Proton Pump Inhibitors and Clopidogrel

Drug interactions are a complex topic tethered to our daily clinical activities by 2 unfortunate facts. The first is that avoidable drug interactions harm an unknown but undoubtedly large number of patients every year. The second is that we know very little about the real-world consequences that ensue when one drug is superimposed on another.Article see p 2322 With this background, the recently postulated drug interaction between proton pump inhibitors (PPIs) and clopidogrel is in a league of its own, spawning a flurry of research and editorializing in a relatively short time, and more is on the way. This attention reflects several factors, including the blockbuster status of the implicated drugs, a theoretically at-risk population in the tens of millions, and guidelines that recommend near-universal use of PPIs in patients taking clopidogrel, most of whom will also be taking aspirin.1 However, skepticism about the clinical importance of this drug interaction is easily understood, especially among clinicians who sense deja vu with the thematically similar interaction between atorvastatin and clopidogrel first described in 2003 but now largely dismissed.2In this issue of Circulation , Rassen and colleagues3 report a well-executed retrospective cohort study of this drug interaction using multijurisdictional data and a highly sophisticated approach to multivariable adjustment. The results suggest that adding a PPI to clopidogrel therapy is associated with an increased risk of myocardial infarction or death (adjusted rate ratio, 1.22; 95% confidence interval, 0.99 to 1.51). This effect size is consistent with previous observational studies but just fails to meet the conventional threshold for statistical significance. The authors conclude that although adding a PPI to clopidogrel therapy may increase the risk of adverse events, the incremental risk is probably not very large. This interpretation is a sensible one, but myocardial infarction and death are …