Signal mining for bleeding risk associated with the concomitant use of direct oral anticoagulants and triazole antifungals

WU Ziyang; ZHU Ying; ZHANG Menghua; HE Na; QIN Qiong; XIE Cheng

doi:10.6039/j.issn.1001-0408.2026.09.13

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Signal mining for bleeding risk associated with the concomitant use of direct oral anticoagulants and triazole antifungals

更新时间：2026-05-14

- Signal mining for bleeding risk associated with the concomitant use of direct oral anticoagulants and triazole antifungals
- ZHONGGUO YAOFANG Vol. 37, Issue 9, Pages: 1185-1189(2026)
- 作者机构：
  
  1.苏州大学附属第一医院药学部，江苏苏州　215006
  2.北京大学第三医院药剂科，北京　100191
- 作者简介：
- 基金信息：
- DOI：10.6039/j.issn.1001-0408.2026.09.13
  CLC： R972;R978
- Received：23 January 2026，
  
  Revised：2026-02-27，
  
  Accepted：13 April 2026，
  
  Published：15 May 2026
- 稿件说明：
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吴紫阳,朱颖,张梦华,等.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 [J].中国药房,2026,37(09):1185-1189.

WU Ziyang,ZHU Ying,ZHANG Menghua,et al.Signal mining for bleeding risk associated with the concomitant use of direct oral anticoagulants and triazole antifungals[J].ZHONGGUO YAOFANG,2026,37(09):1185-1189.
吴紫阳,朱颖,张梦华,等.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 [J].中国药房,2026,37(09):1185-1189. DOI： 10.6039/j.issn.1001-0408.2026.09.13.

WU Ziyang,ZHU Ying,ZHANG Menghua,et al.Signal mining for bleeding risk associated with the concomitant use of direct oral anticoagulants and triazole antifungals[J].ZHONGGUO YAOFANG,2026,37(09):1185-1189. DOI： 10.6039/j.issn.1001-0408.2026.09.13.

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

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

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。

收缩法显示，阿哌沙班-泊沙康唑联用在出血（

＝2.73，

025

＝2.05）和咯血（

＝2.17，

025

＝0.83）方面的信号较强；阿哌沙班-氟康唑联用在血肿（

＝2.30，

025

＝1.47）和血尿（

＝1.71，

025

＝0.74）方面的信号较强；利伐沙班-伊曲康唑联用在鼻衄（

＝2.01，

025

＝0.90）和血肿（

＝1.93，

025

＝0.42）方面的信号较强；颅内出血与上消化道出血未观察到

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P450 3A4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。

Abstract

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

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

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

shrinkage measure showed that the apixaban-posaconazole combination exhibited stronger signals for bleeding （

＝2.73，

025

＝2.05） and hemoptysis （

＝2.17，

025

＝0.83）； the apixaban-fluconazole combination exhibited stronger signals for hematoma （

＝2.30，

025

＝1.47） and hematuria （

＝1.71，

025

＝0.74）； the rivaroxaban-itraconazole combination exhibited stronger signals for epistaxis （

＝2.01，

025

＝0.90） and hematoma （

＝1.93，

025

＝0.42）； no positive

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.

关键词

Keywords

references

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