口服抗凝药的临床治疗研究进展
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摘要
近年来,随着血栓栓塞性疾病的发病率及死亡率的上升,抗凝药物对于预防和治疗血栓栓塞性疾病具有重要的临床意义和应用价值。临床上口服抗凝药主要分为传统口服抗凝药和新型口服抗凝药。华法林作为临床常用的传统口服抗凝药,存在治疗窗窄、剂量需不断调整、易与药物和食物发生相互作用等不足,造成在临床使用过程中有诸多不便。而新型口服抗凝药,如利伐沙班、阿哌沙班、依度沙班、贝曲沙班、达比加群酯等,在治疗血栓栓塞性疾病过程中具有无需频繁调整剂量、无需常规监测凝血功能、出血率低等优点,较华法林优势明显,其安全性和有效性均不劣于华法林。本文对近年来国内外发表的药物治疗血栓栓塞性疾病研究进展的相关文献进行综述,为临床规范化使用口服抗凝药提供参考。
In recent years,with the increasing incidence and mortality of thromboembolic diseases,anticoagulants have important clinical significance and practical value to the prevention and treatment of thromboembolic diseases.Oral anticoagulants are mainly divided into traditional oral drugs and new oral anticoagulants.Clinically,warfarin is commonly used as a traditional oral anticoagulant.However,its treatment window is narrow,dosage needs constantly adjustment,and the interactions between warfarin and other drugs and food bring about inconvenience in clinical use.New oral anticoagulants,such as rivaroxaban,apisaban,edoxaban,betroxaban and dabigatran etexilate,are superior to warfarin,because of the advantages of no frequent dosage adjustment,no routine monitoring of coagulation function and low bleeding rate in the treatment of thrombotic diseases.Besides,their safety and efficacy are by no means inferior to warfarin.This article reviews related literature on the progress of drug therapy for thromboembolic diseases published at home and abroad in recent years,and provides references for the standardized use of oral anticoagulants in clinical practice.
In recent years,with the increasing incidence and mortality of thromboembolic diseases,anticoagulants have important clinical significance and practical value to the prevention and treatment of thromboembolic diseases.Oral anticoagulants are mainly divided into traditional oral drugs and new oral anticoagulants.Clinically,warfarin is commonly used as a traditional oral anticoagulant.However,its treatment window is narrow,dosage needs constantly adjustment,and the interactions between warfarin and other drugs and food bring about inconvenience in clinical use.New oral anticoagulants,such as rivaroxaban,apisaban,edoxaban,betroxaban and dabigatran etexilate,are superior to warfarin,because of the advantages of no frequent dosage adjustment,no routine monitoring of coagulation function and low bleeding rate in the treatment of thrombotic diseases.Besides,their safety and efficacy are by no means inferior to warfarin.This article reviews related literature on the progress of drug therapy for thromboembolic diseases published at home and abroad in recent years,and provides references for the standardized use of oral anticoagulants in clinical practice.
引文
[1] 李海刚,范蓉,马宁,等.华法林药代动力学过程影响因素研究进展[J].中国临床药理学与治疗学,2017,22(11):1292-1298.LI Haigang,FAN Rong,MA Ning,et al.Research progress on pharmacokinetic factors of warfarin[J].Chin J Clin Pharmacol Ther,2017,22(11):1292-1298.In Chinese with English abstract.
[2] 束长城,侯振世.新型口服抗凝药在房颤患者治疗中的研究进展[J].中国当代医药,2019,26(4):26-28.SHU Changcheng,HOU Zhenshi.Research progress of new oral anticoagulants in the treatment of patients with atrial fibrillation[J].China Mod Med,2019,26(4):26-28.In Chinese with English abstract.
[3] Verhoef T I,Redekop W K,Daly A K,et al.Pharmacogenetic-guided dosing of coumarin anticoagulants:algorithms for warfarin,acenocoumarol and phenprocoumon[J].Br J Clin Pharmacol,2014,77(4):626-641.
[4] 项海燕,唐燕华.华法林抗凝治疗的临床应用概述[J].重庆医学,2012,41(16):1652-1654.XIANG Haiyan,TANG Yanhua.Overview of clinical application of warfarin anticoagulant therapy[J].Chongqing Med J,2012,41(16):1652-1654.In Chinese.
[5] 中华医学会心血管病学分会,中国老年学学会心脑血管病专业委员会.华法林抗凝治疗的中国专家共识[J].中华内科杂志,2013,52(1):76-82.Cardiology Branch of Chinese Medical Association,Cardiovascular and Cerebrovascular Diseases Committee of the Chinese Gerontological Society.Chinese expert consensus on warfarin anticoagulant therapy[J].Chin J Intern Med,2013,52(1):76-82.In Chinese.
[6] 康俊萍.华法林临床应用要点[J].中国医刊,2014,49(1):11-14.KANG Junping.Key points in clinical application of warfarin[J].Chin J Med,2014,49(1):11-14.In Chinese.
[7] Flora D R,Rettie A E,Brundage R C,et al.CYP2C9 genotype-dependent warfarin pharmacokinetics:impact of CYP2C9 genotype on R- and S-warfarin and their oxidative metabolites[J].J Clin Pharmacol,2017,57(3):382-393.
[8] Kaye J B,Schultz L E,Steiner H E,et al.Warfarin pharmacogenomics in diverse populations[J].Pharmacotherapy,2017,37(9):1150-1163.
[9] Gemmati D,Burini F,Talarico A,et al.The active metabolite of warfarin (3′-hydroxywarfarin) and correlation with INR,warfarin and drug weekly dosage in patients under oral anticoagulant therapy:a pharmacogenetics study[J].PLoS One,2016,11(9):e0162084.
[10] Ray W A,Chung C P,Murray K T,et al.Association of proton pump inhibitors with reduced risk of warfarin-related serious upper gastrointestinal bleeding[J].Gastroenterology,2016,151(6):1105-1112.
[11] Johnson J A,Caudle K E,GONG Li,et al.Clinical pharmacogenetics implementation consortium(CPIC) guidelines for pharmacogenetics-guided warfarin dosing:2017 update[J].Clin Pharmacol Ther,2017,102(3):397-404.
[12] Shaw K,Amstutz U,Kim R B,et al.Clinical practice recommendations on genetic testing of CYP2C9 and VKORC1 variants in warfarin therapy[J].Ther Drug Monit,2015,37(4):428-436.
[13] Shaw K,Amstutz U,Hildebrand C,et al.VKORC1 and CYP2C9 genotypes are predictors of warfarin-related outcomes in children[J].Pediatr Blood Cancer,2014,61(6):1055-1062.
[14] WEI Meng,YE Fei,XIE Dujiang,et al.A new algorithm to predict warfarin dose from polymorphisms of CYP4F2,CYP2C9 and VKORC1 and clinical variables:derivation in Han Chinese patients with non valvular atrial fibrillation[J].Thromb Haemost,2012,107(6):1083-1091.
[15] Fenger-Eriksen C,Münster A M,Grove E L.New oral anticoagulants:clinical indications,monitoring and treatment of acute bleeding complications[J].Acta Anaesthesiol Scand,2014,58(6):651-659.
[16] 窦丽稳,高伟波,朱继红.新型口服抗凝药物急诊应用指导[J].中国全科医学,2017,20(23):2900-2905.DOU Liwen,GAO Weibo,ZHU Jihong.Emergency application guidance of novel oral anticoagulants[J].Chin Gen Pract,2017,20(23):2900-2905.In Chinese with English abstract.
[17] 周建光,周颖奇.新型口服抗凝药的特点和临床研究[J].临床药物治疗杂志,2013,11(5):8-14.ZHOU Jianguang,ZHOU Yingqi.Characteristics and clinical research of new oral anticoagulants[J].Clin Med J,2013,11(5):8-14.In Chinese with English abstract.
[18] 王兵,刘颖,刘登科,等.直接Ⅹa因子抑制剂贝曲沙班[J].现代药物与临床,2015,30(2):217-221.WANG Bing,LIU Ying,LIU Dengke,et al.Direct factor Ⅹa inhibitor betrixaban[J].Drugs Clin,2015,30(2):217-221.In Chinese with English abstract.
[19] Huisman M V,Klok F A.Pharmacological properties of betrixaban[J].Eur Heart J Suppl,2018,20(Suppl E):E12-E15.
[20] Stangier J.Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate[J].Clin Pharmacokinet,2008,47(5):285-295.
[21] Hankey G J,Eikelboom J W.Dabigatran etexilate:a new oral thrombin inhibitor[J].Circulation,2011,123(13):1436-1450.
[22] Deftereos S,Anatoliotakis N,Giannopoulos G,et al.Novel direct factor Ⅱa and Ⅹa inhibitors:mechanisms of action and preclinical studies[J].Curr Clin Pharmacol,2012,7(3):149-165.
[23] Patel M R,Mahaffey K W,Garg J,et al.Rivaroxaban versus warfarin in nonvalvular atrial fibrillation[J].N Engl J Med,2011,365(10):883-891.
[24] Sherwood M W,Nessel C C,Hellkamp A S,et al.Gastrointestinal bleeding in patients with atrial fibrillation treated with rivaroxaban or warfarin:ROCKET AF trial[J].J Am Coll Cardiol,2015,66(21):2271-2281.
[25] The EINSTEIN-PE investigators,Buller H R,Prins M H,et al.Oral rivaroxaban for the treatment of symptomatic pulmonary embolism[J].N Engl J Med,2012,366(14):1287-1297.
[26] Granger C B,Alexander J H,McMurray J J V,et al.Apixaban versus warfarin in patients with atrial fibrillation[J].N Engl J Med,2011,365(11):981-992.
[27] Schafer J H,Casey A L,Dupre K A,et al.Safety and efficacy of apixaban versus warfarin in patients with advanced chronic kidney disease[J].Ann Pharmacother,2018,52(11):1078-1084.
[28] The Hokusai-VTE investigators,Buller H R,Décousus H,et al.Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism[J].N Engl J Med,2013,369(15):1406-1415.
[29] Giugliano R P,Ruff C T,Braunwald E,et al.Edoxaban versus warfarin in patients with atrial fibrillation[J].N Engl J Med,2013,369(22):2093-2104.
[30] Beyer-Westendorf J,Verhamme P,Bauersachs R.Betrixaban for prevention of venous thromboembolism in acute medically ill patients[J].Eur Heart J Suppl,2018,20(Suppl E):E16-E22.
[31] Gibson C M,Korjian S,Chi G,et al.Comparison of fatal or irreversible events with extended-duration betrixaban versus standard dose enoxaparin in acutely ill medical patients:an APEX trial substudy[J].J Am Heart Assoc,2017,6(7):e006015.
[32] Cohen A T,Harrington R A,Goldhaber S Z,et al.Extended thromboprophylaxis with betrixaban in acutely ill medical patients[J].N Engl J Med,2016,375(6):534-544.
[33] Yee M K,Nafee T,Daaboul Y,et al.Increased benefit of betrixaban among patients with a history of venous thromboembolism:a post-hoc analysis of the APEX trial[J].J Thromb Thrombolysis,2017,45(1):1-8.
[34] Connolly S J,Ezekowitz M D,Yusuf S,et al.Dabigatran versus warfarin in patients with atrial fibrillation[J].N Engl J Med,2009,361(12):1139-1151.
[35] Schulman S,Kearon C,Kakkar A K,et al.Dabigatran versus warfarin in the treatment of acute venous thromboembolism[J].N Engl J Med,2009,361(24):2342-2352.
[36] 汤洁,彭佳惠,张梦媛,等.新型口服抗凝药物拮抗剂的研究进展[J].中国临床保健杂志,2019,22(1):130-134.TANG Jie,PENG Jiahui,ZHANG Mengyuan,et al.Research progress of specific antagonists for new oral anticoagulants[J].Chin J Clin Healthc,2019,22(1):130-134.In Chinese with English abstract.
[37] 刘萧,洪葵.新型口服抗凝药相关出血的治疗策略及其特异性拮抗剂[J].中华心血管病杂志,2016,44(11):921-924.LIU Xiao,HONG Kui.Therapeutic strategies and specific antagonists of novel oral anticoagulant-related bleeding[J].Chin J Cardiol,2016,44(11):921-924.In Chinese.
[2] 束长城,侯振世.新型口服抗凝药在房颤患者治疗中的研究进展[J].中国当代医药,2019,26(4):26-28.SHU Changcheng,HOU Zhenshi.Research progress of new oral anticoagulants in the treatment of patients with atrial fibrillation[J].China Mod Med,2019,26(4):26-28.In Chinese with English abstract.
[3] Verhoef T I,Redekop W K,Daly A K,et al.Pharmacogenetic-guided dosing of coumarin anticoagulants:algorithms for warfarin,acenocoumarol and phenprocoumon[J].Br J Clin Pharmacol,2014,77(4):626-641.
[4] 项海燕,唐燕华.华法林抗凝治疗的临床应用概述[J].重庆医学,2012,41(16):1652-1654.XIANG Haiyan,TANG Yanhua.Overview of clinical application of warfarin anticoagulant therapy[J].Chongqing Med J,2012,41(16):1652-1654.In Chinese.
[5] 中华医学会心血管病学分会,中国老年学学会心脑血管病专业委员会.华法林抗凝治疗的中国专家共识[J].中华内科杂志,2013,52(1):76-82.Cardiology Branch of Chinese Medical Association,Cardiovascular and Cerebrovascular Diseases Committee of the Chinese Gerontological Society.Chinese expert consensus on warfarin anticoagulant therapy[J].Chin J Intern Med,2013,52(1):76-82.In Chinese.
[6] 康俊萍.华法林临床应用要点[J].中国医刊,2014,49(1):11-14.KANG Junping.Key points in clinical application of warfarin[J].Chin J Med,2014,49(1):11-14.In Chinese.
[7] Flora D R,Rettie A E,Brundage R C,et al.CYP2C9 genotype-dependent warfarin pharmacokinetics:impact of CYP2C9 genotype on R- and S-warfarin and their oxidative metabolites[J].J Clin Pharmacol,2017,57(3):382-393.
[8] Kaye J B,Schultz L E,Steiner H E,et al.Warfarin pharmacogenomics in diverse populations[J].Pharmacotherapy,2017,37(9):1150-1163.
[9] Gemmati D,Burini F,Talarico A,et al.The active metabolite of warfarin (3′-hydroxywarfarin) and correlation with INR,warfarin and drug weekly dosage in patients under oral anticoagulant therapy:a pharmacogenetics study[J].PLoS One,2016,11(9):e0162084.
[10] Ray W A,Chung C P,Murray K T,et al.Association of proton pump inhibitors with reduced risk of warfarin-related serious upper gastrointestinal bleeding[J].Gastroenterology,2016,151(6):1105-1112.
[11] Johnson J A,Caudle K E,GONG Li,et al.Clinical pharmacogenetics implementation consortium(CPIC) guidelines for pharmacogenetics-guided warfarin dosing:2017 update[J].Clin Pharmacol Ther,2017,102(3):397-404.
[12] Shaw K,Amstutz U,Kim R B,et al.Clinical practice recommendations on genetic testing of CYP2C9 and VKORC1 variants in warfarin therapy[J].Ther Drug Monit,2015,37(4):428-436.
[13] Shaw K,Amstutz U,Hildebrand C,et al.VKORC1 and CYP2C9 genotypes are predictors of warfarin-related outcomes in children[J].Pediatr Blood Cancer,2014,61(6):1055-1062.
[14] WEI Meng,YE Fei,XIE Dujiang,et al.A new algorithm to predict warfarin dose from polymorphisms of CYP4F2,CYP2C9 and VKORC1 and clinical variables:derivation in Han Chinese patients with non valvular atrial fibrillation[J].Thromb Haemost,2012,107(6):1083-1091.
[15] Fenger-Eriksen C,Münster A M,Grove E L.New oral anticoagulants:clinical indications,monitoring and treatment of acute bleeding complications[J].Acta Anaesthesiol Scand,2014,58(6):651-659.
[16] 窦丽稳,高伟波,朱继红.新型口服抗凝药物急诊应用指导[J].中国全科医学,2017,20(23):2900-2905.DOU Liwen,GAO Weibo,ZHU Jihong.Emergency application guidance of novel oral anticoagulants[J].Chin Gen Pract,2017,20(23):2900-2905.In Chinese with English abstract.
[17] 周建光,周颖奇.新型口服抗凝药的特点和临床研究[J].临床药物治疗杂志,2013,11(5):8-14.ZHOU Jianguang,ZHOU Yingqi.Characteristics and clinical research of new oral anticoagulants[J].Clin Med J,2013,11(5):8-14.In Chinese with English abstract.
[18] 王兵,刘颖,刘登科,等.直接Ⅹa因子抑制剂贝曲沙班[J].现代药物与临床,2015,30(2):217-221.WANG Bing,LIU Ying,LIU Dengke,et al.Direct factor Ⅹa inhibitor betrixaban[J].Drugs Clin,2015,30(2):217-221.In Chinese with English abstract.
[19] Huisman M V,Klok F A.Pharmacological properties of betrixaban[J].Eur Heart J Suppl,2018,20(Suppl E):E12-E15.
[20] Stangier J.Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate[J].Clin Pharmacokinet,2008,47(5):285-295.
[21] Hankey G J,Eikelboom J W.Dabigatran etexilate:a new oral thrombin inhibitor[J].Circulation,2011,123(13):1436-1450.
[22] Deftereos S,Anatoliotakis N,Giannopoulos G,et al.Novel direct factor Ⅱa and Ⅹa inhibitors:mechanisms of action and preclinical studies[J].Curr Clin Pharmacol,2012,7(3):149-165.
[23] Patel M R,Mahaffey K W,Garg J,et al.Rivaroxaban versus warfarin in nonvalvular atrial fibrillation[J].N Engl J Med,2011,365(10):883-891.
[24] Sherwood M W,Nessel C C,Hellkamp A S,et al.Gastrointestinal bleeding in patients with atrial fibrillation treated with rivaroxaban or warfarin:ROCKET AF trial[J].J Am Coll Cardiol,2015,66(21):2271-2281.
[25] The EINSTEIN-PE investigators,Buller H R,Prins M H,et al.Oral rivaroxaban for the treatment of symptomatic pulmonary embolism[J].N Engl J Med,2012,366(14):1287-1297.
[26] Granger C B,Alexander J H,McMurray J J V,et al.Apixaban versus warfarin in patients with atrial fibrillation[J].N Engl J Med,2011,365(11):981-992.
[27] Schafer J H,Casey A L,Dupre K A,et al.Safety and efficacy of apixaban versus warfarin in patients with advanced chronic kidney disease[J].Ann Pharmacother,2018,52(11):1078-1084.
[28] The Hokusai-VTE investigators,Buller H R,Décousus H,et al.Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism[J].N Engl J Med,2013,369(15):1406-1415.
[29] Giugliano R P,Ruff C T,Braunwald E,et al.Edoxaban versus warfarin in patients with atrial fibrillation[J].N Engl J Med,2013,369(22):2093-2104.
[30] Beyer-Westendorf J,Verhamme P,Bauersachs R.Betrixaban for prevention of venous thromboembolism in acute medically ill patients[J].Eur Heart J Suppl,2018,20(Suppl E):E16-E22.
[31] Gibson C M,Korjian S,Chi G,et al.Comparison of fatal or irreversible events with extended-duration betrixaban versus standard dose enoxaparin in acutely ill medical patients:an APEX trial substudy[J].J Am Heart Assoc,2017,6(7):e006015.
[32] Cohen A T,Harrington R A,Goldhaber S Z,et al.Extended thromboprophylaxis with betrixaban in acutely ill medical patients[J].N Engl J Med,2016,375(6):534-544.
[33] Yee M K,Nafee T,Daaboul Y,et al.Increased benefit of betrixaban among patients with a history of venous thromboembolism:a post-hoc analysis of the APEX trial[J].J Thromb Thrombolysis,2017,45(1):1-8.
[34] Connolly S J,Ezekowitz M D,Yusuf S,et al.Dabigatran versus warfarin in patients with atrial fibrillation[J].N Engl J Med,2009,361(12):1139-1151.
[35] Schulman S,Kearon C,Kakkar A K,et al.Dabigatran versus warfarin in the treatment of acute venous thromboembolism[J].N Engl J Med,2009,361(24):2342-2352.
[36] 汤洁,彭佳惠,张梦媛,等.新型口服抗凝药物拮抗剂的研究进展[J].中国临床保健杂志,2019,22(1):130-134.TANG Jie,PENG Jiahui,ZHANG Mengyuan,et al.Research progress of specific antagonists for new oral anticoagulants[J].Chin J Clin Healthc,2019,22(1):130-134.In Chinese with English abstract.
[37] 刘萧,洪葵.新型口服抗凝药相关出血的治疗策略及其特异性拮抗剂[J].中华心血管病杂志,2016,44(11):921-924.LIU Xiao,HONG Kui.Therapeutic strategies and specific antagonists of novel oral anticoagulant-related bleeding[J].Chin J Cardiol,2016,44(11):921-924.In Chinese.