Prescribing Proton Pump Inhibitor and Clopidogrel Together

Current State of Recommendations

Neena S. Abraham


Curr Opin Gastroenterol. 2011;27(6):558-564. 

In This Article

Recommendations to Prevent Antiplatelet-related Gastrointestinal Bleeding: Controversy and Confusion

Proton pump inhibitor (PPI) co-prescription therapy has been conclusively shown to mitigate the risk of antiplatelet-related gastrointestinal bleeding,[15–18] more so than substitution with clopidogrel monotherapy (with no PPI).[15] In 2008, scientific and clinical thought leaders in antiplatelet therapy and peptic ulcer bleeding from the American College of Cardiology (ACC), the American College of Gastroenterology (ACG) and the American Heart Association (AHA) released consensus recommendations to help physicians minimize the gastrointestinal bleeding risk associated with antiplatelet therapy. One of the fundamental recommendations was PPI gastroprotection to minimize antiplatelet-related gastrointestinal bleeding among high-risk patients, including patients prescribed dual-antiplatelet therapy.[19]

Following the publication of this consensus statement, several observational studies were published suggesting blunted clopidogrel activity associated with PPI co-prescription.[20–24] Studies using ex-vivo platelet assays as surrogate clinical endpoints and secondary analyses of pharmacy databases were the first to hypothesize a possible drug–drug interaction that increased the risk of cardiovascular events.[25–28] Early observational studies produced mixed and contradictory results regarding an important drug interaction. The U.S. Food and Drug Administration rapidly released a series of safety communications between January 2009 and March 2010 warning providers of genetic differences in hepatic metabolism of PPI and clopidogrel and the possibility of a potentially dangerous drug–drug interaction based on early contradictory evidence. In November 2009, the clopidogrel label was updated with new warnings regarding the co-prescription of omeprazole, and by March 2010 a box warning was added to the clopidogrel label highlighting reduced effectiveness in poor metabolizers of clopidogrel. In an accompanying safety communication from the FDA, physicians were urged to consider alternative antiplatelet medications or alternative dosing schedules for clopidogrel in poor metabolizers. The most recent update from the FDA (27 October 2010) continues to warn providers about the concomitant use of clopidogrel and omeprazole (only) with the suggestion that pantoprazole may be an alternative choice for gastroprotection.[29]


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