title: Effect of addition of clopidogrel to aspirin on mortality: systematic review of randomized trials.
abstract: OBJECTIVE
  In the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, addition of clopidogrel to aspirin was associated with an unexpected increase in mortality in patients with lacunar strokes. We assessed the effect of the addition of clopidogrel to aspirin on mortality in a meta-analysis of published randomized trials.
  
  
  METHODS
  Randomized trials in which clopidogrel was added to aspirin in subjects with vascular disease or vascular risk factors were identified. Trials were restricted to those with a mean follow-up of ≥14 days in which both the combination of aspirin and clopidogrel was tested and mortality was reported.
  
  
  RESULTS
  Twelve trials included 90 934 participants (mean age, 63 years; 70% men; median follow-up, 1 year) with 6849 observed deaths. There was no significant increase in mortality with the combination therapy either in 4 short-term (14 days-3 months; OR, 0.93; 95% CI, 0.87-0.99) or in 7 long-term (>3 months; hazard ratio, 0.97; 95% CI, 0.91-1.04) trials after 1 long-term trial (the SPS3 trial) was excluded because of heterogeneity. Addition of clopidogrel was associated with an increase in fatal hemorrhage (OR, 1.35; 95% CI, 0.97-1.90) and a reduction in myocardial infarction (OR, 0.82; 95% CI, 0.74-0.91).
  
  
  CONCLUSIONS
  The addition of clopidogrel to aspirin has no overall effect on mortality. The SPS3 trial results are outliers, possibly because of a lower prevalence of coronary artery ischemia. Addition of clopidogrel to aspirin increases fatal bleeding and reduces myocardial infarction.
  
  
  BACKGROUND
  URL: http//www.clinicaltrials.gov. Unique identifier: NCT00059306.
authors: Department of Neurology, University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA. palacios0@uthscsa.edu
authors: Santiago
authors: S
authors: Palacio
authors: Robert G
authors: RG
authors: Hart
authors: Lesly A
authors: LA
authors: Pearce
authors: Oscar R
authors: OR
authors: Benavente
mesh_terms: D000328:Adult; D000368:Aged; D001241:Aspirin / Q000627:therapeutic use*; D002423:Cause of Death; D002543:Cerebral Hemorrhage / Q000401:mortality; D000077144:Clopidogrel; D003627:Data Interpretation, Statistical; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006470:Hemorrhage / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000401:mortality / Q000517:prevention & control; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin