Pharmacoepidemiologic Screening of Potential Oral Anticoagulant Drug Interactions Leading to Thromboembolic Events

Drug-drug interactions (DDIs) with oral anticoagulants may lead to under-anticoagulation and increased risk of thromboembolism. Although warfarin is susceptible to numerous DDIs, few studies have examined DDIs resulting in thromboembolism or those involving direct-acting oral anticoagulants (DOACs). We aimed to identify medications that increase the rate of hospitalization for thromboembolic events when taken concomitantly with oral anticoagulants. We conducted a high-throughput pharmacoepidemiologic screening study using Optum Clinformatics Data Mart, 2000-2016. We performed self-controlled case series studies among adult users of oral anticoagulants (warfarin, dabigatran, rivaroxaban, apixaban, and edoxaban) with at least one hospitalization for a thromboembolic event. Among eligible patients, we identified all oral medications frequently co-prescribed with oral anticoagulants as potential interacting precipitants. Conditional Poisson regression was used to estimate rate ratios comparing precipitant exposed vs. unexposed time for each anticoagulant-precipitant pair. To minimize within-person confounding by indication for the precipitant, we used pravastatin as a negative control object drug. Multiple estimation was adjusted using semi-Bayes shrinkage. We screened 1,622 oral anticoagulant-precipitant drug pairs and identified 226 (14%) drug pairs associated with statistically significantly elevated risk of thromboembolism. Using pravastatin as the negative control object drug, this list was reduced to 69 potential DDI signals for thromboembolism, 33 (48%) of which were not documented in the DDI knowledge databases Lexicomp and/or Micromedex. There were more DDI signals associated with warfarin than DOACs. This study reproduced several previously documented oral anticoagulant DDIs and identified potential DDI signals that deserve to be examined in future etiologic studies.