Proton pump inhibitors and clopidogrel: A difficult dilemma

To the Editor: It was with great interest that we read the article by SillerMatula et al on the effect of pantoprazole and esomeprazole on platelet inhibition by clopidogrel, in particular after several recent studies have suggested a significant interaction between clopidogrel and proton pump inhibitors (PPIs). Recently, results from a randomized double-blind, placebo-controlled trial by Gilard et al suggested that omeprazole decreased the inhibitory effect of clopidogrel on platelet aggregation. A large population-based study from the National Medco Integrated Database file found an odds ratio for major cardiovascular events within 1 year of 1.79 (95% confidence interval 1.62-1.97) in patients on PPIs and clopidogrel compared with those on clopidogrel alone. The study by Siller-Matula et al concludes that in contrast to the negative omeprazole-clopidogrel drug interaction, the intake of pantoprazole or esomeprazole is not associated with impaired response to clopidogrel. However, several remarks can be made concerning the observations by SillerMatula et al. First, although the authors describe that they have corrected for differences in baseline characteristics using multivariable logistic regression, it cannot be ignored that relatively large differences are present in important covariates such as use of calcium-channel blockers, drugs from which these same authors have described that they influence the antiplatelet effect of clopidogrel. Second and most importantly, the conclusions are drawn from a nonrandomized, observational study, and the results are vulnerable to residual confounding. For instance, possible differences in well-known influencing factors such as the indication for the stent implantation (either stable angina or an acute coronary syndrome) as well as the mean duration in clopidogrel pretreatment between the 2 groups could have influenced the magnitude of the effect. The results should therefore be interpreted with caution. Siller-Matula et al should be congratulated for their efforts to shed more light on the difficult dilemma of opting for an increased risk of upper gastrointestinal hemorrhage or for a potential increased risk of thrombosis, but a solution for this problem is not provided. Moreover, a convincing pharmacological explanation for the observed differences between the PPIs, studied is also lacking. Unfortunately the Clopidogrel and Optimization of Gastrointestinal Events (COGENT-1) trial, in which patients were randomized between clopidogrel and omeprazole versus clopidogrel alone, has been aborted, and before more data become available, it is recommended to follow the guidelines and restrict prescription of PPIs to those patients who are at increased risk for gastroduodenal toxicity of aspirin and clopidogrel.