Cardiologists Shocked by New FDA Alert on Clopidogrel-PPI Interaction

Susan Hughes

Disclosures

November 17, 2009

November 17, 2009 — The FDA has today issued a new public-health warning on the possible interaction between clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) and the proton-pump inhibitor (PPI) omeprazole (Prilosec, Procter & Gamble) [1,2]. The alert states: "New data show that when clopidogrel and omeprazole are taken together, the effectiveness of clopidogrel is reduced. Patients at risk for heart attacks or strokes who use clopidogrel to prevent blood clots will not get the full effect of this medicine if they are also taking omeprazole."

But the timing of the this alert appears peculiar, given that just a few weeks ago, what was said to be the definitive answer to this issue--the only randomized clinical trial on the interaction--was reported, showing absolutely no hint of any reduction in effect of clopidogrel in patients taking omeprazole.

Cardiologists contacted by heartwire were surprised at the new FDA announcement.

Dr Peter Berger (Geisinger Medical Center, Danville, PA) said: "I was shocked by the strengthened warning. Proper subgroup analyses from randomized trials, including CREDO, TRITON, PRINCIPLE, and preliminarily from PLATO and CURRENT, all indicate that no interaction exists. And as shown by the registries, all these trials indicate just how different patients on and not on a PPI are from one another. And then a preliminary analysis of data from the COGENT trial, a trial dedicated to specifically examining clopidogrel with a PPI vs placebo, fails to suggest even the slightest signal of a negative interaction. For the FDA to then strengthen the warning of a interaction is baffling, to say the least."

Dr Christopher Cannon (Brigham and Women's Hospital, Boston, MA) had similar concerns: "It is certainly reasonable for the FDA to inform clinicians of the platelet-function data, but their interpretation of the clinical action oversteps the evidence, I believe. As we know from COGENT, there is not a difference in clinical events when combining clopidogrel with omeprazole. Recommendations on clinical care should be based on randomized trials with clinical end points. For clinical effects of this pharmacologic interaction, what we see are no adverse cardiac effects. We need to see how the final published data look--but I don't think the 'info sheet's' recommendation to avoid these medications is the correct advice based on the clinical data."

Cannon added: "I wonder just what vetting of these clinical recommendations FDA has done. Have they consulted with the relevant specialty societies? The [American Gastroenterological Association] AGA, AHA, or ACC? Hopefully the ACC/AHA/AGA expert panel, cochaired by Drs Deepak Bhatt and Robert Harrington, can meet urgently to review the data and make an updated recommendation (or reaffirm their current standing recommendation--which I think is actually correct as written) that for patients at high risk of GI bleeding on aspirin and clopidogrel we should use PPIs."

The FDA says it is aware of the COGENT study and that "it might provide information about the effect of this interaction on clinical outcome." It adds: "Although the FDA has not fully reviewed the study results, the applicability of these data is limited because of the study design and follow-up."

New Studies From Sponsor

The FDA alert says the new information on which its warning is based comes from new studies conducted by the sponsor that compared the amount of clopidogrel's active metabolite in the blood and its effect on platelets in people who took clopidogrel plus omeprazole vs those who took clopidogrel alone. A reduction in active metabolite levels of about 45% was found in people who received clopidogrel with omeprazole compared with those taking clopidogrel alone. The effect of clopidogrel on platelets was reduced by as much as 47% in people receiving clopidogrel and omeprazole together. These reductions were seen whether the drugs were given at the same time or 12 hours apart, the statement adds.

Based on the current scientific information, the clopidogrel label has been updated with new warnings on omeprazole and other drugs that inhibit the CYP2C19 enzyme that could interact with clopidogrel in the same way. In addition, the manufacturer of clopidogrel is conducting follow-up studies to explore this and other drug interactions.

The agency advises patients using clopidogrel to consult with their healthcare provider if they are currently taking or considering taking omeprazole. It adds that patients who use clopidogrel and need a medication to reduce stomach acid can use antacids or H2 antagonists such as ranitidine, famotidine, or nizatidine, because the FDA does not believe that these medicines will interfere with the anti-clotting activity of clopidogrel. However, cimetidine should not be used, it says.

The FDA adds that the manufacturers of clopidogrel have agreed to look at other possible drug interactions with clopidogrel.

It also says that other drugs that are potent inhibitors of the CYP2C19 enzyme would be expected to have a similar effect and should be avoided in combination with clopidogrel. These include: cimetidine, fluconazole, ketoconazole, voriconazole, etravirine, felbamate, fluoxetine, fluvoxamine, and ticlopidine. "Since the level of inhibition among other PPIs varies, it is unknown to what amount other PPIs may interfere with clopidogrel. However, esomeprazole, a PPI that is a component of omeprazole, inhibits CYP2C19 and should also be avoided in combination with clopidogrel," it adds.

The FDA says it is continuing to investigate other drug interactions with clopidogrel and plans to present on this issue at the next meeting of FDA's Drug Safety Oversight Board in November.

  1. Food and Drug Adminstration. Public-health advisory: Updated safety information about a drug interaction between clopidogrel bisulfate (marketed as Plavix) and omeprazole (marketed as Prilosec and Prilosec OTC). November 17, 2009. Available here.

The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

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