Clinical pharmacologist’s answer:
The question of the safety of concurrent therapy with proton pump inhibitors (PPIs) and the antiplatelet drug clopidogrel has been a live issue recently, in part due to a study published in JAMA (JAMA 2009;301[9]:937-44). This demonstrated an 86% greater rate of hospitalization due to a second myocardial infarction among patients who had had a first MI and were on clopidogrel with a PPI — in this study, omeprazole or rabeprazole — vs those on clopidogrel without a PPI. The mechanism of the interaction is believed to be inhibition of the enzyme CYP2C19, which is required for the conversion of clopidogrel to its active metabolite. Omeprazole is known to inhibit this enzyme, and thus concurrent therapy would be expected to reduce the effect of clopidogrel, as per the JAMA study. This raises the question of whether this is an effect that is cross-class, i.e. does this apply to all PPIs? Pantoprazole, for example, doesn’t inhibit CYP2C19 and thus one might expect there to be no interaction. But studies have suggested that the situation is not so clear-cut, and CYP2C19 inhibition may not be the only mechanism involved in this drug interaction.

How to proceed: the current recommendation is to first evaluate whether a PPI is in fact indicated. If it is — as when there are GI symptoms that don’t respond to therapy with other drugs such as ranitidine — then the PPI of choice is probably pantoprazole. It’s important that the patient understands the potential for a drug interaction.

Cardiologist’s answer:
The FDA recently updated the clopidogrel label with new warnings on omeprazole and other drugs that inhibit the CYP2C19 enzyme and could interact with clopidogrel in the same way. The manufacturer of clopidogrel is apparently conducting follow-up studies to explore this and other drug interactions.

The FDA, which is still reviewing this issue, now recommends that patients on clopidogrel who need a medication to reduce stomach acid can use antacids or H2 antagonists such as ranitidine, famotidine, or nizatidine, because the agency doesn’t believe that these medicines will interfere with the anti-clotting activity of clopidogrel. The FDA advises against using cimetidine, however, with clopidogrel.

The bottom line is we just don’t know yet. New and often conflicting information keeps appearing every few months. For the time being, I continue to evaluate whether or not a PPI is necessary with each patient taking clopidogrel.

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