Potential interactions between SSRIs and DOACs: population-based cohort and case-crossover study

BACKGROUND: Bleeding is a side effect of direct oral anticoagulants (DOACs) and selective serotonin reuptake inhibitors (SSRIs). However, it is unknown whether their concomitant use would further exacerbate bleeding risk. AIM: To compare hazard of bleeding in patients with concomitant use of DOACs and SSRIs versus non-SSRI antidepressants. DESIGN & SETTING: Population-based cohort and case-crossover study using primary care data from the UK Clinical Practice Research Datalink (CPRD) Aurum between 1/1/2011 and 29/3/2021. METHOD: We used a cohort design to estimate hazard ratios (HRs) using propensity score weighting, comparing DOAC+SSRI and DOAC+non-SSRI users, and a 6-parameter model case-crossover design comparing odds of exposure to different drug initiation patterns for outcomes in hazard vs referent window within an individual to eliminate time-invariant confounding (confounding that do not change over time). RESULTS: There was no difference in bleeding risk in the cohort design (intracranial bleeding: HR1.16, 99% confidence interval [CI] 0.62-2.20; gastrointestinal bleeding: HR1.09, 99% CI 0.83-1.41; other bleeding: HR1.01, 99% CI 0.78-1.29). In the case-crossover design, we observed higher odds ratio (OR) of 1.64 (99%CI 1.14-2.35) for other bleeding associated with SSRI initiation while taking DOAC than SSRI monotherapy (OR1.06; 99% CI 1.01-1.11; p for Wald test=0.002), but greater odds ratio was not observed in DOAC users initiated non-SSRI (p for Wald test=0.83). CONCLUSION: We found no evidence of increased risk of intracranial and gastrointestinal bleeding during concomitant use of DOAC+SSRI in the cohort analysis. However, the case-crossover analysis suggested some evidence of a higher risk of other bleeding when initiating SSRIs (but not non-SSRIs) while taking DOACs.