Abstract 11: Selective Serotonin Reuptake Inhibitors Increase Major Hemorrhage Risk in Patients with Atrial Fibrillation Taking Warfarin
Authors: Quinn Gene R , Singer Daniel E , Chang Yuchiao , Go Alan S , Borowsky Leila , Pomernacki Niela , Udaltsova Natalia , Fang Margaret C 
Published: December 2021

Background:
Several studies suggest that SSRIs may increase bleeding risk and drug information guides warn about a potential interaction between warfarin and SSRIs. However, the actual association between warfarin, SSRI exposure, and bleeding risk has not been well-quantified. In addition, prior studies have not controlled for baseline bleeding risk or warfarin control.

Objective:
To assess the association between SSRI exposure and major hemorrhage events in patients with nonvalvular atrial fibrillation taking warfarin.

Methods:
We used data from the ATRIA Study, a cohort of 13,559 adults with atrial fibrillation receiving care in a large integrated healthcare delivery system. The analysis was restricted to the 9186 patients who contributed follow-up time while taking warfarin. We assessed exposure to SSRIs using dispensing data from pharmacy databases. Additionally, we searched for exposure to tricyclic antidepressants (TCAs) as a control group. The primary outcome was hospitalization for major hemorrhage on warfarin, defined as fatal, hemorrhage into a critical anatomic space, or requiring transfusion of ≥ 2 units packed red blood cells. Clinical risk factors for hemorrhage were identified using administrative and computerized clinical databases and used to calculate an ATRIA bleeding risk score, a previously-developed measure of anticoagulation-associated bleeding risk. A multivariable Poisson regression model was then used to test the association between hemorrhage and SSRI or TCA exposure, adjusting for bleeding risk and time in an international normalized ratio (INR) range > 3.

Results:
We identified 461 major hemorrhages during a total of 32,888 person-years of follow-up on warfarin. Of these events, 45 events occurred during SSRI use, 12 events during TCA only use, and 404 events without either medication. Rates of hemorrhage 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). In contrast, rates of hemorrhage did not differ comparing TCA use to no antidepressants (1.30 per 100 person-years on TCAs, p = 0.93). The mean ATRIA bleeding risk score during SSRI exposure was higher than periods on no antidepressants (2.43 vs. 2.06, p<0.001); a higher bleeding risk score was also observed during TCA exposure (2.24 vs. 2.06, p<0.001). Exposure time while on SSRIs and TCAs was associated with more time where the INR > 3 (12.3% for SSRIs, 11.9% for TCAs, and 10.3% for neither, p<0.001). In a multivariable model adjusting for bleeding risk score and time with INRs > 3, SSRI exposure was associated with an increased rate of hemorrhage compared with no antidepressants (adjusted relative risk 1.60, 95% CI: 1.18-2.17), whereas TCAs were not associated with increased hemorrhage risk (adjusted relative risk 0.88, 95% CI: 0.50-1.57).

Conclusions:
The risk of major hemorrhage on warfarin was significantly higher during periods of SSRI therapy, but not TCA therapy, even after adjusting for bleeding risk factors and time in a supratherapeutic INR range. Closer monitoring of patients on SSRIs and anticoagulants should be considered.