Did FDA ignore COGENT to slap warning on clopidogrel/PPI interaction?

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The FDA is requiring a labeling change to Sanofi-Aventis and Bristol-Myers Squibb’s blockbuster anti-bloodclotting drug clopidogrel (Plavix) to indicate that it should not be used with AstraZeneca’s proton pump inhibitor (PPI) omeprazole (Prilosec/Prilosec OTC) and some other acid-reducing drugs.

The agency said that “new data suggest that when patients take both Prilosec and Plavix, Plavix’s ability to block platelet aggregation may be reduced by about half.”

However, the American College of Cardiology/American Heart Association issued a joint statement on the FDA’s public health advisory, noting the data referred to by the FDA are not yet “peer-reviewed and published.”

Also, the first and only randomized, placebo-controlled trial, COGENT, found that the combination of PPIs and clopidogrel did not lead to adverse events—the results were presented at the 2009 Transcatheter Cardiovascular Therapeutics (TCT) scientific symposium in late September.

Prior to COGENT’s release, there have been a series of observational studies and smaller trials, published in high-profile peer-reviewed journals, such as JACC and JAMA, which suggested that omeprazole and other PPIs diminished the platelet inhibitory effect of clopidogrel, leading to adverse events—which prompted the FDA to investigate the matter.

Yet, COGENT’s lead investigator Deepak Bhatt, MD, chief of cardiology at VA Boston Healthcare System and director of integrated interventional cardiovascular program at Brigham and Women’s Hospital in Boston, said that there has been a “lack of data” to suggest that PPIs can adversely effect patients also taking Plavix. According to investigators, this trial was the first one powered to answer this question for both GI and cardiovascular events.

After issuing an Early Communication in January about possible drug interactions involving Plavix, the FDA requested new studies from the drug’s manufacturers. The agency said that the “new studies support the existence of a significant interaction that could negatively impact a person’s health. Based on the current scientific information, the Plavix label has been updated with new warnings about the use of Prilosec and other drugs that inhibit the CYP2C19 enzyme and that could interact with Plavix in the same way.”

The FDA public health advisory lists other medications including antacids and medicines that reduce stomach acid (ranitidine, famotidine, nizatidine) that do not interfere with the anti-clotting activity of clopidogrel, but they suggest that cimetidine should not be used.

According to the ACC/AHA, the FDA’s statement is “not based on any new published, peer-reviewed clinical trials showing changes in cardiovascular outcomes.”