直接口服抗凝药联用三唑类抗真菌药的出血风险信号挖掘 点击下载
| 论文标题： | 直接口服抗凝药联用三唑类抗真菌药的出血风险信号挖掘 |
| 英文标题： | |
| 中文摘要： | 目的 评估直接口服抗凝药（DOACs）与三唑类抗真菌药联用的出血风险信号，为临床联合用药的安全性评估与监测提供药物警戒依据。方法提取美国FDA不良事件报告系统2004年第1季度至2025年第3季度DOACs与三唑类抗真菌药联用的不良事件报告，选取9个出血相关的首选术语（PT），采用Ω收缩法、加性模型、乘性模型及组合风险比法开展药物-药物相互作用信号检测，并基于Ω收缩法分析阳性信号的强度。结果共纳入790份DOACs与三唑类抗真菌药联用的不良事件报告，其中涉及9个出血相关PT的报告共229份。经4种方法一致判定为阳性的信号共13个，涉及阿哌沙班-氟康唑、阿哌沙班-泊沙康唑、利伐沙班-伊曲康唑、达比加群酯-氟康唑、阿哌沙班-伏立康唑、达比加群酯-伊曲康唑6种药物联用组合。Ω收缩法显示，阿哌沙班-泊沙康唑联用在出血（Ω＝2.73，Ω025＝2.05）和咯血（Ω＝2.17，Ω025＝0.83）方面的信号较强；阿哌沙班-氟康唑联用在血肿（Ω＝2.30，Ω025＝1.47）和血尿（Ω＝1.71，Ω025＝0.74）方面的信号较强；利伐沙班-伊曲康唑联用在鼻衄（Ω＝2.01，Ω025＝0.90）和血肿（Ω＝1.93，Ω025＝0.42）方面的信号较强；颅内出血与上消化道出血未观察到Ω阳性信号。结论DOACs与三唑类抗真菌药联用可能增加出血相关风险，且不同药物联用组合的信号强度及信号分布存在差异。临床应重点警惕阿哌沙班或利伐沙班与泊沙康唑、伊曲康唑等强效细胞色素P4503A4或P-糖蛋白抑制剂的联用；对于其他DOACs与三唑类抗真菌药的联用方案，也应密切监测出血相关表现并及时调整抗凝或抗真菌治疗方案。 |
| 英文摘要： | OBJECTIVE To assess the bleeding risk signals associated with the concomitant use of direct oral anticoagulants （DOACs） and triazole antifungals， and to provide pharmacovigilance evidence for the safety evaluation and monitoring of combined clinical use. METHODS Adverse event reports involving the concomitant use of DOACs and triazole antifungals were extracted from the US FDA Adverse Event Reporting System （FAERS） from the first quarter of 2004 to the third quarter of 2025. Nine bleeding-related preferred terms （PTs） were selected. The Ω shrinkage measure， additive model， multiplicative model， and combined risk ratio method were employed to detect drug-drug interaction signals. The strength of positive signals was further analyzed based on the Ω shrinkage measure. RESULTS A total of 790 adverse event reports involving the concomitant use of DOACs and triazole antifungals were included， among which 229 reports involved nine bleeding-related PTs. A total of 13 signals were consistently identified as posit ive by all four methods. These signals involved six drug combinations： apixaban-fluconazole， apixaban-posaconazole， rivaroxaban-itraconazole， dabigatran etexilate-fluconazole， apixaban-voriconazole， and dabigatran etexilate-itraconazole. The Ω shrinkage measure showed that the apixaban-posaconazole combination exhibited stronger signals for bleeding （ Ω ＝2.73， Ω 025 ＝2.05） and hemoptysis （ Ω ＝2.17， Ω 025 ＝0.83）； the apixaban-fluconazole combination exhibited stronger signals for hematoma （ Ω ＝2.30， Ω 025 ＝1.47） and hematuria （ Ω ＝1.71， Ω 025 ＝0.74）； the rivaroxaban-itraconazole combination exhibited stronger signals for epistaxis （ Ω ＝2.01， Ω 025 ＝0.90） and hematoma （ Ω ＝1.93， Ω 025 ＝0.42）； no positive Ω signals were observed for intracranial hemorrhage or upper gastrointestinal hemorrhage. CONCLUSION S This study suggests that the concomitant use of DOACs and triazole antifungals may increase the risk of bleeding-related events， with differences in signal strength and signal distribution across various drug combinations. In clinical practice， particular attention should be paid to the concomitant use of apixaban or rivaroxaban with strong cytochrome P450 3A4 or P-glycoprotein inhibitors such as posaconazole and itraconazole. For other DOAC-triazole antifungal combinations， close monitoring for bleeding-related manifestations and timely adjustment of anticoagulation or antifungal regimens are also warranted. |
| 期刊： | 2026年第37卷第09期 |
| 作者： | 吴紫阳；朱颖；张梦华；何娜；秦琼；谢诚 |
| 英文作者： | WU Ziyang，ZHU Ying，ZHANG Menghua，HE Na，QIN Qiong，XIE Cheng |
| 关键字： | 直接口服抗凝药；三唑类抗真菌药；药物-药物相互作用；出血；信号检测 |
| KEYWORDS： | direct oral anticoagulants； triazole antifungals； drug-drug interaction； bleeding； signal mining |
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