Effect of Selective Serotonin Reuptake Inhibitors on Bleeding Risk in Patients With Atrial Fibrillation Taking Warfarin

Abstract

Selective serotonin reuptake inhibitor (SSRI) medications have been linked to increased bleeding risk, however, the actual association between warfarin, SSRI exposure, and bleeding risk has not been well-established. We studied the AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA) cohort of 13,559 adults with atrial fibrillation (AF), restricted to the 9186 patients contributing follow-up time while taking warfarin. Exposure to SSRIs and tricyclic antideprssants (TCAs) were assessed from pharmacy database dispensing data. The main outcome was hospitalization for major hemorrhage. Results were adjusted for bleeding risk and time in an INR range ≥ 3. We identified 461 major hemorrhages during 32,888 person-years of follow-up, 45 events during SSRI use, 12 during TCA only use, and 404 without either medication. Hemorrhage rates were higher during periods of SSRI exposure compared with periods on no antidepressants (2.32 per 100 person-years vs. 1.35 per 100 person-years, p ≤ 0.001) and did not differ between TCA exposure and no antidepressants (1.30 per 100 person-years on TCAs, p = 0.93). After adjusting for bleeding risk and time in INR range > 3, SSRI exposure was associated with an increased rate of hemorrhage compared with no antidepressants (adjusted relative risk 1.41, 95% CI: 1.04-1.92, p=0.03), whereas TCA exposure was not (adjusted relative risk 0.82, 95% CI: 0.46-1.46, p=0.50). In conclusion, SSRI exposure was associated with higher major hemorrhage risk in patients on warfarin and this risk should be considered when selecting antidepressant treatments in those patients.

SSRI co‐medication with NOAC or VKA does not increase hospitalisation for bleeding: A retrospective nationwide cohort study in Austria 2010‐2015

“…[8][9][10][11] This has been reported for upper GI bleedings as well as for the risk of cerebral haemorrhage. Second, bleeding events in patients with SSRI or other antidepressant therapy who received a coprescription with NOAC were higher than those recorded for co-medication with VKA.…”

Selective Serotonin Reuptake Inhibitors and Bleeding Risk in Anticoagulated Patients With Atrial Fibrillation: An Analysis From the ROCKET AF Trial

“…In a large community‐based observational AF cohort, we previously found an adjusted relative risk for major hemorrhage of 1.41 (95% CI, 1.04–1.92) with the addition of SSRIs to warfarin 26. Several studies using large national databases have reported that concomitant use of SSRIs with vitamin K antagonists increased the risk of hospitalized bleeding events by roughly 30% to 70%, and a recent nested case‐control study from the United Kingdom Clinical Practice Datalink found an odds ratio of 1.73 (95% CI, 0.89–3.39) for intracranial hemorrhage in patients taking warfarin when SSRIs were added 15, 24, 25, 27.…”

“…Further, SSRIs inhibit the cytochrome P450 metabolic pathway, potentially increasing warfarin's effect 21, 22, 23. Several studies have reported that the combination of warfarin and SSRIs leads to an increased risk of major hemorrhage 24, 25, 26, 27, 28. No study has yet examined the possible drug‐drug interaction between SSRIs and non–vitamin K antagonist oral anticoagulants.…”

Preadmission use of selective serotonin reuptake inhibitors and short‐term mortality in diabetic patients hospitalized due to stroke

“…The mechanism underlying the elevated mortality is not known, but SSRIs are preferred to tricyclic antidepressants because of their tolerability and safety profile. The benefits of SSRIs may accrue at the expense of an overall increased bleeding risk . Platelets acquire serotonin from plasma, which is released upon platelet activation to amplify aggregation .…”