Treatment with clopidogrel and proton pump inhibitors in combination: a review of emerging evidence

Proton pump inhibitors often are prescribed in combination with clopidogrel to decrease risk of gastrointestinal bleeding after acute coronary syndrome. Clopidogrel is a prodrug that has to be metabolized in the liver to generate the active metabolite. Both medications are metabolized largely by the CYP2C19 enzyme; therefore, concerns exist that a drug-drug interaction during concomitant treatment with clopidogrel and a proton pump inhibitor may result in reduction of platelet inhibition. We have reviewed observational and randomized control studies that have evaluated the potential influence of proton pump inhibitors on the platelet inhibitory effect of clopidogrel, along with cardiovascular outcomes. We also have summarized regulatory and academic guidelines for treatment of patients in which concomitant therapy with clopidogrel and proton pump inhibitors may be indicated. Confounding issues, including differential effects of individual proton pump inhibitors on the pharmacodynamics of clopidogrel and variation in clopidogrel metabolism mediated by CYP2C19 gene polymorphisms, also are discussed.