title: Effect of clopidogrel plus ASA vs. ASA early after TIA and ischaemic stroke: a substudy of the CHARISMA trial.
abstract: BACKGROUND
  The Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilisation, Management and Avoidance (CHARISMA) trial reported no statistically significant benefit of adding clopidogrel to acetylsalicylic acid in the long-term management of a broad population of patients with stable vascular disease. However, a subanalysis raised the hypothesis that dual antiplatelet therapy with clopidogrel plus acetylsalicylic acid may be more effective than aspirin in patients with prior ischaemic stroke, myocardial infarction of symptomatic peripheral arterial disease. We aimed to determine whether the possible benefits of clopidogrel plus acetylsalicylic acid in patients with transient ischaemic attack and ischaemic stroke may be 'front-loaded', and maximal within the first 30-days of randomisation, without being unduly hazardous.
  
  
  METHODS
  This was a subanalysis of a randomised, double-blind, placebo-controlled trial of clopidogrel vs. placebo, in addition to background therapy with low-dose acetylsalicylic acid (CHARISMA trial), restricted to all patients with transient ischaemic attack or ischaemic stroke. The primary efficacy outcome was stroke, and safety outcome severe bleeding, during the follow-up period.
  
  
  RESULTS
  Among all transient ischaemic attack and ischaemic stroke patients randomised to placebo (n=2163), 131 (6·1%) experienced a stroke during follow-up compared with 105 (4·9%) of 2157 patients assigned clopidogrel (hazard ratio: 0·80, 95% confidence intervals: 0·62-1·03). There was no significant difference in severe bleeding (1·7% placebo vs. 1·9% clopidogrel, hazard ratio: 1·11, 95% confidence intervals: 0·71-1·73). Among all patients randomised within 30-days of their qualifying transient ischaemic attack or ischaemic stroke to placebo (n=667), 46 (6·9%) experienced a stroke compared with 34 (5·1%) of 664 patients assigned clopidogrel (hazard ratio: 0·74, 0·46-1·16). There was no significant difference in severe bleeding (1·6% placebo vs. 1·4% clopidogrel, hazard ratio: 0·83, 95% confidence intervals: 0·34-2·01).
  
  
  CONCLUSIONS
  The data are consistent with, but do not prove the hypothesis that early addition of clopidogrel to acetylsalicylic acid in patients with transient ischaemic attack and ischaemic stroke of arterial origin may be more effective and acceptably safe compared with acetylsalicylic acid alone. Adequately powered clinical trials that are dedicated to exploring this hypothesis are needed.
authors.affiliation: Neurology Department, Stroke Unit, Royal Perth Hospital, Perth, Australia. gjhankey@cyllene.uwa.edu.au
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Hankey
authors.forename: S Claiborne
authors.initials: SC
authors.lastname: Johnston
authors.forename: J Donald
authors.initials: JD
authors.lastname: Easton
authors.forename: Werner
authors.initials: W
authors.lastname: Hacke
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mas
authors.forename: Danielle
authors.initials: D
authors.lastname: Brennan
authors.forename: Koon Hou
authors.initials: KH
authors.lastname: Mak
authors.forename: Deepak L
authors.initials: DL
authors.lastname: Bhatt
authors.forename: Keith A A
authors.initials: KA
authors.lastname: Fox
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Topol
mesh_terms: D000368:Aged; D001241:Aspirin / Q000009:adverse effects / Q000627:therapeutic use*; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy; D000077144:Clopidogrel; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D002546:Ischemic Attack, Transient / Q000188:drug therapy*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011379:Prognosis; D018401:Sample Size; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin