Principal Findings:

There were 1960 first events included in the primary endpoint. By intention-to-treat, there were 939 events in the clopidogrel group during 17 636 patient-years at risk, an average rate per year of 5.32 percent. There were 1021 events in the aspirin group during 17 519 patient-years at risk, an average rate per year of 5.83 percent. These rates reflect a statistically significant (p = 0.043) relative-risk reduction of 8.7% (95% Cl, 0.3 to 16.5) in favor of clopidogrel.

For patients with stroke, the average event rate per year in the clopidogrel group was 7.15 percent compared with 7.71 percent in the aspirin group, a relative-risk reduction of 7.3 percent (-5.7 to 18.7) in favor of clopidogrel (p=0.26).

For patients with myocardial infarction, the average event rate per year was 5.03 percent in the clopidogrel group compared with 4.84 percent in the aspirin group; a relative-risk increase of 3.7 percent (22.1 to -12.0) associated with clopidogrel (p=0.66).

For patients with peripheral arterial disease, the average event rate per year in the clopidogrel group was 3.71 percent compared with 4.86 percent in the aspirin group; a relative-risk reduction of 23.8 percent (8.9 to 36.2) in favor of clopidogrel (p=0.0028).

Previous history of vascular events and vascular risk factors show that there was an overlap in the three clinical subgroups. For example, 12 percent of the stroke subgroup and 8 percent peripheral arterial disease reported a history of myocardial infarction. Two percent of the younger myocardial infarction subgroup reported previous stroke and 6 percent peripheral arterial disease. Six percent of the peripheral arterial disease group had experienced a previous stroke and 21 percent a previous myocardial infarction.

To help interpret the apparently discrepant finding in the myocardial infarction subgroup, an additional analysis, not specified in the protocol, was considered relevant because aspirin has similar benefits in preventing major ischaemic events in patients with acute myocardial infarction and in those with a remote history of myocardial infarction. There were 2144 patients in the stroke and peripheral arterial disease groups who had a distant past history of myocardial infarction. When this cohort was combined with the 6302 patients who presented with myocardial infarction as the qualifying event, the overall relative-risk reduction was 7.4 percent (-5.2 to 18.6) in favor of clopidogrel.

There were no major differences in terms of safety. Reported adverse experiences in the clopidogrel and aspirin groups judged to be severe included rash (0.26% vs 0.10%), diarrhoea (0.23% vs 0.11%), upper gastrointestinal discomfort (0.97% vs 1.22%), intracranial haemorrhage (0.33% vs 0.47%), and gastrointestinal haemorrhage (0.52% vs 0.72%), respectively.

There were ten (0.10%) patients in the clopidogrel group with significant reductions in neutrophils (< 1.2 x 10(9)/L) and 16 (0.17%) in the aspirin group.