Selective Serotonin Reuptake Inhibitor Use and Risk of Major Bleeding during Treatment with Vitamin K Antagonists: Results of A Cohort Study

Abstract

Background: Selective serotonin reuptake inhibitors (SSRIs) may increase the risk of major bleeding by decreasing platelet function or decreasing vitamin K antagonist (VKA) metabolism via cytochrome P450 (CYP) inhibition. Aims: To determine whether SSRIs are associated with major bleeding during VKA treatment and investigate the possible mechanisms. Methods: In this cohort study, information on SSRI use and bleeding complications was obtained from patient records of VKA initiators between 2006 and 2018 from two anticoagulation clinics. Conditional logistic regression and time-dependent Cox regression were used to estimate the effect of SSRIs on a high INR (≥ 5) within 2 months after SSRI initiation and on major bleeding during the entire period of SSRI use, respectively. SSRI use was stratified for (non-)CYP2C9 inhibitors. Results: 58,918 patients were included, of whom 1504 were SSRI users. SSRI initiation versus non-use was associated with a 2.41-fold (95% confidence interval [CI] 2.01-2.89) increased risk for a high INR, which was 3.14-fold (95%CI 1.33-7.43) among CYP2C9 inhibiting SSRI users. The adjusted hazard ratio of major bleeding was 1.22 (95%CI 0.99-1.50) in all SSRI users and 1.31 (95%CI 0.62-2.72) in CYP2C9 inhibiting SSRI users compared to non-users. Conclusion: SSRI use is associated with an increased risk of high INR and might be associated with major bleeding. The risk of a high INR was slightly more elevated for CYP2C9 inhibiting SSRI users, suggesting there might be a pharmacokinetic interaction (by CYP2C9 inhibition) next to a pharmacodynamic effect of SSRIs on platelet activation.