had significantly lower levels of AM. Platelets of both poor responders and diabetic patients responded fully to AM added ex vivo.
  
  
  CONCLUSIONS
  Prasugrel treatment results in significantly fewer PD poor responders compared with clopidogrel after a 600-mg clopidogrel LD and during MD. The mechanism of incomplete platelet inhibition in clopidogrel poor-responder groups and in diabetic patients is lower plasma levels of its AM and not differences in platelet P2Y(12) receptor function.
authors.affiliation: Department of Cardiology, Lund University, Lund, Sweden. david.erlinge@med.lu.se
authors.forename: David
authors.initials: D
authors.lastname: Erlinge
authors.forename: Christoph
authors.initials: C
authors.lastname: Varenhorst
authors.forename: Oscar O
authors.initials: OO
authors.lastname: Braun
authors.forename: Stefan
authors.initials: S
authors.lastname: James
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Winters
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Jakubowski
authors.forename: John T
authors.initials: JT
authors.lastname: Brandt
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Sugidachi
authors.forename: Agneta
authors.initials: A
authors.lastname: Siegbahn
authors.forename: Lars
authors.initials: L
authors.lastname: Wallentin
mesh_terms: D000328:Adult; D000368:Aged; D000077144:Clopidogrel; D015897:Comorbidity; D003324:Coronary Artery Disease / Q000097:blood* / Q000188:drug therapy* / Q000503:physiopathology; D048909:Diabetes Complications / Q000097:blood* / Q000503:physiopathology; D004311:Double-Blind Method; D004351:Drug Resistance; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use; D000068799:Prasugrel Hydrochloride; D015995:Prevalence; D011725:Pyridines / Q000627:therapeutic use*; D013876:Thiophenes / Q000627:therapeutic use; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D017211:Treatment Failure; D016896:Treatment Outcome
chemical_list: D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D013876:Thiophenes; C446540:thienopyridine; D000077144:Clopidogrel; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine