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Clinical Assistant Professor, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, 313 Cooke Hall, Buffalo, NY 14260, fax 716/645-3688, nnorgard{at}buffalo.edu
Internal Medicine Clinical Pharmacist, Iowa Methodist Medical Center, Associate Professor of Pharmacy Practice, College of Pharmacy and Health Sciences, Drake University, Des Moines, IA
Published Online, December 22, 2009. www.theannals.com, DOI 10.1345/aph.1M051b
Our recommendation of pantoprazole was based more on pharmacologic evidence than on data from observational studies. Pharmacologically, pantoprazole, compared with other PPIs, has little influence on the CYP2C19 isoenzyme, making an interaction with clopidogrel unlikely. This argument was strengthened by a prospective, randomized study that compared the influence of omeprazole and pantoprazole on the pharmacodynamic effect of clopidogrel.2 Patients in the pantoprazole group had a significantly better platelet response to clopidogrel and fewer clopidogrel nonresponders.
While all PPIs were shown to be associated with harm in a majority of observational studies, pantoprazole was found to lack this association in one large analysis.3 That claim cannot currently be made for any of the other PPIs. The Clopidogrel Medco Outcomes Study showed that all PPIs were associated with a higher risk of major adverse cardiovascular events.4 The study did not directly compare the PPIs; therefore, it is inappropriate to claim that pantoprazole was the PPI associated with the highest risk. If a comparison were made, it would likely not be statistically significant. When we looked at the data as a whole, pantoprazole stood out as the PPI of choice when used concurrently with clopidogrel. Additionally, pantoprazole's availability as a generic medication further increases its preference in our recommendations. However, platelet assays and observational data are not substitutes for randomized, placebo-controlled data.
Fortunately, this interaction was recently evaluated in a study in which patients were randomized either to a fixed dose of clopidogrel and omeprazole or to clopidogrel with placebo.1 There was no significant difference in the incidence of adverse cardiac events between the clopidogrel plus omeprazole and the clopidogrel-alone groups (HR 1.02, 95% CI 0.70 to 1.51)1 Additionally, the incidence of composite gastrointestinal events was significantly lower in the clopidogrel/omeprazole group. The results of this trial indicate that the concomitant use of clopidogrel with omeprazole may not be associated with an increase in adverse cardiovascular events, as suggested by observational studies. However, we must consider that this study was stopped early, did not reach the target enrollment of 5000 patients, and was not powered to evaluate cardiac outcomes, putting it at risk of type 2 error.
Medical history is replete with examples of observational data not being confirmed prospectively. To date, PPIs seem to have a modest effect on clopidogrel response, which may have an influence on clinical events in a moderate-risk population. However, we feel that we must still be cautious in patients at high risk or in those having intrinsic platelet problems (ie, diabetes). More prospective studies are needed in this population.
Footnotes
Financial disclosure: None reported
References
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