What is the clinical evidence from this study?

Study design: Cohort. Population: Patients receiving DOACs (n=75527). Intervention: DOACs and SSRIs vs. DOACs and non-SSRI antidepressants. Primary outcome: Intracranial bleeding (HR 1.16, 95% CI 0.62-2.20).

What does this research mean for the field?

Concomitant use of DOACs and SSRIs does not significantly increase the risk of intracranial or gastrointestinal bleeding compared to DOACs and non-SSRI antidepressants. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

The study aims to evaluate whether the concurrent use of SSRIs and DOACs increases bleeding risk compared to non-SSRI antidepressants.

April 24, 2026BJGP Open0 citationsOpen Access

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

MCMarco Chau CWCharlotte Warren-Gash KBKrishnan Bhaskaran

Key Result

Concomitant use of DOACs and SSRIs did not significantly increase the risk of intracranial bleeding (HR 1.16) or gastrointestinal bleeding (HR 1.09) compared to DOACs and non-SSRI antidepressants.

Key Points

The study aims to evaluate whether the concurrent use of SSRIs and DOACs increases bleeding risk compared to non-SSRI antidepressants.
Conducted a population-based cohort and case-crossover study using UK CPRD data from 2011 to 2021.
Estimated hazard ratios (HRs) using propensity score weighting to compare DOAC+SSRI and DOAC+non-SSRI users.
Utilized a 6-parameter case-crossover design to compare odds of exposure to different drug initiation patterns.
No significant difference in bleeding risk for intracranial and gastrointestinal bleeding between DOAC+SSRI and DOAC+non-SSRI users.
Increased odds of other bleeding (OR 1.64) associated with initiating SSRIs while on DOACs compared to SSRIs alone.
No greater odds observed when initiating non-SSRIs in DOAC users.

Study Design

Type

Cohort (n=75,527)

Multicenter

Yes

Structured PICO

Does concomitant use of DOACs and SSRIs increase the risk of bleeding compared to DOACs and non-SSRI antidepressants in adult patients?

Population

75,527 adults aged ≥18 years receiving their first direct oral anticoagulant (DOAC: dabigatran, rivaroxaban, apixaban, or edoxaban) with concurrent use of either an SSRI (n=35,782) or a non-SSRI antidepressant (n=39,745) between January 1, 2011, and March 29, 2021, in the United Kingdom (CPRD Aurum database).

Intervention

Concomitant use of a DOAC and a selective serotonin reuptake inhibitor (SSRI: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, or sertraline).

Comparator

Concomitant use of a DOAC and a non-SSRI antidepressant.

Outcome

Intracranial bleeding, gastrointestinal bleeding, and other bleeding.safety

Concomitant use of DOACs and SSRIs does not appear to increase the risk of intracranial or gastrointestinal bleeding compared to non-SSRI antidepressants, though there may be a transient increased risk of other bleeding upon SSRI initiation.

Main Result

Effect estimate: HR 1.16 (95% CI 0.62-2.20)

Limitations

Drug adherence and persistence were unknown, leading to potential misclassification bias of drug exposure
Did not have large cohorts for some drug outcome pairs, specifically for intracranial bleeding, which limited study power
Study population was predominantly White, so results may not be generalizable to other ethnic groups
Could not eliminate residual confounding

Abstract

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 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.

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