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Article(id=1207314223596675110, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1207314214872518754, articleNumber=null, orderNo=null, doi=10.14109/j.cnki.xyylc.2025.04.10, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1718553600000, receivedDateStr=2024-06-17, revisedDate=null, revisedDateStr=null, acceptedDate=1736006400000, acceptedDateStr=2025-01-05, onlineDate=1765775741712, onlineDateStr=2025-12-15, pubDate=1745510400000, pubDateStr=2025-04-25, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1765775741712, onlineIssueDateStr=2025-12-15, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1765775741712, creator=13701087609, updateTime=1765775741712, updator=13701087609, issue=Issue{id=1207314214872518754, tenantId=1146029695717560320, journalId=1205117082300743687, year='2025', volume='44', issue='4', pageStart='241', pageEnd='320', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=1, specialIssue=0, createTime=1765775739638, creator=13701087609, updateTime=1765775882010, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1207314812124635584, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1207314214872518754, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1207314812124635585, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1207314214872518754, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=299, endPage=306, ext={EN=ArticleExt(id=1207314227732258874, articleId=1207314223596675110, tenantId=1146029695717560320, journalId=1205117082300743687, language=EN, title=Investigation and countermeasure of potential adverse drug interactions of non-vitamin K antagonist oral anticoagulants, columnId=1207314218647392369, journalTitle=Chinese Journal of New Drugs and Clinical Remedies, columnName=Original Article, runingTitle=null, highlight=null, articleAbstract=

AIM To analyze the potential adverse drug interactions （pADIs） of non-vitamin K antagonist oral anticoagulants （NOAC）, and to promote rational drug use. METHODS Outpatient prescriptions of using NOAC in combination with other drugs were surveyed from January 1, 2024 to May 31, 2024 through the information system of the third people's hospital of Bengbu, and pADIs were identified and their severities were graded. Refined prescription pre-review rules were developed by rational drug software. RESULTS Among 1 153 NOAC combined prescriptions, 406 prescriptions had 511 cases of pADIs, including 180 cases of dabigatran etexilate, 288 cases of rivaroxaban and 43 cases of apixaban.The combined drugs involved antiepileptic, antiplatelet, Chinese medicines containing salvia/ginseng/ginkgo biloba and antiarrhythmic drugs. Rivaroxaban + phenobarbital severity classification was contraindicated. Refined rules included 1 interception rule and 10 alert information + double-signature rules and 8 attention information rules. CONCLUSION There are pADIs between NOAC and other drugs in the hospital. The medication risks can be prevented through targeted intervention based on evidence-based refined prescription pre-review rules.

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目的 分析非维生素K拮抗剂口服抗凝药（NOAC）潜在不良药物相互作用（pADIs），促进合理用药。方法 利用医院信息系统抽取2024年1月1日至5月31日蚌埠市第三人民医院门诊NOAC联合用药处方，鉴别pADIs并对其严重性进行分级；利用合理用药软件制定精细化审方规则。结果 1 153张NOAC联合用药处方中，406张处方发生511例次pADIs，包括达比加群酯180例次、利伐沙班288例次和阿哌沙班43例次，联用药物涉及抗癫痫药物、抗血小板药物、含丹参/人参/银杏类中药和抗心律失常药物等。利伐沙班+苯巴比妥严重性分级为禁忌。精细化审方规则包括“处方拦截”规则1项、“警示信息提醒+双签确认”规则10项和“注意信息提醒”规则8项。结论 该院NOAC与其他药物存在pADIs，通过循证制定的精细化审方规则进行针对性干预，能够防范用药风险。

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汪龙，男，副主任药师，硕士，主要从事临床药学的研究，E-mail:

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汪龙，男，副主任药师，硕士，主要从事临床药学的研究，E-mail:

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汪龙，男，副主任药师，硕士，主要从事临床药学的研究，E-mail:

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Curr Drug Metab,2012, 13（5）: 640-651., articleTitle=Herb-drug interactions and mechanistic and clinical considerations, refAbstract=null)], funds=[Fund(id=1207314235063902498, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1207314223596675110, awardId=2024ZD0050, language=CN, fundingSource=蚌埠市科技创新指导类项目(2024ZD0050), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1207314229154127970, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1207314223596675110, xref=1., ext=[AuthorCompanyExt(id=1207314229162516579, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1207314223596675110, companyId=1207314229154127970, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1. 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处方相关特征达比加群酯（n=328）利伐沙班（n=853）阿哌沙班（n=93）NOAC（n=1 274）
性别
男167（50.9）402（47.1）39（41.9）608（47.7）
女161（49.1）451（52.9）54（58.1）666（52.3）
年龄/岁
18~491（0.3）41（4.8）0（0）42（3.3）
50~5916（4.9）61（7.2）7（7.5）84（6.6）
60~6937（11.3）146（17.1）5（5.4）188（14.8）
70~79139（42.4）339（39.7）27（29.0）505（39.6）
80~89124（37.8）236（27.7）50（53.8）410（32.1）
90~9911（3.4）30（3.5）4（4.3）45（3.5）
主要合并诊断*
高血压228（69.5）477（55.9）66（70.1）771（60.5）
冠心病222（67.7）434（50.9）60（64.5）716（56.2）
糖尿病112（34.2）192（22.5）28（30.1）332（26.1）
脑卒中53（16.2）81（9.5）21（22.6）155（12.2）
胸痹心痛病（中医）27（8.2）46（5.4）7（7.5）80（6.3）
血管支架植入后26（7.9）56（6.6）16（17.2）98（7.7）
脑血管病23（7.0）30（3.5）10（10.8）63（4.9）
心功能不全21（6.4）47（5.5）2（2.2）70（5.5）
心力衰竭13（4.0）65（7.6）1（1.1）79（6.2）
联用药物数量/种
015（4.6）95（11.1）11（11.8）121（9.5）
1~4192（58.5）486（57.0）49（52.7）727（57.1）
5~8106（32.3）240（28.1）28（30.1）374（29.4）
9~1215（4.6）28（3.3）5（5.4）48（3.8）
12~150（0 ）4（0.5）0（0）4（0.3）
), ArticleFig(id=1207314233361015042, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1207314223596675110, language=CN, label=表1, caption=

非维生素K拮抗剂口服抗凝药（NOAC）门诊处方基本特征

, figureFileSmall=null, figureFileBig=null, tableContent=
处方相关特征达比加群酯（n=328）利伐沙班（n=853）阿哌沙班（n=93）NOAC（n=1 274）
性别
男167（50.9）402（47.1）39（41.9）608（47.7）
女161（49.1）451（52.9）54（58.1）666（52.3）
年龄/岁
18~491（0.3）41（4.8）0（0）42（3.3）
50~5916（4.9）61（7.2）7（7.5）84（6.6）
60~6937（11.3）146（17.1）5（5.4）188（14.8）
70~79139（42.4）339（39.7）27（29.0）505（39.6）
80~89124（37.8）236（27.7）50（53.8）410（32.1）
90~9911（3.4）30（3.5）4（4.3）45（3.5）
主要合并诊断*
高血压228（69.5）477（55.9）66（70.1）771（60.5）
冠心病222（67.7）434（50.9）60（64.5）716（56.2）
糖尿病112（34.2）192（22.5）28（30.1）332（26.1）
脑卒中53（16.2）81（9.5）21（22.6）155（12.2）
胸痹心痛病（中医）27（8.2）46（5.4）7（7.5）80（6.3）
血管支架植入后26（7.9）56（6.6）16（17.2）98（7.7）
脑血管病23（7.0）30（3.5）10（10.8）63（4.9）
心功能不全21（6.4）47（5.5）2（2.2）70（5.5）
心力衰竭13（4.0）65（7.6）1（1.1）79（6.2）
联用药物数量/种
015（4.6）95（11.1）11（11.8）121（9.5）
1~4192（58.5）486（57.0）49（52.7）727（57.1）
5~8106（32.3）240（28.1）28（30.1）374（29.4）
9~1215（4.6）28（3.3）5（5.4）48（3.8）
12~150（0 ）4（0.5）0（0）4（0.3）
), ArticleFig(id=1207314233436512519, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1207314223596675110, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
pADIs发生频次/次达比加群酯利伐沙班阿哌沙班NOAC
0178（56.9）523（69.0）46（56.1）747（64.8）
1101（32.3）188（24.8）30（36.6）319（27.7）
224（7.7）43（5.7）5（6.1）72（6.2）
39（2.9）2（0.3）1（1.2）12（1.0）
41（0.3）2（0.3）0（0）3（0.3）
合计313758821 153
), ArticleFig(id=1207314233532981515, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1207314223596675110, language=CN, label=表2, caption=

非维生素K拮抗剂口服抗凝药（NOAC）潜在不良药物相互作用（pADIs）处方概况

, figureFileSmall=null, figureFileBig=null, tableContent=
pADIs发生频次/次达比加群酯利伐沙班阿哌沙班NOAC
0178（56.9）523（69.0）46（56.1）747（64.8）
1101（32.3）188（24.8）30（36.6）319（27.7）
224（7.7）43（5.7）5（6.1）72（6.2）
39（2.9）2（0.3）1（1.2）12（1.0）
41（0.3）2（0.3）0（0）3（0.3）
合计313758821 153
), ArticleFig(id=1207314233629450511, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1207314223596675110, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
联用药物种类/通用名严重性分级pADIs发生例次
达比加群酯利伐沙班阿哌沙班NOAC
抗癫痫药物
苯巴比妥禁忌0303
丙戊酸严重6309
抗血小板药物
阿司匹林严重37679113
氯吡格雷严重4148998
替格瑞洛严重0606
非甾体抗炎药
双氯芬酸严重0404
塞来昔布严重0202
布洛芬严重0101
抗菌药物
阿莫西林严重1001
红霉素严重1001
罗红霉素严重1203
免疫抑制剂
环孢素严重0303
甲氨蝶呤严重0022
抗凝血药物
利伐沙班严重1-01
达比加群酯严重-101
抗心律失常药
胺碘酮严重/中度8（严重）27（中度）035
甲状腺激素类药物
左甲状腺素中度314118
糖皮质激素
地塞米松中度0303
泼尼松中度0101
含丹参类中药
心可舒片/胶囊中度166729
脑心通胶囊中度823536
血栓心脉宁片中度78015
冠心舒通胶囊中度75012
复方丹参滴丸中度57416
丹参（饮片）中度2305
冠心丹参胶囊中度0303
含人参类中药
芪苈强心胶囊中度2124449
参松养心胶囊中度612018
通心络胶囊中度28010
含银杏类中药
银杏酮酯分散片中度6219
银杏叶丸中度1214
), ArticleFig(id=1207314234732552469, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1207314223596675110, language=CN, label=表3, caption=

非维生素K拮抗剂口服抗凝药（NOAC）联合用药潜在不良药物相互作用（pADIs）发生情况及严重性分级

, figureFileSmall=null, figureFileBig=null, tableContent=
联用药物种类/通用名严重性分级pADIs发生例次
达比加群酯利伐沙班阿哌沙班NOAC
抗癫痫药物
苯巴比妥禁忌0303
丙戊酸严重6309
抗血小板药物
阿司匹林严重37679113
氯吡格雷严重4148998
替格瑞洛严重0606
非甾体抗炎药
双氯芬酸严重0404
塞来昔布严重0202
布洛芬严重0101
抗菌药物
阿莫西林严重1001
红霉素严重1001
罗红霉素严重1203
免疫抑制剂
环孢素严重0303
甲氨蝶呤严重0022
抗凝血药物
利伐沙班严重1-01
达比加群酯严重-101
抗心律失常药
胺碘酮严重/中度8（严重）27（中度）035
甲状腺激素类药物
左甲状腺素中度314118
糖皮质激素
地塞米松中度0303
泼尼松中度0101
含丹参类中药
心可舒片/胶囊中度166729
脑心通胶囊中度823536
血栓心脉宁片中度78015
冠心舒通胶囊中度75012
复方丹参滴丸中度57416
丹参（饮片）中度2305
冠心丹参胶囊中度0303
含人参类中药
芪苈强心胶囊中度2124449
参松养心胶囊中度612018
通心络胶囊中度28010
含银杏类中药
银杏酮酯分散片中度6219
银杏叶丸中度1214
), ArticleFig(id=1207314234829021464, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1207314223596675110, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
序号联合用药情况可能机制潜在风险审方规则
警示/注意信息内容审方路径
1苯巴比妥联用利伐沙班苯巴比妥为CYP3A4强效诱导剂和P-糖蛋白（P-gp）可能诱导剂血栓事件苯巴比妥降低利伐沙班血药浓度，增加血栓事件的发生风险，两者禁止联用①
2丙戊酸联用达比加群酯/利伐沙班丙戊酸可能诱导或抑制CYP3A4，对P-gp可能既诱导又抑制血栓或出血事件丙戊酸降低或增加达比加群酯/利伐沙班血药浓度，血栓或出血风险不可预测；药物相互作用分级为“严重”，谨慎联用；联用时应监测血栓或出血体征和症状②
3阿司匹林联用达比加群酯/利伐沙班/阿哌沙班阿司匹林乙酰化环氧化酶（COX）、抑制血栓素A2（TXA2）生成，抑制血小板聚集出血事件阿司匹林与达比加群酯/利伐沙班/阿哌沙班联用产生抗凝血增效作用；药物相互作用分级为“严重”，谨慎联用（若因房颤合并冠心病而联用，应严格把握疗程）；联用时应监测出血体征和症状③ 有“冠心病”等诊断；
② 无“冠心病”等诊断
4氯吡格雷联用达比加群酯/利伐沙班/阿哌沙班氯吡格雷经肝脏代谢为活性产物，与二磷酸腺苷（ADP）竞争性结合血小板膜表面的ADP受体P2Y12，抑制血小板膜蛋白复合物活化出血事件氯吡格雷与达比加群酯/利伐沙班/阿哌沙班联用产生抗凝血增效作用；药物相互作用分级为“严重”，谨慎联用（若因房颤合并冠心病而联用，应严格把握疗程）；联用时应监测出血体征和症状③ 有“冠心病”等诊断；
② 无“冠心病”等诊断
5替格瑞洛联用利伐沙班替格瑞洛拮抗血小板膜表面的P2Y12，阻断ADP对GPⅡb/Ⅲa的激活作用，使其无法与纤维蛋白原结合；替格瑞洛经CYP3A4代谢，且为P-gp底物和弱效抑制剂出血事件替格瑞洛与利伐沙班联用产生抗凝血增效作用；药物相互作用分级为“严重”，谨慎联用（若因房颤合并冠心病而联用，应严格把握疗程）；联用时应监测出血体征和症状③ 有“冠心病”等诊断；
② 无“冠心病”等诊断
6双氯芬酸/塞来昔布/布洛芬联用利伐沙班双氯芬酸/塞来昔布/布洛芬抑制COX，减少前列腺素生成，损伤消化道黏膜；还能抑制TXA2分泌，减少黏膜血供及抗血小板聚集，诱发消化道黏膜糜烂、溃疡及出血出血事件双氯芬酸/塞来昔布/布洛芬与利伐沙班联用增加出血事件的发生风险；药物相互作用分级为“严重”，谨慎联用；联用时应监测出血体征和症状②
7阿莫西林/红霉素/罗红霉素联用达比加群酯/利伐沙班阿莫西林/红霉素/罗红霉素为CYP3Y4和P-gp抑制剂，还可能通过影响肠道菌群而干扰凝血过程出血事件阿莫西林/红霉素/罗红霉素能够提高达比加群酯/利伐沙班血药浓度；药物相互作用分级为“严重”，谨慎联用；联用时应监测出血体征和症状②
8环孢素联用利伐沙班环孢素为CYP3Y4和P-gp底物，且为中强效P-gp抑制剂、中效CYP3Y4抑制剂出血事件环孢素能够提高利伐沙班血药浓度，增加出血事件发生风险；药物相互作用分级为“严重”，谨慎联用；联用时应监测出血体征和症状②
9甲氨蝶呤联用阿哌沙班甲氨蝶呤的蛋白结合率约为50%，当联用蛋白结合率高（87%）的阿哌沙班时，游离甲氨蝶呤水平升高；它还能导致甲氨蝶呤的活性代谢产物生成减少，降低疗效甲氨蝶呤毒性事件阿哌沙班增加甲氨蝶呤毒性反应的发生风险，降低甲氨蝶呤疗效；药物相互作用分级为“严重”，谨慎联用；联用时应监测甲氨蝶呤相关毒性反应，如骨髓抑制、口腔黏膜炎和肝功能异常等②
10达比加群酯联用利伐沙班达比加群酯与利伐沙班能通过不同机制产生抗凝血协同增效作用，且两者均为P-gp底物出血事件达比加群酯联用利伐沙班产生抗凝血增效作用，增加出血事件发生风险；药物相互作用分级为“严重”，谨慎联用；联用时应监测出血体征和症状②
11胺碘酮联用达比加群酯胺碘酮为中效P-gp抑制剂出血事件胺碘酮能够提高达比加群酯血药浓度；药物相互作用分级为“严重”，谨慎联用；联用时应监测出血体征和症状②
12胺碘酮联用利伐沙班胺碘酮为中效P-gp抑制剂出血事件胺碘酮可能提高利伐沙班血药浓度；药物相互作用分级为“中度”；联用时需关注出血体征和症状③
13左甲状腺素联用达比加群酯/利伐沙班/阿哌沙班未知出血事件左甲状腺素可能增强患者对达比加群酯/利伐沙班/阿哌沙班抗凝治疗的反应；药物相互作用分级为“中度”；联用时需关注出血体征和症状③
14含丹参类中药联用达比加群酯/利伐沙班/阿哌沙班丹参的多种活性成分具有扩张血管、增加血流量或抗血小板聚集等作用，且丹参酮为CYP3Y4抑制剂出血事件含丹参类中药联用达比加群酯/利伐沙班/阿哌沙班可能产生抗凝血增效作用，增加出血事件发生风险；药物相互作用分级为“中度”；联用时需关注出血体征和症状③
15含人参类中药联用达比加群酯/利伐沙班/阿哌沙班人参皂苷类成分能够抑制ADP诱导的血小板聚集、增强纤维蛋白溶解活性，还能促进血管内皮NO的释放而产生抗凝血作用，且人参皂苷为P-gp底物及抑制剂出血事件含人参类中药联用达比加群酯/利伐沙班/阿哌沙班可能产生抗凝血增效作用，增加出血事件发生风险；药物相互作用分级为“中度”；联用时需关注出血体征和症状③
16含银杏类中药联用达比加群酯/利伐沙班/阿哌沙班银杏内酯成分为血小板活化因子受体拮抗剂，能够抑制血小板活性、抗血小板黏附及聚集，且可抑制P-gp外排功能出血事件含银杏类中药联用达比加群酯/利伐沙班/阿哌沙班可能产生抗凝血增效作用，增加出血事件发生风险；药物相互作用分级为“中度”；联用时需关注出血体征和症状③
), ArticleFig(id=1207314234921296156, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1207314223596675110, language=CN, label=表4, caption=

潜在不良药物相互作用（pADIs）可能机制及审方规则

, figureFileSmall=null, figureFileBig=null, tableContent=
序号联合用药情况可能机制潜在风险审方规则
警示/注意信息内容审方路径
1苯巴比妥联用利伐沙班苯巴比妥为CYP3A4强效诱导剂和P-糖蛋白（P-gp）可能诱导剂血栓事件苯巴比妥降低利伐沙班血药浓度，增加血栓事件的发生风险，两者禁止联用①
2丙戊酸联用达比加群酯/利伐沙班丙戊酸可能诱导或抑制CYP3A4，对P-gp可能既诱导又抑制血栓或出血事件丙戊酸降低或增加达比加群酯/利伐沙班血药浓度，血栓或出血风险不可预测；药物相互作用分级为“严重”，谨慎联用；联用时应监测血栓或出血体征和症状②
3阿司匹林联用达比加群酯/利伐沙班/阿哌沙班阿司匹林乙酰化环氧化酶（COX）、抑制血栓素A2（TXA2）生成，抑制血小板聚集出血事件阿司匹林与达比加群酯/利伐沙班/阿哌沙班联用产生抗凝血增效作用；药物相互作用分级为“严重”，谨慎联用（若因房颤合并冠心病而联用，应严格把握疗程）；联用时应监测出血体征和症状③ 有“冠心病”等诊断；
② 无“冠心病”等诊断
4氯吡格雷联用达比加群酯/利伐沙班/阿哌沙班氯吡格雷经肝脏代谢为活性产物，与二磷酸腺苷（ADP）竞争性结合血小板膜表面的ADP受体P2Y12，抑制血小板膜蛋白复合物活化出血事件氯吡格雷与达比加群酯/利伐沙班/阿哌沙班联用产生抗凝血增效作用；药物相互作用分级为“严重”，谨慎联用（若因房颤合并冠心病而联用，应严格把握疗程）；联用时应监测出血体征和症状③ 有“冠心病”等诊断；
② 无“冠心病”等诊断
5替格瑞洛联用利伐沙班替格瑞洛拮抗血小板膜表面的P2Y12，阻断ADP对GPⅡb/Ⅲa的激活作用，使其无法与纤维蛋白原结合；替格瑞洛经CYP3A4代谢，且为P-gp底物和弱效抑制剂出血事件替格瑞洛与利伐沙班联用产生抗凝血增效作用；药物相互作用分级为“严重”，谨慎联用（若因房颤合并冠心病而联用，应严格把握疗程）；联用时应监测出血体征和症状③ 有“冠心病”等诊断；
② 无“冠心病”等诊断
6双氯芬酸/塞来昔布/布洛芬联用利伐沙班双氯芬酸/塞来昔布/布洛芬抑制COX，减少前列腺素生成，损伤消化道黏膜；还能抑制TXA2分泌，减少黏膜血供及抗血小板聚集，诱发消化道黏膜糜烂、溃疡及出血出血事件双氯芬酸/塞来昔布/布洛芬与利伐沙班联用增加出血事件的发生风险；药物相互作用分级为“严重”，谨慎联用；联用时应监测出血体征和症状②
7阿莫西林/红霉素/罗红霉素联用达比加群酯/利伐沙班阿莫西林/红霉素/罗红霉素为CYP3Y4和P-gp抑制剂，还可能通过影响肠道菌群而干扰凝血过程出血事件阿莫西林/红霉素/罗红霉素能够提高达比加群酯/利伐沙班血药浓度；药物相互作用分级为“严重”，谨慎联用；联用时应监测出血体征和症状②
8环孢素联用利伐沙班环孢素为CYP3Y4和P-gp底物，且为中强效P-gp抑制剂、中效CYP3Y4抑制剂出血事件环孢素能够提高利伐沙班血药浓度，增加出血事件发生风险；药物相互作用分级为“严重”，谨慎联用；联用时应监测出血体征和症状②
9甲氨蝶呤联用阿哌沙班甲氨蝶呤的蛋白结合率约为50%，当联用蛋白结合率高（87%）的阿哌沙班时，游离甲氨蝶呤水平升高；它还能导致甲氨蝶呤的活性代谢产物生成减少，降低疗效甲氨蝶呤毒性事件阿哌沙班增加甲氨蝶呤毒性反应的发生风险，降低甲氨蝶呤疗效；药物相互作用分级为“严重”，谨慎联用；联用时应监测甲氨蝶呤相关毒性反应，如骨髓抑制、口腔黏膜炎和肝功能异常等②
10达比加群酯联用利伐沙班达比加群酯与利伐沙班能通过不同机制产生抗凝血协同增效作用，且两者均为P-gp底物出血事件达比加群酯联用利伐沙班产生抗凝血增效作用，增加出血事件发生风险；药物相互作用分级为“严重”，谨慎联用；联用时应监测出血体征和症状②
11胺碘酮联用达比加群酯胺碘酮为中效P-gp抑制剂出血事件胺碘酮能够提高达比加群酯血药浓度；药物相互作用分级为“严重”，谨慎联用；联用时应监测出血体征和症状②
12胺碘酮联用利伐沙班胺碘酮为中效P-gp抑制剂出血事件胺碘酮可能提高利伐沙班血药浓度；药物相互作用分级为“中度”；联用时需关注出血体征和症状③
13左甲状腺素联用达比加群酯/利伐沙班/阿哌沙班未知出血事件左甲状腺素可能增强患者对达比加群酯/利伐沙班/阿哌沙班抗凝治疗的反应；药物相互作用分级为“中度”；联用时需关注出血体征和症状③
14含丹参类中药联用达比加群酯/利伐沙班/阿哌沙班丹参的多种活性成分具有扩张血管、增加血流量或抗血小板聚集等作用，且丹参酮为CYP3Y4抑制剂出血事件含丹参类中药联用达比加群酯/利伐沙班/阿哌沙班可能产生抗凝血增效作用，增加出血事件发生风险；药物相互作用分级为“中度”；联用时需关注出血体征和症状③
15含人参类中药联用达比加群酯/利伐沙班/阿哌沙班人参皂苷类成分能够抑制ADP诱导的血小板聚集、增强纤维蛋白溶解活性，还能促进血管内皮NO的释放而产生抗凝血作用，且人参皂苷为P-gp底物及抑制剂出血事件含人参类中药联用达比加群酯/利伐沙班/阿哌沙班可能产生抗凝血增效作用，增加出血事件发生风险；药物相互作用分级为“中度”；联用时需关注出血体征和症状③
16含银杏类中药联用达比加群酯/利伐沙班/阿哌沙班银杏内酯成分为血小板活化因子受体拮抗剂，能够抑制血小板活性、抗血小板黏附及聚集，且可抑制P-gp外排功能出血事件含银杏类中药联用达比加群酯/利伐沙班/阿哌沙班可能产生抗凝血增效作用，增加出血事件发生风险；药物相互作用分级为“中度”；联用时需关注出血体征和症状③
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非维生素K拮抗剂口服抗凝药潜在不良药物相互作用处方调查及对策
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汪龙 1 , 张莉 2 , 朱玲娜 1 , 程军 1
中国新药与临床杂志 | 论著 2025,44(4): 299-306
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中国新药与临床杂志 | 论著 2025, 44(4): 299-306
非维生素K拮抗剂口服抗凝药潜在不良药物相互作用处方调查及对策
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汪龙1 , 张莉2, 朱玲娜1, 程军1
作者信息
  • 1.蚌埠市第三人民医院　药学部，安徽　蚌埠　233099
  • 2.蚌埠医科大学第二附属医院　药学部，安徽　蚌埠　233004

    • 汪龙，男，副主任药师，硕士，主要从事临床药学的研究，E-mail:

Investigation and countermeasure of potential adverse drug interactions of non-vitamin K antagonist oral anticoagulants
Long WANG1 , Li ZHANG2, Ling-na ZHU1, Jun CHENG1
Affiliations
  • 1. Department of Pharmacy, the Third People's Hospital of Bengbu, Bengbu ANHUI 233099, China
  • 2. Department of Pharmacy, the Second Affiliated Hospital of Bengbu Medical University, Bengbu ANHUI 233004, China
出版时间: 2025-04-25 doi: 10.14109/j.cnki.xyylc.2025.04.10
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摘要
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目的 分析非维生素K拮抗剂口服抗凝药（NOAC）潜在不良药物相互作用（pADIs），促进合理用药。方法 利用医院信息系统抽取2024年1月1日至5月31日蚌埠市第三人民医院门诊NOAC联合用药处方，鉴别pADIs并对其严重性进行分级；利用合理用药软件制定精细化审方规则。结果 1 153张NOAC联合用药处方中，406张处方发生511例次pADIs，包括达比加群酯180例次、利伐沙班288例次和阿哌沙班43例次，联用药物涉及抗癫痫药物、抗血小板药物、含丹参/人参/银杏类中药和抗心律失常药物等。利伐沙班+苯巴比妥严重性分级为禁忌。精细化审方规则包括“处方拦截”规则1项、“警示信息提醒+双签确认”规则10项和“注意信息提醒”规则8项。结论 该院NOAC与其他药物存在pADIs，通过循证制定的精细化审方规则进行针对性干预，能够防范用药风险。

抗凝药  /  药物相互作用  /  循证医学  /  细胞色素P450 CYP3A4  /  P-糖蛋白

AIM To analyze the potential adverse drug interactions （pADIs） of non-vitamin K antagonist oral anticoagulants （NOAC）, and to promote rational drug use. METHODS Outpatient prescriptions of using NOAC in combination with other drugs were surveyed from January 1, 2024 to May 31, 2024 through the information system of the third people's hospital of Bengbu, and pADIs were identified and their severities were graded. Refined prescription pre-review rules were developed by rational drug software. RESULTS Among 1 153 NOAC combined prescriptions, 406 prescriptions had 511 cases of pADIs, including 180 cases of dabigatran etexilate, 288 cases of rivaroxaban and 43 cases of apixaban.The combined drugs involved antiepileptic, antiplatelet, Chinese medicines containing salvia/ginseng/ginkgo biloba and antiarrhythmic drugs. Rivaroxaban + phenobarbital severity classification was contraindicated. Refined rules included 1 interception rule and 10 alert information + double-signature rules and 8 attention information rules. CONCLUSION There are pADIs between NOAC and other drugs in the hospital. The medication risks can be prevented through targeted intervention based on evidence-based refined prescription pre-review rules.

anticoagulants  /  drug interactions  /  evidence-based medicine  /  cytochrome P-450 CYP3A4  /  p-glycoprotein
汪龙, 张莉, 朱玲娜, 程军. 非维生素K拮抗剂口服抗凝药潜在不良药物相互作用处方调查及对策. 中国新药与临床杂志, 2025 , 44 (4) : 299 -306 . DOI: 10.14109/j.cnki.xyylc.2025.04.10
Long WANG, Li ZHANG, Ling-na ZHU, Jun CHENG. Investigation and countermeasure of potential adverse drug interactions of non-vitamin K antagonist oral anticoagulants[J]. Chinese Journal of New Drugs and Clinical Remedies, 2025 , 44 (4) : 299 -306 . DOI: 10.14109/j.cnki.xyylc.2025.04.10
正文
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非维生素K拮抗剂口服抗凝药（non-vitamin K antagonist oral anticoagulants，NOAC）又称为直接或新型口服抗凝药，避免了传统口服抗凝药华法林的诸多弊端，如治疗窗窄、起效缓慢、个体差异大、围术期桥接管理等，已成为世界范围内非瓣膜性房颤和相关静脉血栓预防及治疗的一线药物[1]。目前，我国批准上市的NOAC依据作用靶点可分为直接凝血酶抑制剂（达比加群酯）和直接Ⅹa因子抑制剂（利伐沙班、阿哌沙班和艾多沙班）[2]。NOAC适用人群多为老年患者，常并发其他疾病，联合用药情况普遍，得到不少学者关注[2-4]。土耳其的一项回顾性研究表明，老年房颤患者终点事件（死亡）的发生率与其应用NOAC的潜在不良药物相互作用（potential adverse drug interactions，pADIs）存在关联[4]。目前，国内NOAC药物相互作用文献多以个案报道、生理药动学模型研究和综述型研究为主[5-7]，缺乏针对医疗机构pADIs处方进行药学干预的应用型研究。近年来，各级卫健委要求医疗机构重视处方前置审核工作，但目前商业化处方审核软件普遍存在系统知识库宽泛、审查规则粗浅等问题[8]。本研究调查蚌埠市第三人民医院（综合性三级甲等医院）NOAC联合用药处方，参考相关循证医学证据，对pADIs情况进行鉴别、分级，并据此制定精细化的处方前置审核规则，对存在pADIs的处方行为进行实时用药干预，旨在提高患者用药的安全性。
资料与方法
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数据来源
利用医院信息系统抽取蚌埠市第三人民医院（下文简称“该院”）2024年1月1日至5月31日所有包含NOAC的门诊处方数据，该院NOAC共有3种，包括达比加群酯胶囊（正大天晴药业集团股份有限公司，国药准字H202003098）、利伐沙班片（广东东阳光药业股份有限公司，国药准字H20213374）和阿哌沙班片（常州恒邦药业有限公司，国药准字H20193003）。同一患者同日如果开具≥2张处方（包括不同科室），合并为一张处方处理；剔除合并后仍仅为单药的处方，即筛选出NOAC联合用药处方。
pADIs鉴别及严重程度分级
以国内外药品说明书、相关临床诊疗指南和专家共识为基础[9-11]，依据Micromedex和Medscape数据库的药物相互作用信息（Micromedex包括禁忌、严重、中等、轻微和未知；Medscape包括禁忌、严重/使用替换方案、密切监视和轻微），对NOAC联合用药处方的pADIs进行鉴别和分级；如遇Micromedex和Medscape数据库对某种药物组合的pADIs评价不一致时，通过查阅Lexicomp数据库［包括X级（避免合用）、D级（需调整治疗方案）、C级（需加强监测）、B级（可能存在相互作用，不需调整治疗）和A级（无已知的药物相互作用）］及相关研究报道，并经团队讨论进行判断。
本研究参照上述循证医学证据将NOAC联合用药的pADIs情况对应划分为4个等级，包括禁忌（pADIs可危及生命，禁止同时使用这些药物）、严重（pADIs可能危及生命/需要医疗干预以减少或避免严重的不良影响）、中度（pADIs可能导致加重病情和/或需要在治疗中发生改变）和轻度（pADIs可能增加不良反应发生频率或严重程度，但一般不需要在治疗中发生改变），对相关处方的pADIs进行鉴别、分级后，统计各级处方数量、发生频次及相关药物等信息。
梳理pADIs可能机制及制定审方规则
以上述发现pADIs情况的“涉及药物”为检索词，在中国知网、中华医学期刊、万方、PubMed、UpToDate和Embase等数据库中检索相关文献，梳理“涉及药物”发生pADIs的可能机制。
利用合理用药管理系统Ipharmacare V4.0版本（杭州逸曜信息技术有限公司）的自定义规则程序，针对NOAC不同联合用药情况循证设置精细化的处方前置审核规则，当合理用药管理系统审查到医师处方行为存在pADIs时，实时进行用药干预（警示/注意信息提醒、处方拦截或双签确认）。
结果
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处方基本特征
2024年1月1日至5月31日，该院门诊NOAC处方共计1 274张，涉及患者男性608例（47.7%）、女性666例（52.3%），主要合并诊断为高血压（60.5%）、冠心病（56.2%）和糖尿病（26.1%）。NOAC联合用药处方1 153张（90.5%），包括达比加群酯313张（24.6%）、利伐沙班758张（59.5%）和阿哌沙班82张（6.4%）；联用药物数量以1~4种最常见（57.1%）。见表1。
pADIs处方概况、相关药物和严重性分级
1 153张NOAC联合用药处方中，存在pADIs（1~4次）的处方有406张（35.2%），包括达比加群酯135张（11.7%）、利伐沙班235张（20.4%）和阿哌沙班36张（3.1%）。见表2。
406张NOAC联合用药处方共发生pADIs 511例次，包括达比加群酯180例次、利伐沙班288例次和阿哌沙班43例次。严重性分级为“禁忌”的有3例次，为苯巴比妥联用利伐沙班；“严重”的有253例次，包括NOAC联用抗血小板药物、丙戊酸、非甾体抗炎药、抗菌药物和免疫抑制剂，以及胺碘酮联合达比加群酯；“中度”的有255例次，包括NOAC联用含丹参/人参/银杏类中药、左甲状腺素钠和糖皮质激素，以及胺碘酮联合利伐沙班。见表3。
pADIs可能机制及审方规则
达比加群酯为小分子前体药物，口服吸收后，在体内水解转化为达比加群，能够可逆、强效地直接抑制凝血酶，从而阻碍凝血级联反应中纤维蛋白原转化为纤维蛋白；药物血浆蛋白结合率为35%，主要通过葡萄糖醛酸结合途径代谢（不通过细胞色素P450酶系代谢），为外排转运蛋白P-糖蛋白（P-gp）的底物。利伐沙班和阿哌沙班能够选择性直接阻断Ⅹa因子的活性位点（无需辅因子），显著抑制凝血酶瀑式增加，进而阻止凝血级联反应；两者均通过CYP3A4代谢，均为P-gp的底物，药物血浆蛋白结合率分别为95%、87%[10,12]。
相关文献提示，NOAC联合用药pADIs的机制可能涉及药动学和药效学药物相互作用。药动学方面，主要影响CYP3A4、P-gp等；药效学方面，主要影响血小板功能、中药活血化瘀功效等。据此设置16项精细化审方规则，包括“处方拦截”规则1项、“警示信息提醒+双签确认”规则10项（含诊断相关亚路径3项）和“注意信息提醒”规则8项（含诊断相关亚路径3项）。具体pADIs可能机制及审方规则见表4[9-32]。
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本研究发现，与NOAC联用发生pADIs的抗癫痫药物包括苯巴比妥（“禁忌”等级）和丙戊酸（“严重”等级）。苯巴比妥为CYP3A4强效诱导剂和P-gp可能诱导剂，能降低利伐沙班血药浓度，增加血栓事件的发生风险[14]。一项回顾性队列研究提示，未联用和联用抗癫痫药物（苯巴比妥、苯妥英和卡马西平）患者的NOAC血药浓度分别低于预期范围的9.3%和37.5%[15]。DAGAN等[16]报道1例长期服用苯巴比妥的癫痫患者，在联用利伐沙班1个月后发生左腘动脉附壁血栓而接受截肢手术。一项针对9 693例直接Ⅹ a因子抑制剂联用抗癫痫药物致不良事件案例的研究表明，发生血栓栓塞或缺血性事件的患者占14.7%；其中联用酶促型（苯巴比妥、苯妥英和卡马西平）和非酶促型抗癫痫药物的发生率分别为22.4%和13.4%[17]。值得注意的是，丙戊酸对CYP3A4的影响目前存在争议，NOAC与其联用的pADIs风险尚不明确。STOLLBERGER等[18]报道1例癫痫并发房颤患者在丙戊酸联用利伐沙班后，出现国际标准化比值升高、活化部分凝血活酶时间（aPTT）延长，提示利伐沙班抗凝血活性因pADIs而增强；而LANGENBRUCH等[19]则报道了1例难治性局灶癫痫患者在丙戊酸联用利伐沙班后发生深静脉血栓的案例，其利伐沙班的血药峰、谷浓度均因pADIs而降低。
本研究的pADIs处方中，抗血小板药与NOAC的联用最为常见，风险等级为“严重”。FERNANDEZ等[20]分析了世界卫生组织药物不良反应数据库VigiBase中利伐沙班与其他药物因相互作用而发生不良事件的21 109例案例数据，排名前2的联用药物即为阿司匹林（60.3%）和氯吡格雷（11.7%），两者消化道出血的发生率分别为38.0%和40.9%。另一项多中心、随机、双盲、事件驱动研究也表明，服用利伐沙班或华法林的房颤患者在联用阿司匹林后，临床出血事件的发生风险显著升高[21]。然而，NOAC联用抗血小板药物也会降低相关患者心肌梗死、脑卒中或终点事件（死亡）的发生风险，为其带来疾病治疗的获益[22]。国内外诊疗指南也提示，在房颤患者合并急性冠状动脉综合征或冠脉介入治疗时，NOAC联用抗血小板药物是抗凝治疗的推荐策略，但应严格控制联用疗程，以降低不良事件的发生风险[9,10]。因此，本研究设置审方规则时，针对房颤合并“冠心病”等相关诊断时的联合用药，未要求医师双签确认，以保障指南用药的便捷性；而对pADIs的风险提醒增加“严格把握疗程”的警示信息。
含丹参/人参/银杏类中药制剂与NOAC的联用也较为常见，风险等级为“中度”。WANG等[28]利用体外实验表明，丹参是利伐沙班在人肝脏微粒体代谢的混合抑制剂（抑制常数为0.25 mg·mL-1）；且丹参活性成分二氢丹参酮Ⅰ可剂量依赖性地抑制细胞内Ca2+动员而产生抗血小板聚集作用[29]。舒盼盼等[30]考察了人参属药材提取物的体外凝抗血活性，发现人参皂苷Rb2可延长凝血酶原时间（PT）和aPTT，且人参皂苷Rb2含量与PT呈正相关。银杏内酯是一种天然血小板活化因子受体拮抗剂，能够抑制血小板活性、抗血小板聚集，增加血流通量[28]。另外，人参皂苷与银杏内酯为P-gp底物或抑制剂，可能影响NOAC的外排转运[10,32]。此外，NOAC还与非甾体抗炎药、抗菌药物和糖皮质激素类等药物存在pADIs[10,13,23-25]，合理用药管理系统也将依据本研究的审方规则对相关联合用药情况进行针对性干预，以便处方医师叮嘱患者在NOAC用药期间注意出血体征或症状的自我监测。本研究结果可为医疗机构开展循证、精细化审方工作提供参考，但也存在一定的局限性。本调查仅限于一家三甲医院的门诊处方数据，样本量较小；且仅涉及两种药物联用情况，未将药物多重联用、使用剂量等因素纳入考量，开展进一步研究，以便更全面地提高临床用药的有效性和安全性。
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  • 蚌埠市科技创新指导类项目(2024ZD0050)
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2025年第44卷第4期
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doi: 10.14109/j.cnki.xyylc.2025.04.10
  • 接收时间：2024-06-17
  • 首发时间：2025-12-15
  • 出版时间：2025-04-25
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  • 收稿日期：2024-06-17
  • 录用日期：2025-01-05
基金
蚌埠市科技创新指导类项目(2024ZD0050)
作者信息
    1.蚌埠市第三人民医院　药学部，安徽　蚌埠　233099
    2.蚌埠医科大学第二附属医院　药学部，安徽　蚌埠　233004
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2种不同金属材料的力学参数
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Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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