Clopidogrel, Proton-Pump Inhibitors, and Cardiovascular Events

Concerns about the combined use of clopidogrel and proton-pump inhibitors (PPIs) began when studies suggested that PPIs impaired the intended antiplatelet activity of clopidogrel. This effect was attributed to a competitive interaction at the cytochrome P450 pathway, which is required for the biotransformation of the prodrug clopidogrel to its active metabolite. These studies led to a rapid onslaught of retrospective observational database analyses that reported an increased likelihood of clinical adverse cardiovascular events in patients taking this drug combination. However, a fundamental problem with these retrospective analyses has been their reliance on discharge prescription data, without accounting for varying medication exposures af…