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Heartwire 2009. © 2009 Medscape

April 10, 2009 (Munich, Germany) — A new study using platelet-aggregometry testing to assess the effects of different proton-pump inhibitors (PPIs) on platelet response to clopidogrel suggests that omeprazole might be alone in adversely interacting with the widely used antiplatelet therapy [1]. The study, published in the April issue of Thrombosis and Haemostasis, hints that other PPIs tested--pantoprazole and esomeprazole--might be a safer bet for minimizing gastrointestinal side effects and bleeding in patients requiring long-term clopidogrel treatment.

But the authors also caution that their study was restricted to testing platelet response, using just one of many tests developed to evaluate platelet function and that it included no hard clinical end points. "Specifically designed and randomized clinical studies are needed to define the impact of concomitant PPI treatment on adverse events after percutaneous coronary intervention," Dr Dirk Sibbing and colleagues (Deutsches Herzzentrum, Munich, Germany) write.

Sibbing et al performed platelet-function testing (using the Dynabyte Multiplate point-of-care impedance aggregometer) in 1000 patients who had undergone PCI and stenting and were taking dual antiplatelet therapy (aspirin and clopidogrel 75 mg/day). Of these, 268 patients were also taking PPIs at the time of testing (162 were taking pantoprazole, 64 omeprazole, and 42 esomeprazole); the remainder were not taking a PPI.

As the authors report, platelet aggregation was significantly different between the four groups, with platelet aggregation significantly higher in the omeprazole group than in the group not taking a PPI. By contrast, patients in the pantoprazole and esomeprazole groups had similar platelet aggregation to those in the group not taking a PPI. In multivariate analyses, only administration of omeprazole was associated with a reduced response to clopidogrel, they note.

"This is the first study comparing the impact of concomitant treatment with three different PPIs (pantoprazole, omeprazole, and esomeprazole) on platelet response to clopidogrel treatment in a large cohort of patients with previous coronary stent placement," Sibbing told heartwire "Diverging effects on clopidogrel response for different PPIs in one and the same study population have never been demonstrated before and are now shown by our study."

An Important Contribution

The role and relative value of different platelet-function tests continue to prompt debate; the authors of the current study point out that their findings corroborate those of the OCLA study, which used a different type of assay to gauge clopidogrel responsiveness. "Both assays provided similar results regarding the impact of omeprazole on clopidogrel response, which is a strong clue for the effect observed," they note.

Sibbing told heartwire that the point-of-care assay used for platelet-function testing in this study "is widely used and accepted." Other recent work by Sibbing's group has also demonstrated the ability of the same assay to predict the occurrence of stent thrombosis and other ischemic events following PCI in more than 1600 patients [2].

An editorial accompanying Sibbing et al's paper by Drs Victor Serebruany (Johns Hopkins University, Baltimore, MD) and Shinya Goto (Tokai University, Kanagawa, Japan) [3] calls the study a "timely, elegant, well-designed . . . important contribution to the field."

Drs Serebruany and Goto point out that PPIs are widely prescribed by physicians for symptomatic relief, rather than as therapy for a confirmed diagnosis of a range of gastrointestinal syndromes. Sibbing et al's study, on top of other recent studies, suggests that omeprazole, but not other PPIs, diminish the antiplatelet potency of clopidogrel--the upshot being that physicians could be putting patients at risk for little gain. "Use of [a] clopidogrel and PPI combination is difficult to justify since the gastrointestinal protection comes at the expense of reducing the vascular benefit of clopidogrel," they write. For now, they conclude, the combination "cannot be recommended until more randomized and mechanistic data become available."

That advice directly contradicts current guidelines, which recommend prescription of a PPI in all patients taking dual antiplatelet therapy. "Findings of the present study may have important clinical implications in terms of PPI selection in patients under dual antiplatelet treatment," Sibbing et al write.

Sibbing also agreed that the way omeprazole and clopidogrel interact requires further study. "Based on the clinical and platelet-function data available, it must be assumed that the adverse effects of omeprazole are, to a significant proportion, related to platelet effects," he said. "Other mechanisms, however, cannot be excluded and warrant further investigations."

They also offer the caveat that although their study showed similar results for both pantoprazole and esomeprazole, the study was only powered to consider pantoprazole treatment.

More answers are expected at the upcoming SCAI meeting in Las Vegas, where investigators for the Clopidogrel Medco Outcomes Study, addressing the effects of clopidogrel and individual PPIs, will be releasing new results.

Sibbing disclosed receiving speaker fees from Dynabyte (modest level), and fees for advisory-board activities from Eli Lilly (modest level). The study was funded by Dynabyte.

1. Sibbing D, Morath T, Stegherr J, et al. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost 2009; 101:714-719. Abstract
2. Sibbing D, Braun S, Morath T, et al. Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol 2009; 53:849-856. Abstract
3. Serebruany V, Goto S. Clopidogrel and proton pump inhibitors: Gastric protection at expense of vascular benefit? Thromb Haemost 2009; 101:607-609. Abstract

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