Absence of pharmacovigilance signals for bleeding events associated with warfarin-SSRI drug interactions: a comparative analysis of FAERS and CVARD databases

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Background: Warfarin and selective serotonin reuptake inhibitors (SSRIs) are frequently co-prescribed in clinical practice, particularly among elderly patients with comorbid cardiovascular and psychiatric conditions. Although theoretical pharmacological mechanisms suggest an increased bleeding risk from their concurrent use, real-world evidence remains conflicting. Objectives: To comprehensively evaluate drug-drug interaction signals for bleeding events and international normalized ratio (INR) elevation associated with warfarin-SSRI combinations using large-scale pharmacovigilance databases from different healthcare systems (FDA Adverse Event Reporting System (FAERS) and Canada Vigilance Adverse Reaction Database (CVARD)). Design: A retrospective pharmacovigilance study. Methods: Adverse event reports from the FAERS (2004-2025) and the CVARD (1965-2025) were systematically analysed. Six warfarin-SSRI combinations were examined. Disproportionality and network analyses were utilized to characterize adverse event profiles. Multiple complementary signal detection algorithms were employed for interaction assessment, including the Omega shrinkage model, Additive Model, Multiplicative Model, and combination risk ratio (CRR) model, further supported by sensitivity analyses. Results: Disproportionality analysis revealed that the SSRIs&Warfarin group exhibited a significantly higher reporting odds ratio for international normalized ratio increased compared to the Warfarin-single group. However, regarding interaction signals, in the FAERS database, five of the six warfarin-SSRI combinations demonstrated consistent negative Ω values for bleeding events (range: -1.04 to -0.75), indicating no synergistic interaction. While the warfarin-fluvoxamine combination showed isolated positive signals in secondary models, the primary Ω shrinkage measure remained statistically nonsignificant (95% CI: encompassed zero). Results for international normalized ratio increased largely paralleled these findings. Network analysis confirmed a safety profile predominantly shaped by warfarin-associated risks rather than a synergistic amplification. The CVARD database corroborated these patterns with regional variations. Conclusion: Contrary to theoretical pharmacological expectations, this large-scale, cross-database pharmacovigilance analysis failed to detect positive safety signals for bleeding events or INR elevation associated with warfarin-SSRI combinations. Clinical vigilance and individualized risk assessment remain warranted, but routine combinations do not show synergistic bleeding risks at the population level. Trial registration: This study is a real-world pharmacovigilance investigation based on publicly accessible databases. As such, it does not involve a formal clinical trial, and therefore, no clinical trial registration number is applicable.

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