Brest, France -The proton pump inhibitor (PPI) omeprazole reduces the antiplatelet effect of clopidogrel, a new study shows [1]. But researchers prominent in the antiplatelet field warn about attaching too much significance to this ex vivo study.

The study is published in the January 22, 2008 issue of the Journal of the American College of Cardiology and is available online January 14.

The authors, led by Dr Martine Gilard (Brest University Hospital, France), explain that clopidogrel is converted to its active metabolite by P-450 isoenzymes, which are also involved in the metabolism of PPIs such as omeprazole. They also point out that patients receiving clopidogrel and aspirin dual therapy after coronary stenting are commonly treated with proton pump inhibitors to protect against gastrointestinal bleeding. They note that in a previous observational study of patients taking clopidogrel, those who were PPI users had a higher platelet reactivity index, and they therefore conducted the current randomized double-blind study to assess whether the action of clopidogrel would be reduced in patients also taking omeprazole.

The study included 124 consecutive patients undergoing coronary stenting and receiving aspirin (75 mg daily) and clopidogrel (loading dose and then 75 mg daily), who were randomized to receive omeprazole (20 mg/day) or placebo for seven days. The effectiveness of clopidogrel on platelet inhibition was tested on day 1 and day 7 by measuring intraplatelet vasodilator-stimulated phosphoprotein phosphorylation, which provides an index of platelet reactivity with clopidogrel: the higher the platelet reactivity index, the more frequently thrombosis occurs under clopidogrel.

Results showed that omeprazole significantly reduced the inhibitory effect of clopidogrel on platelets.

Using the definition of Barragan et al for "bad" clopidogrel responders that correlated with an increase risk of stent thrombosis (platelet reactivity index greater than 50%) [2], Gilard et al report there was a more than a fourfold greater chance of being a clopidogrel "bad responder" when patients were treated with omeprazole.

Gilard et al conclude: "The clinical impact of these results must be assessed by further investigations, but we recommend not systematically adding a PPI treatment to the antiplatelet dual therapy without formal indication."

In an accompanying editorial [3], a group led by Dr Paul Gurbel (Sinai Hospital of Baltimore, MD) notes that this study is of significant interest, as proton pump inhibitors are commonly coadministered with clopidogrel in the hope of attenuating gastrointestinal bleeding. However, there are no data or guideline recommendations to support prophylactic PPI administration in reducing GI bleeding in asymptomatic elective stent patients, they add. They suggest that the influence of omeprazole may be more important in patients who receive high-dose lipophilic statins that may potentiate significant drug-drug interactions with clopidogrel.

Gurbel et al further point out that the study has several limitations, including the fact that it did not exclude clopidogrel nonresponders and did not include any mechanistic investigations. "An improved patient selection scheme and pharmacokinetic/pharmacodynamic investigations are required before any clinical significance can be attributed to this reported drug-drug interaction or any suggestions are made that cardiologists should delete omeprazole therapy when clinically indicated in patients treated with dual antiplatelet therapy," they say.

Gurbel et al also make the point that there is a need for a definitive large-scale trial to determine whether high platelet reactivity determined by an ex vivo test truly identifies the patient at risk for thrombotic events. "If the relationship indeed exists and if subsequent studies can demonstrate that lower platelet reactivity in the individual patient leads to better outcomes, then the 'one-size-fits-all' approach to treatment that we currently employ will vanish. At that time the observations of Gilard et al will have increased relevance. We will then live in the era of personalized medicine, where measurements of platelet reactivity in all patients with cardiovascular disease will be routine and treatment will be adjusted accordingly. However, a lot of work remains before we are there," they conclude.

Other antiplatelet experts are also cautious about taking any clinical implications from this ex vivo study.

Dr Peter Berger (Geisinger Medical Center, Danville, PA) commented to heartwire: "Remember atorvastatin and clopidogrel? This feels so like déjà vu all over again." He notes that there are "a very large number of studies suggesting that there does not appear be to any clinically apparent interaction between clopidogrel and atorvastatin, nicely summarized in an excellent American Heart Journal editorial by Steve Steinhubl et al [4]." This conclusion has been further strengthened by subsequent analyses from two randomized trials, the >16 000-patient CHARISMA trial and the >4000 patient PROVE-IT study (which administered high-dose 80 mg of atorvastatin), both of which also found no clinically significant interaction between atorvastatin and clopidogrel, he adds. "Maybe the situation with omeprazole and other proton pump inhibitors will be different from atorvastatin and other lipophilic statins. But to downplay the large number of studies suggesting no clinically significant interaction between atorvastatin and clopidogrel and at the same time raise similar concerns among physicians and patients about another common drug or class of drugs exactly as was done with atorvastatin raises questions," Berger said.

Dr Steven Steinhubl (University of Kentucky, Lexington) has similar concerns. He told heartwire: "Unfortunately, it is too rare for investigators in this field to acknowledge the multiple limitations to platelet function testing and its applicability to clinical outcomes. Certainly, our experience with the oral GP IIb/IIIa antagonists should have raised some red flags about the lack of correlation between inhibition of platelet aggregation in a test tube and clinical outcomes." Nonetheless, when a small but well-done study found that some statins significantly reduced clopidogrel-induced platelet inhibition, many warnings were issued against prescribing clopidogrel with atorvastatin or simvastatin, Steinhubl notes. A vast amount of clinical data subsequently refuted the importance of these ex vivo findings, but not before a large number of patients were likely harmed by being forced to stop their statin therapy, he adds.

"Could the proton-pump-inhibitor-clopidogrel interaction be clinically important? Possibly. But it must be acknowledged that these ex vivo data may be clinically meaningless, and in fact, if history is a guide, that is more likely than not to be the case," he says.