Interaction of Clopidogrel and Omeprazole

Interaction of Clopidogrel and OmeprazoleTo the Editor: The label for clopidogrel warns physicians to "avoid concomitant use of . . .strong or moderate CYP2C19 inhibitors."Such inhibitors (e.g., omeprazole) decrease the formation of the active metabolite of clopidogrel, the source of its antiplatelet effects.The results of the Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT; ClinicalTrials.govnumber, NCT00557921), described by Bhatt and colleagues 1 in this issue of the Journal, have been interpreted as showing that the clopidogrel-omeprazole interaction is unimportant.The study, however, does not support that conclusion.Clopidogrel therapy reduces the rate of major cardiovascular events in patients with an acute coronary syndrome by approximately 20%.Its effects on other cardiovascular events and in patients without an acute coronary syndrome are unknown.In COGENT, fewer than half the patients had an acute coronary syndrome at the time of enrollment, and the primary cardiovascular end point included not only major cardiovascular events but also coronary revascularization.Thus, the clinical setting and cardiovascular end point evaluated in COGENT are inconsistent with the clinical-trial environment that was the basis for the clopidogrel label.These dissimilarities are critical to the ability of COGENT to have revealed any difference between the omeprazole group and the placebo group and limit the interpretability of the findings.Even if these dissimilarities were not an issue, there were 43 major cardiovascular events in COGENT: 23 in the omeprazole group and 20 in the placebo group, for a relative risk of 1.15 favoring placebo -too few events to draw any conclusions but certainly not reassuring as to the absence of an effect of omeprazole.With respect to the relatively few cardiovascular-end-point events (109) that occurred, the authors' conclusion that "our results do not rule out a clinically meaningful difference in cardiovascular events due to use of a PPI [proton-pump inhibitor]" is entirely correct.We believe that the evidence indicates that, as stated in the clopidogrel label, concomitant use of clopidogrel and omeprazole should be avoided.