Clopidogrel Drug Interactions and Serious Bleeding: Generating Real World Evidence via Automated High‐Throughput Pharmacoepidemiologic Screening

: Few population-based studies have examined bleeding associated with clopidogrel drug-drug interactions (DDIs). We sought to identify precipitant drugs taken concomitantly with clopidogrel (an object drug) that increased serious bleeding rates. We screened 2000-2015 Optum commercial health insurance claims to identify DDI signals. We performed self-controlled case series studies for clopidogrel plus precipitant pairs, examining associations with gastrointestinal bleeding or intracranial hemorrhage. To distinguish native bleeding effects of a precipitant, we reexamined associations using pravastatin as a negative control object drug. Among 431 analyses, 28 clopidogrel plus precipitant pairs were statistically significantly positively associated with serious bleeding. Ratios of rate ratios ranged from 1.13-3.94. Among these pairs, 13 were expected given precipitant drugs alone increased and/or were harbingers of serious bleeding. The remaining 15 pairs constituted new DDI signals, none of which are currently listed in two major DDI knowledge bases.