心房颤动伴肝功能不全患者口服抗凝药物的合理使用
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摘要
心房颤动(atrial fibrillation,AF)血栓栓塞中高危患者需要长期服用口服抗凝药(oral anticoagulants,OACs)预防卒中及全身性栓塞事件。肝功能不全患者更易出现血栓或出血并发症。业已证明华法林和新型口服抗凝剂(new oral anticoagulants,NOACs)能安全地减少AF患者的血栓事件,但目前对于AF合并肝功能不全患者的最佳抗凝策略仍不清楚。鉴于目前批准上市的OACs都经肝脏代谢,肝功能不全不仅对这些药物的药代动力学有不同程度的影响,同时对凝血系统影响复杂。本文拟综述国内已批准的OACs在AF合并肝功能不全患者中的药代动力学变化及安全有效性情况,并据此提供该类人群OACs选择方案及剂量推荐,以期为临床上OACs的合理使用提供指导。
Patients at high risk of thromboembolism in atrial fibrillation(AF)need to take oral anticoagulants(OACs)for a long time to prevent stroke and systemic embolism,while patients with liver dysfunction are at increased risk of thrombosis and bleeding complications.Warfarin and new oral anticoagulants(NOACs)have been shown to safely reduce thrombotic events in patients with AF.However,the optimal anticoagulation strategy for AF patients with liver dysfunction is still unclear.Since all currently approved OACs undergo metabolism in the liver,hepatic dysfunction has different effects on the pharmacokinetics of these drugs,and liver dysfunction has a complicated effect on the coagulation system.This review is intended to explore the pharmacokinetic changes and safety and efficacy of approved OACs in patients with AF and liver dysfunction.Based on this,the OACs selection scheme and dose recommendation for this population are provided,in order to provide guidance for the rational use of clinical OACs.
Patients at high risk of thromboembolism in atrial fibrillation(AF)need to take oral anticoagulants(OACs)for a long time to prevent stroke and systemic embolism,while patients with liver dysfunction are at increased risk of thrombosis and bleeding complications.Warfarin and new oral anticoagulants(NOACs)have been shown to safely reduce thrombotic events in patients with AF.However,the optimal anticoagulation strategy for AF patients with liver dysfunction is still unclear.Since all currently approved OACs undergo metabolism in the liver,hepatic dysfunction has different effects on the pharmacokinetics of these drugs,and liver dysfunction has a complicated effect on the coagulation system.This review is intended to explore the pharmacokinetic changes and safety and efficacy of approved OACs in patients with AF and liver dysfunction.Based on this,the OACs selection scheme and dose recommendation for this population are provided,in order to provide guidance for the rational use of clinical OACs.
引文
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[14]Williams RL,Schary WL,Blaschke TF,et al.Influence of acute viral hepatitis on disposition and pharmacologic effect of warfarin[J].Clin Pharmacol Ther,1976,20(1):90-97.
[15]Stangier J,Sthle H,Rathgen K,et al.Pharmacokinetics and pharmacodynamics of dabigatran etexilate,an oral direct thrombin inhibitor,are not affected by moderate hepatic impairment[J].J Clin Pharmacol,2008,48(12):1411-1419.
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[18]卢振华,洪李锋,罗松辉,等.新型口服抗凝药时代华法林的应用[J].临床心血管病杂志,2016,32(11):1083-1086.
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[22]Patel MR,Mahaffey KW,Garg J,et al.Rivaroxaban versus warfarin in nonvalvular atrial fibrillation[J].NEngl J Med,2011,365:883-891.
[23]Granger CB,Alexander JH,Mcmurray JJ,et al.Apixaban versus warfarin in patients with atrial fibrillation[J].N Engl J Med,2011,365:981-992.
[24]Graff J,Harder S.Anticoagulant therapy with the oral direct factor Xa inhibitors rivaroxaban,apixaban and edoxaban and the thrombin inhibitor dabigatran etexilate in patients with hepatic impairment[J].Clin Pharmacokinet,2013,52(4):243-254.
[25]Intagliata N M,Henry Z H,Maitland H,et al.Direct oral anticoagulants in cirrhosis patients pose similar risks of bleeding when compared to traditional anticoagulation[J].Dig Dis Sci,2016,61(6):1721-1727.
[26]De Gottardi A,Trebicka J,Klinger C,et al.Antithrombotic treatment with direct‐acting oral anticoagulants in patients with splanchnic vein thrombosis and cirrhosis[J].Liver Int,2017,37(5):694-699.
[27]Hum J,Shatzel JJ,Jou JH,et al.The efficacy and safety of direct oral anticoagulants vs traditional anticoagulants in cirrhosis[J].Eur J Haematol,2017,98(4):393-397.
[28]Heidbuchel H,Verhamme P,Alings M,et al.European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with nonvalvular atrial fibrillation[J].Europace,2013,15(5):625-651.
[29]Mokdad AA,Lopez AD,Shahraz S,et al.Liver cirrhosis mortality in 187countries between 1980and 2010:a systematic analysis[J].BMC Med,2014,12:145-145.
[2]刘英明,杨晔.新型抗凝药物的研究进展[J].临床心血管病杂志,2012,28(7):489-491.
[3]Baczek VL,Chen WT,Kluger J,et al.Predictors of warfarin use in atrial fibrillation in the United States:a systematic review and meta-analysis[J].BMC Fam Pract,2012,13:5-5.
[4]Holford NH.Clinical pharmacokinetics and pharmacodynamics of warfarin.Understanding the dose-effect relationship[J].Clin Pharmacokinet,1986,11(6):483-504.
[5]Tripodi A,Mannucci PM.The coagulopathy of chronic liver disease[J].N Engl J Med,2011,365:147-156.
[6]Caldwell SH,Hoffman M,Lisman T,et al.Coagulation disorders and hemostasis in liver disease:pathophysiology and critical assessment of current management[J].Hepatology,2006,44(4):1039-1046.
[7]Tripodi A,Primignani M,Mannucci PM,et al.Changing concepts of cirrhotic coagulopathy[J].Am J Gastroenterol,2017,112(2):274-281.
[8]Mahfood Haddad T,Hamdeh S,Kanmanthareddy A,et al.Nonalcoholic fatty liver disease and the risk of clinical cardiovascular events:A systematic review and meta-analysis[J].Diabetes Metab Syndr,2017,11:S209-S216.
[9]Kuo L,Chao TF,Liu CJ,et al.Liver cirrhosis in patients with atrial fibrillation:would oral anticoagulation have a net clinical benefit for stroke prevention?[J].J Am Heart Assoc,2017,6(6):e005307.
[10]Hu J,Xu Y,He Z,et al.Increased risk of cerebrovascular accident related to non-alcoholic fatty liver disease:a meta-analysis[J].Oncotarget,2018,9(2):2752-2760.
[11]Zhang X,Qi X,Yoshida EM,et al.Ischemic stroke in liver cirrhosis:epidemiology,risk factors,and in-hospital outcomes[J].Eur J Gastroenterol Hepatol,2018,30(2):233-240.
[12]Lisman T,Bongers TN,Adelmeijer J,et al.Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity[J].Hepatology,2006,44(1):53-61.
[13]Feys HB,Canciani MT,Peyvandi F,et al.ADAMTS13activity to antigen ratio in physiological and pathological conditions associated with an increased risk of thrombosis[J].Br J Haematol,2007,138(4):534-540.
[14]Williams RL,Schary WL,Blaschke TF,et al.Influence of acute viral hepatitis on disposition and pharmacologic effect of warfarin[J].Clin Pharmacol Ther,1976,20(1):90-97.
[15]Stangier J,Sthle H,Rathgen K,et al.Pharmacokinetics and pharmacodynamics of dabigatran etexilate,an oral direct thrombin inhibitor,are not affected by moderate hepatic impairment[J].J Clin Pharmacol,2008,48(12):1411-1419.
[16]Kubitza D,Roth A,Becka M,et al.Effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban,an oral,direct Factor Xa inhibitor[J].Br J Clin Pharmacol,2013,76(1):89-98.
[17]Frost CE,Yu Z,Wang J,et al.Single-dose safety and pharmacokinetics of apixaban in subjects with mild or moderate hepatic impairment[J].Clin Pharmacol T-her,2009,85:S34.
[18]卢振华,洪李锋,罗松辉,等.新型口服抗凝药时代华法林的应用[J].临床心血管病杂志,2016,32(11):1083-1086.
[19]Levi M,Hovingh GK,Cannegieter SC,et al.Bleeding in patients receiving vitamin K antagonists who would have been excluded from trials on which the indication for anticoagulation was based[J].Blood,2008,111(9):4471-4476.
[20]Efird LM,Mishkin DS,Berlowitz DR,et al.Stratifying the risks of oral anticoagulation in patients with liver disease[J].Circ Cardiovasc Qual Outcomes,2014,7(3):461-467.
[21]Connolly SJ,ezekowitz MD,Yusuf S,et al.Dabigatran versus warfarin in patients with atrial fibrillation[J].N Engl J Med,2009,361:1139-1151.
[22]Patel MR,Mahaffey KW,Garg J,et al.Rivaroxaban versus warfarin in nonvalvular atrial fibrillation[J].NEngl J Med,2011,365:883-891.
[23]Granger CB,Alexander JH,Mcmurray JJ,et al.Apixaban versus warfarin in patients with atrial fibrillation[J].N Engl J Med,2011,365:981-992.
[24]Graff J,Harder S.Anticoagulant therapy with the oral direct factor Xa inhibitors rivaroxaban,apixaban and edoxaban and the thrombin inhibitor dabigatran etexilate in patients with hepatic impairment[J].Clin Pharmacokinet,2013,52(4):243-254.
[25]Intagliata N M,Henry Z H,Maitland H,et al.Direct oral anticoagulants in cirrhosis patients pose similar risks of bleeding when compared to traditional anticoagulation[J].Dig Dis Sci,2016,61(6):1721-1727.
[26]De Gottardi A,Trebicka J,Klinger C,et al.Antithrombotic treatment with direct‐acting oral anticoagulants in patients with splanchnic vein thrombosis and cirrhosis[J].Liver Int,2017,37(5):694-699.
[27]Hum J,Shatzel JJ,Jou JH,et al.The efficacy and safety of direct oral anticoagulants vs traditional anticoagulants in cirrhosis[J].Eur J Haematol,2017,98(4):393-397.
[28]Heidbuchel H,Verhamme P,Alings M,et al.European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with nonvalvular atrial fibrillation[J].Europace,2013,15(5):625-651.
[29]Mokdad AA,Lopez AD,Shahraz S,et al.Liver cirrhosis mortality in 187countries between 1980and 2010:a systematic analysis[J].BMC Med,2014,12:145-145.