Background Selective serotonin reuptake inhibitors (SSRIs) may increase the risk ofmajor bleeding by decreasing platelet function or decreasing vitamin K antagonist(VKA) metabolism via cytochrome... Show moreBackground Selective serotonin reuptake inhibitors (SSRIs) may increase the risk ofmajor 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 VKAtreatment and investigate the possible mechanisms. Methods In this cohort study, information on SSRI use and bleeding complicationswas obtained from patient records of VKAinitiators between 2006 and 2018 from twoanticoagulation clinics. Conditional logistic regression and time-dependent Cox re-gression were used to estimate the effect of SSRIs on a high international normalizedratio (INR >= 5) within 2 months after SSRI initiation and on major bleeding during theentire period of SSRI use, respectively. SSRI use was stratified for (non-)CYP2C9inhibitors. Results A total of 58,918 patients were included, of whom 1,504 were SSRI users.SSRI initiation versus nonuse 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 was1.22 (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 with nonusers. Conclusion SSRI use is associated with an increased risk of high INR and might beassociated with major bleeding. The risk of a high INR was slightly more elevated forCYP2C9-inhibiting SSRI users,suggesting theremight bea pharmacokineticinteraction(byCYP2C9 inhibition) next to a pharmacodynamic effect of SSRIs on platelet activation Show less
