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Clinical Pharmacy Specialist—Cardiology, Providence Health Care—Vancouver Coastal Medication Use, Management Group, Pharmacy Department, St. Paul's Hospital, 1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada, fax 604/806-8154, dchua{at}providencehealth.bc.ca
Head, Providence Health Care—Vancouver Coastal Medication Use, Management Group
Medication Use Management Pharmacist, Providence Health Care—Vancouver Coastal Medication Use, Management Group
Medication Use Management Pharmacist, Providence Health Care—Vancouver Coastal Medication Use, Management Group
Clinical Coordinator, Providence Health Care—Vancouver Coastal Medication Use, Management Group
Published Online, December 22, 2009. www.theannals.com, DOI 10.1345/aph.1M051a
Norgard et al. based their conclusion on the Ontario Public Drug Program study2 and the Veterans Health Administration study.3 However, it was only the Ontario study that suggested that pantoprazole does not appear to clinically interact with clopidogrel, compared to other PPIs. This was based on subgroup analysis of this retrospective study, and the statistical significance of the pantoprazole group is questionable. As well, the Ontario study was a retrospective cohort study that only established an association between the use of pantoprazole and the lack of increased adverse cardiac outcomes. The Veterans Health Administration study mainly involved omeprazole and rabeprazole usage; the pantoprazole cohort had too few patients for any meaningful analyses. Thus, the conclusion of Norgard et al. to use pantoprazole is supported only by the Ontario study and is not based on robust data.
As well, the authors failed to place more emphasis on the largest clinical trial to date, the Clopidogrel Medco Outcomes Study, which involved 16,690 patients.4 This study showed that all PPIs were associated with adverse outcomes when used in conjunction with clopidogrel. Interestingly, this study showed that pantoprazole was associated with the highest risk of cardiac adverse effects compared to all other PPIs. This directly contradicts the results of the Ontario Public Drug Program study.
Finally, there are emerging data that demonstrate that this drug-drug interaction may be a class effect of all PPIs. Subgroup analysis of 2 landmark prospective, randomized clinical trials, TIMI 44 and TRITON 38, provides more robust data.5 TIMI 44 revealed that concurrent use of a PPI with clopidogrel resulted in lower inhibition of platelet aggregation compared with the subgroup not on a PPI. However, TRITON 38 showed that there was no significant difference in death, myocardial infarction (MI), or stroke in patients on clopidogrel and a PPI versus those not on a PPI. Results from TRITON 38, the most robust clinical data to date, suggest that there is no clinical interaction between clopidogrel and PPIs. There was no significant difference in the risk of death, MI, or stroke between the different types of PPIs used in TRITON 38 (omeprazole, pantoprazole, esomeprazole, lansoprazole).
Thus, the conclusion that pantoprazole should be used if clopidogrel is required is based on laboratory and retrospective studies. Larger retrospective and prospective trials with more robust methodologies do not support this recommendation and question whether there is a clinically significant drug-drug interaction between clopidogrel and PPIs. Recommending a specific PPI is premature and there are conflicting data as to whether one PPI is less likely to interact with clopidogrel than another and whether there actually is a drug-drug interaction at all.
Footnotes
Financial disclosure: None reported
References
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