Major Bleeding Risk in Patients With Non-valvular Atrial Fibrillation Concurrently Taking Direct Oral Anticoagulants and Antidepressants.

Kuo-Hsuan Chang,Yu-Tung Huang,Chun-Li Wang,Shang-Hung Chang,Chiung-Mei Chen,Chien-Hung Chang,Hsiu-Chuan Wu,Hui-Tzu Tu

doi:10.3389/fnagi.2022.791285

Abstract

Direct oral anticoagulants (DOACs) are commonly prescribed with antidepressants that may increase bleeding risk. Here we assessed the association between DOACs with and without concurrent antidepressants and major bleeding risk in patients with atrial fibrillation (AF) by a retrospective cohort study included patients with AF who received prescriptions of DOACs in Taiwan’s National Health Insurance database between 2012 and 2017. Adjusted rate ratio (ARR) of major bleeding was calculated by comparing incidence rate adjusted with Poisson regression and inverse probability of treatment weighting using the propensity score between patient-times with and without antidepressants. Among 98863 patients with AF, concurrent use of bupropion with DOACs increased the risks of all major bleeding (ARR: 1.49, 95% CI: 1.02–2.16) and gastrointestinal hemorrhage (ARR: 1.57, 95% CI: 1.04–2.33). An increased risk of intracerebral hemorrhage (ICH) was associated with the combinations of DOACs with selective serotonin reuptake inhibitors (SSRIs, ARR: 1.38, 95% CI: 1.08–1.76), particularly in paroxetine (ARR: 2.11, 95% CI: 1.17–3.81), and tetracyclic antidepressants (TeCAs, ARR: 1.34, 95% CI: 1.01–1.78). In subgroup analyses stratified by individual NOACs, SSRIs increased the risk of ICH in the dabigatran-treated patients (ARR: 1.55, 95% CI: 1.04–2.33). The combinations of apixaban and serotonin-norepinephrine reuptake inhibitors (SNRIs) were associated with a higher risk of all major bleeding (ARR: 1.63, 95% CI: 1.04–2.55). These results clearly indicate the drug–drug interactions between DOACs and antidepressants, which should be carefully considered when prescribing DOACs in adult patients. Careful monitoring for bleeding should be performed while concurrently prescribing DOACs with bupropion, SSRI, SNRI, and TeCA. Concomitant use of DOACs and TCAs may be a relatively safe strategy for patients with AF.

Highlights

Atrial fibrillation (AF) is a prominent cause of ischemic stroke, and oral anticoagulation is frequently indicated for stroke prevention in patients with non-valvular AF (Rasmussen et al, 2012)
Separate analyses showed that selective serotonin reuptake inhibitors (SSRIs) increased the risk of intracerebral hemorrhage (ICH) in the dabigatrantreated patients with AF (ARR: 1.55, 95% CI: 1.04–2.33, P = 0.033, Table 6 and Supplementary Table 14)
We found concurrent use of bupropion with Direct antagonist oral anticoagulants (DOACs) in patients with non-valvular AF was associated with an increased risk of major bleeding, in gastrointestinal hemorrhage

Summary

Introduction

Atrial fibrillation (AF) is a prominent cause of ischemic stroke, and oral anticoagulation is frequently indicated for stroke prevention in patients with non-valvular AF (Rasmussen et al, 2012). Over the past few years, four DOACs, apixaban, rivaroxaban, dabigatran, and edoxaban, have been shown to offer several advantages over warfarin (Yeh et al, 2015). These DOACs have a rapid onset of therapeutic action, shorter half-life, and predictable pharmacodynamic effects; and do not require routine laboratory monitoring (Mekaj et al, 2015). Medications that inhibit CYP3A4 or P-gp activities, such as amiodarone and fluconazole, may increase DOAC levels and the bleeding risk (Chang et al, 2017; Wang et al, 2020). Avoidance of concurrent prescribing of these medications with DOACs would be necessary for patients with high risk of bleeding

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