There Is No Evidence That the Benefit of Clopidogrel Over Aspirin Is Amplified in Patients With a History of Ischemic Events
To the Editor:
The article by Ringleb et al1 does not prove that the benefit of clopidogrel over aspirin is amplified in patients with a history of ischemic events. The article showed that among a subgroup of patients with preexisting atherosclerotic disease, taken from the CAPRIE trial,2 the relative risk reduction for the outcome of ischemic stroke, myocardial infarction or vascular death for clopidogrel over aspirin was 14.9% (95% CI, 0.3% to 27.3%). This was then compared with the results from the entire CAPRIE population, where the relative risk reduction was 8.7% (95% CI, 0.3% to 16.5%). The CIs for these 2 relative risk reductions overlap greatly, so (ignoring issues around the subgroup not being independent of the whole population) all one can say is that clopidogrel performed somewhat better than aspirin in the whole trial population, and clopidogrel also performed better than aspirin in the subgroup. The apparently increased treatment effect in the high-risk patients could easily have been a chance fluctuation.
To prove that the effect of clopidogrel is amplified in high-risk patients, one would need to test whether the treatment effect is different in high-risk patients to low-risk patients, using a formal test for interaction.3 The appropriate data for this calculation were not presented in the article, but from a rough calculation, we think it is unlikely that such a test would be statistically significant.
In addition to the problems with the statistical analysis, ‘high-risk’ has been defined by simply using a history of atherosclerotic disease. This is overly simplistic, and a more appropriate approach would be to use a prognostic model to divide patients into high-risk and low-risk groups.
It is worrying that an article with such a biased conclusion has been published in the name of the CAPRIE investigators. The authors were, we believe, from contributing clinical centers to the CAPRIE trial, but this article was not approved by the steering committee, as far as we know by the trial statistician.