Investigator Declares End to Clopidogrel-PPI Controversy

Cheryl A. Thompson

SAN FRANCISCO, CA 25 September 2009—The first randomized clinical trial of a proton pump inhibitor in patients taking clopidogrel and aspirin found no increase in the rate of major cardiovascular events, an investigator announced Thursday at a medical conference in San Francisco.

Deepak L. Bhatt, director of the Integrated Interventional Cardiovascular Program at Brigham and Women's Hospital and the Veterans Affairs Boston Healthcare System, presented preliminary results of the Phase III study known as Clopidogrel and the Optimization of Gastrointestinal Events, or COGENT.

The study was terminated early by the sponsor, Cogentus Pharmaceuticals Inc., because of bankruptcy.

Cogentus had been developing a combination product containing 75 mg of clopidogrel and 20 mg of omeprazole.

The goal, the company had said, was to market a product that had a standard dose of the antiplatelet drug and enough omeprazole to reduce the likelihood of gastrointestinal bleeding and symptomatic ulcer disease during concomitant aspirin therapy.

Dual antiplatelet therapy with clopidogrel and aspirin has been recommended for certain patients by two prominent cardiology associations.

Patients receiving clopidogrel and concomitant aspirin or a nonsteroidal antiinflammatory drug, however, have a higher risk of bleeding and ulcer disease than those taking only one of the drugs, Cogentus said in explaining its rationale.

Despite early termination of the study and bankruptcy of the company, Bhatt, other COGENT investigators, and the former study director decided to analyze the data that had been accumulated.

Bhatt reported there were 69 occurrences of cardiovascular-related death, nonfatal myocardial infarction, coronary artery bypass graft surgery, percutaneous coronary intervention, or confirmed ischemic stroke among the 1806 patients who received enteric-coated aspirin and the clopidogrel–omeprazole capsule daily. Two fewer such events occurred among the 1821 patients who received enteric-coated aspirin and clopidogrel but not omeprazole.

Bhatt said clopidogrel–omeprazole therapy had a hazards ratio of 1.02, which is insignificant, with respect to cardiovascular events.

As for gastrointestinal events, fewer occurred in the group that received omeprazole. The hazards ratio was 0.55.

"The data provide strong reassurance that there is no clinically relevant adverse cardiovascular interaction between clopidogrel and proton pump inhibitors," Bhatt told attendees of Transcatheter Cardiovascular Therapeutics 2009.

But Esther J. Last, coauthor of the publish-ahead-of-print AJHP article (PDF) "Review of Recent Evidence: Potential Interaction Between Clopidogrel and Proton Pump Inhibitors," disagreed.

What Bhatt announced about the study’s data "doesn’t completely answer the question," Last said. "I think it’s an important piece of the entire clinical picture that we’re facing right now in patients who either need both clopidogrel and a proton pump inhibitor or have been put on both of them."

"But," she continued, "given that it is a preliminary report, I’m not sure that we can draw clinical conclusions at this stage."

According to the registry at ClinicalTrials.gov, the COGENT study started in December 2007 and was expected to end in November 2009.

Even though the study ended early, enrollment exceeded the initial target of 3200 patients, Bhatt said. The final target was 5000 because gastrointestinal events, the primary outcome, had been occurring at a lower-than-expected rate overall.

Half of the patients, he said, had been followed by the investigators for 19 weeks or less when the study was stopped.

Bhatt, who served as a consultant to Cogentus, publicly dismissed the study’s early termination as a limitation to the findings on cardiovascular events.

The cardiovascular events that clopidogrel helps prevent tend to happen soon after the occurrence of acute coronary syndrome symptoms or new placement of a coronary artery stent, he said.

Last said clinicians need to keep in mind that the study was designed primarily to measure the rates of gastrointestinal events. The study might have lacked the power to find a difference in the rates of cardiovascular events, she said.

Bhatt noted that the cardiovascular-event rate in the COGENT study may not transfer to a setting in which patients receive commercially available clopidogrel and proton pump inhibitor products.

According to the patent application for the combination product, the capsules’ dissolution characteristics for the omeprazole component were significantly different from those of omeprazole capsules from AstraZeneca, maker of the brand-name product Prilosec. Also, the omeprazole component of the combination product was absorbed later then the omeprazole in Prilosec delayed-release capsules.

Bhatt suggested that clinicians concerned about the difference in formulations could have their patients take clopidogrel in the morning and omeprazole in the evening.

His suggestion may not work, however. Last said most, if not all, of the observational studies in which a cardiovascular risk was found for concomitant clopidogrel and proton pump inhibitor therapy did not control for the time of day when patients took the drugs. Those patients might have taken the medications separately, she said.

Last said her employer, Clarian Health Partners in Indianapolis, would not be inclined to incorporate the preliminary results described by Bhatt into practice just yet.

"What we know from what’s been published already is that there may be a safety concern," Last said. "It is our opinion that it’s better to err on the side of being safer rather than insist on jumping when . . . new changes in information come out, especially when we have some questions about the data and how they were analyzed and presented as results."

Transcatheter Cardiovascular Therapeutics is an annual symposium sponsored by the Cardiovascular Research Foundation. The foundation calls its event the largest global medical and scientific symposium on interventional cardiovascular medicine.