Systematic review and meta-analysis of adverse events of low-dose aspirin and clopidogrel in randomized controlled trials

Am J Med. 2006 Aug;119(8):624-38. doi: 10.1016/j.amjmed.2005.10.039.


Purpose: We performed a systematic review to define the relative and absolute risk of clinically relevant adverse events with the antiplatelet agents, aspirin and clopidogrel.

Materials and methods: Databases were searched for randomized controlled trials of low-dose aspirin (75-325 mg/day) or clopidogrel administered for cardiovascular prophylaxis. Relative risks (RR) were determined by meta-analysis of 22 trials for aspirin versus placebo and from single studies for aspirin versus clopidogrel, aspirin versus aspirin/clopidogrel, and clopidogrel versus aspirin/clopidogrel. Absolute risk increase was calculated by multiplying RR increase by the pooled weighted incidence of the control.

Results: Aspirin increased the risk of major bleeding (RR=1.71; 95% confidence interval [CI], 1.41-2.08), major gastrointestinal (GI) bleeding (RR=2.07; 95% CI, 1.61-2.66), and intracranial bleeding (RR=1.65; 95% CI, 1.06-5.99) versus placebo. No difference between 75-162.5 mg/day and >162.5-325 mg/day aspirin versus placebo was seen. The absolute annual increases attributable to aspirin were major bleeding: 0.13% (95% CI, 0.08-0.20); major GI bleeding: 0.12% (95% CI, 0.07-0.19), intracranial bleeding: 0.03% (95% CI, 0.01-0.08). No study compared clopidogrel with placebo. One study showed increased major GI bleeding (but not non-GI bleeding endpoints) with aspirin versus clopidogrel (RR=1.45; 95% CI, 1.00-2.10). The absolute annual increase was 0.12% (95% CI, 0.00-0.28).

Conclusions: Low-dose aspirin increases the risk of major bleeding by approximately 70%, but the absolute increase is modest: 769 patients (95% CI, 500-1250) need to be treated with aspirin to cause one additional major bleeding episode annually. Compared with clopidogrel, aspirin increases the risk of GI bleeding but not other bleeding; however, 883 patients (95% CI, 357-infinity) would need to be treated with clopidogrel versus aspirin to prevent one major GI bleeding episode annually at a cost of over 1 million dollars.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Aspirin / administration & dosage*
  • Aspirin / adverse effects*
  • Aspirin / economics
  • Clopidogrel
  • Humans
  • Platelet Aggregation Inhibitors / administration & dosage*
  • Platelet Aggregation Inhibitors / adverse effects*
  • Ticlopidine / adverse effects
  • Ticlopidine / analogs & derivatives*
  • Ticlopidine / economics


  • Platelet Aggregation Inhibitors
  • Clopidogrel
  • Ticlopidine
  • Aspirin