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Concomitant SSRI and DOAC Use Increases Risk of Major Bleeding, Including ICH: New Findings


Overall, a 33% increased risk of major bleeding was seen, with risk highest during the first 30 days of concomitant use and persistent, but lower, after 6 months.


Concomitant treatment with a selective serotonin reuptake inhibitor (SSRI) and an oral anticoagulant (OAC) in individuals with atrial fibrillation (AF) was associated with a 33% increased risk of major bleeding compared with use of an OAC alone, according to researchers from McGill University in Quebec, Canada.

The risk was found greatest within the initial months of treatment, particularly during the first 30 days, and remained elevated for up to 6 months, the researchers reported in JAMA Network Open. They found no variation in risk based on age, sex, bleeding history, kidney function or potency of SSRI and, importantly, observed the association with SSRIs and vitamin K antagonists (VKAs) as well as with direct OACs.

Christel Renoux, MD, PhD, assistant professor in the department of neurology and neurosurgery at the McGill University Centre for Clinical Epidemiology and colleagues reported significantly higher risk for 3 specific types of bleeding: intracranial hemorrhage (56%), gastrointestinal bleeding (38%), and other major bleeding (23%). They noted that if there was any interaction at all between SSRIs and OACs, it was extremely limited—ie, both drug classes independently increase the risk of bleeding.

GI bleeding: aIRR 1.38 (95% CI 1.24-1.53) ICH: aIRR 1.56 (95% CI 1.32-1.85)
Other major bleeding: aIRR 1.23 (95% CI 1.12-1.36)

The findings were not unanticipated, wrote the authors; the risk of bleeding during combined treatment for depression with SSRIs and AF with OAC has been assessed in previous observational studies, albeit with some variability in outcomes. The current study sought to close information gaps left by prior research, including controlling for potential confounding from age, sex, clinical characteristics or from differences between direct OACs and VKAs, a goal Renoux et al say they achieved.

The population-based nested case-control study recruited participants from the UK Clinical Practice Research Datalink, a primary care database of comprehensive electronic medical record data for more than 60 million individuals from more than 2000 general practices.

Eligible participants were aged 18 years or older who had an incident diagnosis of AF and had initiated OAC therapy (apixaban, dabigatran, edoxaban, rivaroxaban, or warfarin) between January 2, 1998, and March 29, 2021. Participants were followed until a first major bleeding event, death, end of registration with a clinical practice, or end of the study period (March 29, 2021), whichever occurred first.

Cases were defined as participants with a first recorded diagnosis of major bleeding during follow-up and each case was matched with up to 30 controls.

The main outcome was incidence rate ratios (IRRs) of hospitalization for bleeding or death due to bleeding, according to the study.


Renoux and team identified 42 190 cases who were matched to 1 156 461 controls, each group with an average age of 74 years and approximately 60% men. Concomitant use of SSRIs and OACs was associated with an increased risk of major bleeding compared with OAC use alone (IRR, 1.33; 95% CI, 1.24-1.42), was highest during the first 30 days of continuous use (IRR, 1.74; 95% CI, 1.37-2.22), and then decreased. The increased risk of major bleeding was observed with both VKAs and direct OACs, however the magnitude of risk was slightly lower with the latter (IRR 1.25, 95% CI 1.12-1.40) than the former (IRR 1.36, 95% CI 1.25-1.47), reported researchers.

The association was strongest for intracranial hemorrhage aIRR 1.56 (95% CI 1.32-1.85) followed by gastrointestinal bleeding aIRR 1.38 (95% CI 1.24-1.53), and other bleeding aIRR 1.23 (95% CI 1.12-1.36). The concomitant use of the 2 drug classes was also associated with a 22% increased risk of any bleeding(95% CI, 1.16-1.28) vs use of OACs alone.

The SSRI mechanism of action may play a role in the increased bleeding risk when the 2 classes are taken simultaneously, Renoux et al suggested. SSRIs block the serotonin reuptake transporter on platelet membranes, and research shown depletion of platelet serotonin content by up to 80% to 90% within a period of 2 to 3 weeks. Some SSRIs (eg, fluoxetine, fluvoxamine) inhibit isoenzymes of the cytochrome P450 enzyme, essential in the metabolism of warfarin. However, they point to the findings of their interaction analysis that showed negligible interaction, supporting an effect of the combined individual bleeding risk posed by each class.

“Although the increased risk of major bleeding does not suggest withholding treatment with either SSRIs or OACs, measures can be taken to mitigate this risk,” wrote authors in their discussion. “Overall, risk factors for bleeding should be monitored and managed to improve the safety of the concomitant use of SSRIs and OACs Close monitoring is particularly essential within the first few months of concomitant use,” they concluded.

Rahman AA, Platt RW, Beradid SB, et al. Concomitant use of selective serotonin reuptake inhibitors with oral anticoagulants and risk of major bleeding. JAMA Netw Open. 2024;7(3):e243208. doi:10.1001/jamanetworkopen.2024.3208

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