Therapeutic Advances in Drug Safety

Zhang, Pan; Cheng, Siyuan; Diao, Junlin; Zhu, Haoran

doi: 10.1177/20420986261454180pmid: N/A

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.

Chen, Yuzhu; Wang, Chunhua; Jiang, Peng; Chen, Yida; Zhang, Tongmei; Cai, Shanshan

doi: 10.1177/20420986261454190pmid: N/A

Background:Understanding of the possible vasoactive toxicities associated with platinum‑containing chemotherapeutic drugs for solid tumors remains limited.Objectives:This study comprehensively identifies the vessel-threatening effects of cisplatin (CDDP), carboplatin (CBP), and oxaliplatin (OXA) and aims to compile an analytical model.Design:A retrospective pharmacovigilance study was combined with network pharmacology analysis and in vitro experimental validation.Methods:Disproportionality analyses, including reporting odds ratio, proportional reporting ratio, empirical Bayesian geometric mean, and Bayesian confidence propagation neural network, were conducted to identify vascular adverse events (VAEs) related to the three drugs using data from the FDA Adverse Event Reporting System (FAERS) database from 2004 to 2024. Network pharmacology was used to identify potential molecular targets and pathways. Human umbilical vein endothelial cells were treated with cisplatin, carboplatin, or oxaliplatin to evaluate cell viability (CCK-8 assay), apoptosis (flow cytometry), and gene expression by reverse transcription quantitative polymerase chain reaction (RT-qPCR) including Nrf2, ICAM1, VCAM1, NOS3, and HIF1A.Results:Among the 10,536 VAEs identified, all three drugs showed strong correlations with vascular events. Oxaliplatin had a correlation coefficient of 2.05 (95% confidence interval (CI): 1.99–2.11). Early failure characteristics (Weibull β ⩽ 1) were observed for all three drugs. The most frequently reported VAEs were hypotension, flushing, hypertension, and thrombosis. Network analysis highlighted the HIF-1, EGFR, and oxidative stress pathways. In vitro, oxaliplatin significantly reduced Nrf2 expression and cell viability, while cisplatin upregulated ICAM1 expression.Conclusion:Platinum compounds induce a short‑term vasoconstrictive effect, with oxaliplatin showing a relatively lower association. The results suggest activation of the oxidative stress pathway through Nrf2 inhibition and increased ICAM1 levels, alongside pathway‑specific alterations such as reduced HIF1A and NOS3 expression and decreased VCAM1 levels. Early cardiovascular monitoring and Nrf2‑targeted therapy warrant further investigation.