title: High maintenance dosage of clopidogrel is associated with a reduced risk of stent thrombosis in clopidogrel-resistant patients.
abstract: BACKGROUND
  Stent thrombosis remains an important complication after stent implantation, despite the use of dual antiplatelet therapy with aspirin (acetylsalicylic acid) and clopidogrel. Several studies have shown an increased risk of thrombotic events in patients with resistance to clopidogrel. Some recent studies have suggested that a higher clopidogrel maintenance dosage could enhance ex vivo platelet inhibition and thereby overcome resistance to clopidogrel.
  
  
  OBJECTIVE
  To investigate whether a higher clopidogrel maintenance dosage is associated with a reduced risk of stent thrombosis after percutaneous coronary intervention (PCI) in clopidogrel-resistant patients and to evaluate the frequency of hemorrhagic accidents that could be associated with a high clopidogrel maintenance dosage.
  
  
  METHODS
  An observational study was performed in 52 consecutive clopidogrel-resistant patients (resistance defined according to adenosine diphosphate-induced platelet aggregation assessment) who underwent a PCI with stenting at a tertiary referral center (Toulouse University Hospital, France). All patients received a clopidogrel loading dose of 300 mg, then 32 patients received a clopidogrel maintenance dosage of 75 mg/day (patients admitted between 2004 and 2005) and 20 patients received 150 mg/day (patients admitted in 2006). We compared the occurrence of definite stent thrombosis and hemorrhagic accidents between these two groups, using a regression model.
  
  
  RESULTS
  Among the patients treated with clopidogrel 75 mg/day, 26 (81.3%) had definite stent thrombosis versus seven (35.0%) treated with 150 mg/day (adjusted relative risk [RR] 2.46; 95% CI 1.63, 2.76; p = 0.002). The risk of major adverse cardiac events (MACE) was also significantly lower in patients treated with 150 mg/day (adjusted RR 2.63; 95% CI 1.82, 2.82; p = 0.001). There was no significant difference between the two groups regarding hemorrhagic accidents.
  
  
  CONCLUSIONS
  Our data suggest that a high maintenance dosage of clopidogrel (150 mg/day) is associated with a reduced risk of definite stent thrombosis and MACE compared with a maintenance dosage of 75 mg/day. The frequency of hemorrhagic accidents was similar between the two groups, underlining a positive benefit-risk ratio of this strategy in clopidogrel-resistant patients. These findings deserve confirmation in a prospective, well conducted study.
authors.affiliation: Medical and Clinical Pharmacology Laboratory, Pharmacoepidemiology Unit, Faculty of Medicine, Toulouse University, Toulouse, France. neda67@yahoo.com
authors.forename: Neda
authors.initials: N
authors.lastname: Tavassoli
authors.forename: Sophie
authors.initials: S
authors.lastname: Voisin
authors.forename: Didier
authors.initials: D
authors.lastname: Carrie
authors.forename: Maryse
authors.initials: M
authors.lastname: Lapeyre-Mestre
authors.forename: Michel
authors.initials: M
authors.lastname: Galinier
authors.forename: Jean Louis
authors.initials: JL
authors.lastname: Montastruc
authors.forename: Atul
authors.initials: A
authors.lastname: Pathak
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015906:Angioplasty, Balloon, Coronary / Q000379:methods*; D000077144:Clopidogrel; D003328:Coronary Thrombosis / Q000209:etiology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D054855:Drug-Eluting Stents / Q000009:adverse effects; D005260:Female; D005500:Follow-Up Studies; D005602:France; D006470:Hemorrhage / Q000139:chemically induced; D006785:Hospitals, University; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D012044:Regression Analysis; D012306:Risk; D015607:Stents / Q000009:adverse effects; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine