Concomitant use of antidepressants, oral anticoagulants raises bleeding risk in AF patients

Patients with atrial fibrillation (AF) who take oral anticoagulants (OACs) and selective serotonin reuptake inhibitors (SSRIs) at the same time appear to have a higher likelihood of major bleeding.

In a population-based, nested case-control study, the concomitant use of SSRIs and OACs was associated with a 33-percent higher incidence rate of major bleeding compared with OAC use alone (incidence rate ratio [IRR], 1.33, 95 percent confidence interval [CI], 1.24–1.42). [JAMA Netw Open 2024;7:e243208]

The initial 30 days of treatment saw the sharpest rise in the incidence of major bleeding, with an IRR of 1.74 (95 percent CI, 1.37–2.22). Factors such as age, sex, history of bleeding, chronic kidney disease, and potency of SSRIs did not influence the association between concomitant use of SSRIs and OACs and major bleeding.

Additionally, concomitant use of SSRIs and direct OACs was also associated with a greater incidence rate of major bleeding compared with direct OAC use alone (IRR, 1.25, 95 percent CI, 1.12–1.40), as well as concomitant use of SSRIs and vitamin K antagonists (VKAs) compared with VKA use alone (IRR, 1.36, 95 percent CI, 1.25–1.47).

For the study, the investigators used data from the Clinical Practice Research Datalink and identified 331,305 AF patients (mean age 73.7 years, 57.1 percent men) initiating OACs. Over a mean follow-up of 4.6 years, 42,391 patients were hospitalized with major bleeding. Of these, 42,190 patients (mean age 74.2 years, 59.8 percent men) were matched to 1,156,641 controls (mean age 74.2 years, 59.8 percent men) and were included in the analysis.

Impact of SSRIs

“In light of these findings, the risk of major bleeding may be a pertinent safety consideration for patients using SSRIs and OACs concomitantly. This finding has been echoed in the summary of product characteristics for different OACs, which describe SSRIs as interacting drugs given that they independently increase the risk of bleeding,” the investigators said.

Serotonin helps enhance platelet activation and aggregation, and SSRIs reduce serotonin in platelets by up to 80 percent to 90 percent, effectively weakening the clotting process. This may explain the increased bleeding risk seen when SSRIs are combined with OACs, according to the investigators. [Dialogues Clin Neurosci 2007;9:47-59]

Moreover, SSRIs such as fluoxetine and fluvoxamine block enzymes in the liver that are responsible for metabolizing warfarin. As a result, warfarin stays longer in the body than usual, which may potentially increase the risk of bleeding. [Psychiatry 2009;6:24-29]

“Nonetheless, the interaction analysis suggests that the joint association of SSRIs and OACs is mainly owing to their individual risks of major bleeding; hence, any additional risk posed by pharmacokinetic interaction is likely minimal,” they said.

Minimizing bleeding risk

“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,” the investigators said.

Studies show that direct OACs (DOACs) may interact less with SSRIs compared with VKAs. Additionally, guidelines recommend DOACs as the preferred option for managing nonvalvular AF. This, along with the findings from the present study, suggests that DOACs might be safer for patients also taking SSRIs, the investigators pointed out. [Eur Heart J 2021;42:373-498; Circulation 2019;140:e125-e151; Can J Cardiol 2020;36:1847-1948]

Alternatively, proton pump inhibitors may be co-prescribed to prevent gastrointestinal bleeding, they added. [Europace 2021;23:1612-1676; JAMA 2018;320:2221-2230]

“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,” according to the investigators. [Europace 2021;23:1612-1676]