Risk of major bleeding among users of direct oral anticoagulants combined with interacting drugs: a population-based nested case-control study

AIMS: To assess the association between concurrent use of potential pharmacokinetic or pharmacodynamic interacting drugs and major bleeding among DOAC users.

METHODS: We performed a case-control study nested in a cohort of new users of DOACs (dabigatran etexilate, apixaban, or rivaroxaban). Data were obtained from UK Clinical Practice Research Datalink linked to Hospital Episode Statistics (2008-2015). Cases were patients hospitalized having a primary diagnosis of major bleeding. Up to 4 controls were matched on age, sex, index date, and region. Odds ratios (ORs) for the risk of major bleeding were assessed by conditional logistic regression analysis and adjusted for well-known covariates for the risk of bleeding.

RESULTS: We identified 393 patients with a major bleeding from a total of 23492 new users of DOACs and 1494 matched controls. Most subjects were users of rivaroxaban (58.8%) on the index date. The concurrent use of pharmacodynamic interacting drugs was associated with an increased risk of major bleeding (21.6% of cases vs. 13.5% of controls, adjusted OR (aOR) 1.92; 95% CI, 1.40-2.66). For the antiplatelet drugs the aOR was 2.01; 95% CI, 1.29-3.11) and for the selective serotonin reuptake inhibitors (SSRIs) the aOR was 1.68; 95% CI, 1.10-2.59). We found no increased risk of major bleeding for concurrent use of pharmacokinetic interacting drugs vs. DOACs alone (45.0% vs. 51.2%; adjusted OR (aOR): 0.77; 95% CI: 0.53-1.10).

CONCLUSIONS: Among patients taking DOACs the concurrent use of antiplatelet drugs or SSRIs was associated with increased risk of major bleeding, while pharmacokinetic interacting drugs do not increase this risk.