Abstract：
BACKGROUND: Metabolism of oral anticoagulants (OAC) is affected by P-glycoprotein (P-gp)/ CYP3A4 enzyme. However, the P-gp/CYP3A4 inhibitors are unavoidably used with OACs.
METHODS: Medline, Cochrane, and Embase were systematically searched for randomized controlled trials and cohort studies from inception till 23rd November, 2022 to assess the safety and effectiveness of OACs when concomitantly used with P-gp/CYP3A4 inhibitors. The primary outcomes were major bleeding and gastrointestinal (GI) bleeding. Secondary outcomes were stroke/systemic embolism (SE), all-cause mortality, any bleeding as well as intracranial hemorrhage (ICH). We estimated summary odds ratios (OR) with 95% credible intervals (CI) using pairwise and network meta-analysis with random effects.
RESULTS: A total of 11 studies involving 37,973 patients were included. When concomitantly used with P-pg/ CYP3A4 inhibitors, network meta-analysis indicated that dabigatran, apixaban, and edoxaban were associated with significantly lower risk of major bleeding compared to rivaroxaban, with ORs of 0.56, 0.51 and 0.48, respectively. Rivaroxaban and dabigatran were associated with a significantly increased risk of GI bleeding than warfarin, apixaban and edoxaban. Dabigatran and apixaban were linked with significantly lower risk of any bleeding compared with warfarin (ORs were 0.75 and 0.68, respectively) or rivaroxaban (ORs were 0.67 and 0.60, respectively). Apixaban (OR 0.32) and edoxaban (OR 0.35) were associated with a lower risk of ICH compared with warfarin. There was no difference between any OACs in terms of stroke/SE or all-cause mortality.
CONCLUSIONS: When concomitantly used with P-gp/CYP3A4 inhibitors, apixaban and edoxaban were associated with a lower risk of bleeding, though no significant difference in effectiveness was observed among all OACs.
METHODS: Medline, Cochrane, and Embase were systematically searched for randomized controlled trials and cohort studies from inception till 23rd November, 2022 to assess the safety and effectiveness of OACs when concomitantly used with P-gp/CYP3A4 inhibitors. The primary outcomes were major bleeding and gastrointestinal (GI) bleeding. Secondary outcomes were stroke/systemic embolism (SE), all-cause mortality, any bleeding as well as intracranial hemorrhage (ICH). We estimated summary odds ratios (OR) with 95% credible intervals (CI) using pairwise and network meta-analysis with random effects.
RESULTS: A total of 11 studies involving 37,973 patients were included. When concomitantly used with P-pg/ CYP3A4 inhibitors, network meta-analysis indicated that dabigatran, apixaban, and edoxaban were associated with significantly lower risk of major bleeding compared to rivaroxaban, with ORs of 0.56, 0.51 and 0.48, respectively. Rivaroxaban and dabigatran were associated with a significantly increased risk of GI bleeding than warfarin, apixaban and edoxaban. Dabigatran and apixaban were linked with significantly lower risk of any bleeding compared with warfarin (ORs were 0.75 and 0.68, respectively) or rivaroxaban (ORs were 0.67 and 0.60, respectively). Apixaban (OR 0.32) and edoxaban (OR 0.35) were associated with a lower risk of ICH compared with warfarin. There was no difference between any OACs in terms of stroke/SE or all-cause mortality.
CONCLUSIONS: When concomitantly used with P-gp/CYP3A4 inhibitors, apixaban and edoxaban were associated with a lower risk of bleeding, though no significant difference in effectiveness was observed among all OACs.
摘要：
背景：口服抗凝剂（OAC）的代谢受P-糖蛋白（P-gp）/CYP3A4酶的影响。然而,P-gp/CYP3A4抑制剂不可避免地与OAC一起使用。
方法：Medline，科克伦,从开始到11月23日，系统搜索Embase的随机对照试验和队列研究，2022年评估与P-gp/CYP3A4抑制剂同时使用时OAC的安全性和有效性。主要结果是大出血和胃肠道（GI）出血。次要结果为卒中/全身性栓塞(SE),全因死亡率,任何出血以及颅内出血（ICH）。我们使用具有随机效应的成对和网络荟萃分析来估计具有95％可信区间（CI）的汇总优势比（OR）。
结果：共纳入11项研究，涉及37,973名患者。当与P-pg/CYP3A4抑制剂同时使用时，网络荟萃分析表明，达比加群，阿哌沙班,与利伐沙班相比，依度沙班的大出血风险显著降低，ORs分别为0.56、0.51和0.48。与华法林相比，利伐沙班和达比加群与胃肠道出血风险显著增加相关，阿哌沙班和edoxaban.与华法林（OR分别为0.75和0.68）或利伐沙班（OR分别为0.67和0.60）相比，达比加群和阿哌沙班的出血风险显著降低。与华法林相比，阿哌沙班（OR0.32）和依度沙班（OR0.35）与ICH风险较低相关。任何OAC在卒中/SE或全因死亡率方面没有差异。
结论：当与P-gp/CYP3A4抑制剂同时使用时，阿哌沙班和依度沙班与较低的出血风险相关,尽管在所有OAC中没有观察到有效性的显著差异。
方法：Medline，科克伦,从开始到11月23日，系统搜索Embase的随机对照试验和队列研究，2022年评估与P-gp/CYP3A4抑制剂同时使用时OAC的安全性和有效性。主要结果是大出血和胃肠道（GI）出血。次要结果为卒中/全身性栓塞(SE),全因死亡率,任何出血以及颅内出血（ICH）。我们使用具有随机效应的成对和网络荟萃分析来估计具有95％可信区间（CI）的汇总优势比（OR）。
结果：共纳入11项研究，涉及37,973名患者。当与P-pg/CYP3A4抑制剂同时使用时，网络荟萃分析表明，达比加群，阿哌沙班,与利伐沙班相比，依度沙班的大出血风险显著降低，ORs分别为0.56、0.51和0.48。与华法林相比，利伐沙班和达比加群与胃肠道出血风险显著增加相关，阿哌沙班和edoxaban.与华法林（OR分别为0.75和0.68）或利伐沙班（OR分别为0.67和0.60）相比，达比加群和阿哌沙班的出血风险显著降低。与华法林相比，阿哌沙班（OR0.32）和依度沙班（OR0.35）与ICH风险较低相关。任何OAC在卒中/SE或全因死亡率方面没有差异。
结论：当与P-gp/CYP3A4抑制剂同时使用时，阿哌沙班和依度沙班与较低的出血风险相关,尽管在所有OAC中没有观察到有效性的显著差异。
