What's the latest word on the clopidogrel-PPI interaction?

Some time ago I linked to a study on the clopidogrel-PPI interaction. The nature of the interaction is inhibition of CYP 2C19, the enzyme responsible for biotransformation of the parent drug clopidogrel to the active drug, thus diminishing the effectiveness of clopidogrel (Plavix). In that study pantoprazole (Protonix), which does not inhibit cytochrome P450 2C19, was singular in its lack of association with bad outcomes. Although I tentatively concluded that pantoprazole was safe, controversy and uncertainty has persisted.

A subsequent retrospective cohort study confirmed adverse outcomes associated with the combined use of PPIs and clopidogrel in patients with ACS. That study did not distinguish between PPIs and the number of patients taking pantoprazole was too small to analyze.

ACC/AHA has addressed this issue in a recent focused guideline update:

Some studies have suggested that adverse cardiovascular outcomes with the combination of clopidogrel and a PPI are explained by the individual PPI, in particular the use of a PPI that inhibits CYP450 2C19, which includes omeprazole, lansoprazole, and rabeprazole. The PPI omeprazole notably has been reported to significantly decrease the inhibitory effect of clopidogrel on platelet aggregation (63,64). One study reported that the PPI pantoprazole was not associated with recurrent MI among patients receiving clopidogrel, possibly because of its lack of inhibition of CYP450 2C19 (33).

...The FDA communication concerning an ongoing safety review of clopidogrel bisulfate (66) advises that healthcare providers avoid the use of clopidogrel in patients with impaired CYP2C19 function due to known genetic variation or due to drugs that inhibit CYP2C19 activity. The FDA notes there is no evidence that other drugs that reduce stomach acid, such as H2 blockers or antacids, interfere with the antiplatelet activity of clopidogrel.

Further research with thienopyridines and PPI combinations, particularly drugs that are not dependent on CYP450 2C19, is needed.

...The writing committee concluded that additional data, notably randomized controlled clinical trial data that have been peer reviewed and published, are needed before an official recommendation can be made about the use of dual antiplatelet therapy with PPIs in the setting of ACS.

So, ACC and AHA come short of a formal recommendation. What's the most prudent course of action? Patients on the combination should have their indications for the PPI reviewed carefully. Many patients are on PPIs for weak indications and should have the PPI discontinued. Consider an H2 blocker as an alternative. If PPI therapy cannot be discontinued pantoprazole may be safe.