Article

Original Article

Clopidogrel with or without Omeprazole in Coronary Artery Disease

 

 

On the basis of data from several studies, clopidogrel has become the second most commonly used prescription drug worldwide.1-9 Gastrointestinal hemorrhage is the most common serious bleeding complication from the use of long-term antiplatelet therapy.10,11 Data from randomized studies support the concept that therapies reducing acidity decrease gastrointestinal complications of antiplatelet therapy involving aspirin, though the data are largely based on endoscopic end points; observational data also support this effect.12-16 Randomized, controlled trials have shown that proton-pump inhibitors (PPIs) reduce the rate of recurrent gastrointestinal bleeding in high-risk patients receiving aspirin.17 Observational studies, however, have suggested that there may be an interaction between clopidogrel and PPIs that, if real, could have significant clinical effects.18,19 These studies have been bolstered by results of ex vivo analyses, many of which have shown inhibition of the antiplatelet effect of clopidogrel by PPIs, omeprazole most consistently.20-22 In addition, genetic polymorphisms have been identified that could affect the response to clopidogrel and, at least theoretically, could increase the likelihood of drug interactions mediated by cytochrome P-450.23-27 A number of other observational studies, however, did not show an interaction between clopidogrel and PPIs.28,29 Given the conflicting data regarding a possible interaction, the optimal care of patients who require concomitant therapy with clopidogrel and PPIs remains uncertain.30-34
We initiated the Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT) to assess the efficacy and safety of concomitant administration of clopidogrel and PPIs in patients with coronary artery disease who are receiving clopidogrel plus aspirin.

Methods

Study Conduct

The trial was designed by an academic steering committee (see the Supplementary Appendix, available with the full text of this article at NEJM.org) and the sponsor, Cogentus Pharmaceuticals. The steering committee was responsible for the overall leadership of the trial. A clinical research organization, Parexel, performed the data management and site monitoring. Randomization was performed centrally with the use of an interactive voice-response system before the initiation of study treatment. Parexel generated the randomization sequence. All sites operated under approval from institutional review boards or ethics committees, and all patients gave written informed consent to participate in the trial. The study was conducted according to the study protocol (available at NEJM.org). At the conclusion of the trial, the full database was transferred to an academic principal investigator. The analyses were performed independently of the sponsor, by two academic authors. An academic principal investigator prepared the first draft of the manuscript, which was then reviewed and edited by the academic steering committee and other authors; all the academic authors made the decision to submit the paper for publication. There was no agreement made regarding confidentiality of the data between the sponsor and the academic authors or their institutions. The sponsor did not have the right to approve the final manuscript. The academic principal investigators vouch for the accuracy and integrity of the analyses and interpretation of the data.