Potential interactions between antimicrobials and direct oral anticoagulants: population-based cohort and case-crossover study.

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Although drug interactions between clarithromycin/erythromycin/fluconazole and direct oral anticoagulants (DOACs) are mechanistically plausible, it is uncertain whether they are clinically relevant. To investigate the association between co-prescribed DOACs and antimicrobials and bleeding, cardiovascular disease and mortality. We identified DOAC users in the Clinical Practice Research Datalink Aurum from 1/1/2011-29/3/2021. We used a cohort design to estimate hazard ratios for bleeding outcomes (intracranial bleeding, gastrointestinal bleeding, other bleeding), comparing DOACs+clarithromycin/erythromycin/fluconazole users with DOACs users not receiving these antimicrobials. Cardiovascular outcomes were ischaemic stroke, myocardial infarction, venous thromboembolism, cardiovascular mortality and all-cause mortality. A 6-parameter case-crossover design comparing odds of exposure to different drug initiation patterns for all outcomes in hazard window versus referent window within an individual was also conducted. Of 483,815 DOAC users, we identified 21,701 co-prescribed clarithromycin, 4,532 co-prescribed erythromycin and 4,840 co-prescribed fluconazole. We observed an increased risk of gastrointestinal bleeding over 7-days following co-prescription of DOAC+erythromycin versus DOAC alone (HR:3.66; 99%CI:1.27-10.51), with wide CIs in case-crossover analysis. No evidence of increased risk of bleeding outcomes was seen for DOAC+clarithromycin/fluconazole in cohort and case-crossover analyses. For cardiovascular outcomes, compared with DOAC alone, an increased risk of cardiovascular mortality with DOAC+clarithromycin(HR:3.36; 99%CI:1.73-6.52) and increased risk of all-cause mortality with DOAC+clarithromycin/erythromycin/fluconazole were observed in cohort analysis. However, similar risks were found when initiating erythromycin/fluconazole with and without DOAC. We found no strong evidence of increased risks of bleeding and cardiovascular outcomes in DOACs+clarithromycin/fluconazole/erythromycin users except a possible short-term increased risk of gastrointestinal bleeding in DOACs+erythromycin users.