Concurrent use of DOACs and pharmacodynamic interacting drugs is associated with an increased risk of major bleeding compared with patients using DOACs alone: Nested case-control study in UK CPRD

Background: Although many studies on bleeding risk associated with use of direct oral anticoagulants (DOACs) are conducted, the effect of concurrent use of potentially interacting drugs on this risk is not well studied. Objectives: To evaluate the association between concurrent use of DOACs with concurrent use of potential pharmacokinetic or pharmacodynamic interacting drugs on major bleeding. Methods: We used data from the UK Clinical Practice Research Datalink (period 2008-2015) to conduct a nested case-control study in a cohort of new users of DOACs (dabigatran, apixaban, and rivaroxaban). Cases were patients who were hospitalized with a primary discharge diagnosis of major bleeding while taking DOACs. Up to four controls were matched to each case on age, sex, and index date. Controls also had to be a current user of a DOAC on the index date. Conditional logistic regression analysis was used to calculate odds ratios (OR) and 95% confidence intervals (CI) to estimate the risk of major bleeding associated with concurrent use (30 days prior to the index date) of potential pharmacokinetic or pharmacodynamic interacting drugs. The analysis was adjusted for well-known risk factors for bleeding Results: We identified 393 cases from 29 120 new users of DOACs and 1494 controls. Most subjects were current users of rivaroxaban (58.8%). The concurrent use of DOACs and pharmacokinetic interacting drugs did not increase the risk of major bleeding vs use of DOACs alone (45.0% vs 51.2%, adjusted OR 0.90; 95% CI 0.60-1.36). However, concurrent use of pharmacodynamic interacting drugs was associated with an increased risk of major bleeding (21.6% vs 13.5%, adjusted OR, 1.91; 95% CI, 1.39-2.62). This effect was mainly driven by selective serotonin reuptake inhibitors (SSRIs, adjusted OR, 1.73; 95% CI, 1.12-2.65) and antiplatelet drugs (adjusted OR, 1.90; 95% CI, 1.23-2.93), respectively. Conclusions: Among patients taking a DOAC, concurrent use of an SSRIs or antiplatelet drug was associated with increased risk of major bleeding compared with DOAC use without these drugs