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Why the COGENT trial results matter
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A major concern for practitioners and the public revolves around the potential interaction between proton pump inhibitor medications and clopidogrel, an agent widely used with aspirin to prevent thrombotic complications after the deployment of drug-eluting stents during percutaneous coronary intervention.
Because proton pump inhibitors (PPIs), notably omeprazole and clopidogrel, are commonly combined in clinical practice, these concerns have received widespread coverage in the lay press, as well as in the medical literature. Ultimately, such issues require event studies that examine clinical endpoints to determine the net effect of pharmacokinetic and pharmacodynamic consequences of drug-drug interactions. Although other antiplatelet drugs that target the purinergic receptor P2Y12 are on the clinical horizon, the interaction of PPIs with clopidogrel, specifically, will have enduring clinical importance as this thienopyridine derivative becomes available in a generic form.
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Clopidogrel and Optimization of Gastrointestinal Events (COGENT), a randomized clinical trial, addressed this important issue by examining patients on dual antiplatelet therapy with or without co-administration of omeprazole. The study also provided an opportunity to ask whether the addition of omeprazole to dual antiplatelet therapy would influence gastrointestinal endpoints in a cohort of patients under the care of clinical cardiologists.
Indeed, this randomized trial of almost 4,000 patients showed a clear-cut and highly statistically significant decrease in gastrointestinal events in those receiving omeprazole besides dual antiplatelet therapy. The gastrointestinal endpoints included bleeding outcomes and gastroduodenal ulcers or erosion — all endpoints of high clinical importance. Thus, COGENT provided important new information about the benefits of omeprazole combined with dual antiplatelet therapy, consisting of aspirin plus clopidogrel. The other goal of the study, a definitive evaluation of a clinically important interaction between PPIs and clopidogrel, did not show a signal for increased CV events in the PPI-treated group.
The COGENT trial was terminated prematurely because of the inability of the industry sponsor to continue its financial support. For this reason, the anticipated number of patients enrolled and the follow-up time were less than planned. Hence, the trial suffers from the potential of being underpowered for events — a type II error. The result, however, agrees with previous observational data that suggest a lack of clinically important interaction between omeprazole and a clopidogrel-based dual antiplatelet regimen.
While tests of platelet aggregation ex vivo do show a pharmacodynamic interaction, neither COGENT nor previous observational studies support a clinically important interaction. Because of the clear benefit on gastrointestinal events, clinicians should consider PPI therapy for patients with risk factors for gastrointestinal bleeding or ulcer disease who require dual antiplatelet therapy.
Thus, COGENT provided important clinical information that informs our approach to the optimum management of patients with CVD who are at risk for gastrointestinal complications. The trial also provides an illustration of why non-industrial support for comparative effectiveness or risk-benefit studies should remain a priority. This well-designed clinical trial did not provide as much information to guide our practice as it should have because of the financial straits of its industry sponsor. There should be mechanisms for noncommercial and stable support for asking important questions about clinical effectiveness to facilitate the performance of key studies to guide our practice and promote public health.
Peter Libby, MD, is chief of cardiovascular medicine at Brigham and Women’s Hospital, in Boston, and is co-section editor of the Vascular Medicine/Intervention section of the Cardiology Today Editorial Board.