华法林剂量预测公式对其临床使用的安全性和有效性Meta分析

摘要/Abstract

摘要： 目的: 采用Meta分析的方法探讨华法林剂量预测公式对其临床使用的安全性和有效性的影响。方法: 计算机检索Cochrane图书馆(1995-2013)、Pubmed(1995-2013)、荷兰医学文摘(EMBASE) (1995-2013)、中国期刊全文数据库(CNKI) (1995-2013)、中国生物医学文献数据库CBM(1995-2013)和万方数据库,按纳入与排除标准选择试验,并按Cochrane系统评价的方法评价纳入的文献质量,提取资料,并采用Review Mananger 5.1 软件对符合纳入标准的文献进行Meta分析。结果: 共纳入9篇前瞻性研究(3 238 患者)。其中英文5篇,中文4篇。Meta分析结果显示:(1)华法林剂量预测公式可以减少临床使用过程中的不良反应发生率 [RR=0.56,95%CI(0.44,0.77),P<0.00001],具有统计学意义,敏感性分析显示结果稳定﹑可靠。(2)到达稳定剂量时间:有5篇研究做出评价,但是存在异质性(P<0.00001,I²=97%)。进行敏感性分析去掉2篇低质量研究后,实验组优于对照组[SMD=-0.97,95%CI(-4.36,3.68),P<0.00001],具有统计学意义。(3)调整剂量比较:实验组要少于对照组,具有统计学意义[SMD=-0.74,95%CI(-1.23,-0.26),P=0.003]。结论: 华法林剂量预测公式能提高华法林抗凝治疗的疗效,并且能降低血栓栓塞和出血等不良反应发生率。

关键词: 基因多态性, 华法林, Meta分析

Abstract: AIM: To evaluate the efficacy and safety of warfarin dosage algorithms in clinical application by the use of Meta-analysis.METHODS: Cochrane library (1995-2013),Pubmed (1995-2013), EMBASE (1995-2013), CNKI (1995-2013), CBM(1995-2013) and Wanfang Data were searched by computer for investigating the prospective studies . The quality of included studies and data adoptions were assessed by Cochrane system. A Meta analysis for included Study was performed with The Cochrane Collaboration's Review Manager 5.1.RESULTS: Nine prospective studies including 5 in English and 4 in Chinese were included(n＝3238).The results of Meta analysis showed that: (1) warfarin dosage algorithms could decrease the risk of adverse reactions in the course of warfarin treatment[RR=0.56,95%CI(0.44,0.77),P<0.01]. The results had statistical difference and sensitivity analysis showed that the analysis results were stable and reliable. (2)The mean times to reach stable dosage:5 studies involved have heterogenicity(P<0.01,I²=97%).The mean times to reach stable dosage in the individual group were shorter than those in the control after excluding two studies of low quality[SMD=-0.97,95%CI(-4.36,3.68),P<0.01],and had statistical difference . (3) The adjusted dosage in the individual group was less than that in the control and had statistical difference[SMD=-0.74,95%CI(-1.23,-0.26),P=0.003].CONCLUSION: Warfarin dosage algorithms could improve the efficacy of anticoagulant therapy and decrease the risk of thrombocmbolism and hemorrhagic events.

Key words: warfarin, genetic polymorphism, Meta-analysis

中图分类号:

R969.1

胡静, 朱君荣, 于锋. 华法林剂量预测公式对其临床使用的安全性和有效性Meta分析[J]. 中国临床药理学与治疗学, 2015, 20(3): 296-303.

HU Jing, ZHU Jun-rong, YU Feng. Efficacy and safety of warfarin dosage algorithms in clinical application:A Meta-analysis[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2015, 20(3): 296-303.

参考文献

[1] Lal S,Jada SR, Xiang X,et al.Pharmacogenetics of target genes across the warfarin pharmacological pathway[J].Clin Pharmacokinet, 2006,45(12):1189-200.
[2] Daly AK,King BP.Pharmacogenetics of oral anticoagulants[J].Pharmacogenetics, 2003,13(5):247-252.
[3] Miao L,Yang J,Huang C, et al.Contribution of age,body weight,and CYP2C9 and VKORCl genotype to the anticoagulant response to warfarin:proposal for a new dosing regimen in Chinese patients[J] .Eur J Clin Pharmacol,2007,63(12):1l35-1141.
[4] Johnson JA, Gong L, Whirl-Carrillo M, et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing[J]. Clin Pharmacol Ther, 2011,90(4):625-629.
[5] 李纳,施孝金. 细胞色素P450酶基因多态性的研究进展及临床意义[J].中国临床药理学与治疗学,2009,14(10):1193-1200.
[6] Yin T, Miyata T. Warfarin dose and the pharmacogenomics of CYP2C9 and VKORC1-rationale and perspectives[J]. Thromb Res, 2007,120(1):1-10.
[7] Bodin L, Verstuyft C, Tregouet DA, et al. Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1)genotypes as determinants of acenocoumarol sensitivity[J]. Blood, 2005,106(1): 135-140.
[8] Anderson JL, Horne BD, Stevens SM. A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (CoumaGen-II) [J]. Circulation, 2012,125(16):1997-2005.
[9] Hillman MA, Wilke RA, Steven H, et al. A prospective, randomized pilot trial of model-based warfarin dose initiation using CYP2C9 genotype and clinical data[J]. Clin Med Res, 2005,3(3):137-145.
[10]薛领,沈振亚,马心超,等. 基于CYP2C9和VKORCI的基因多态性华法林抗凝剂量模型的临床验证[C]. 2010年第五次中美医院药学服务高级论坛论文集.
[11]黄盛文,向道康,安邦权,等.华法林稳定剂量预测算法的临床应用[J].中华医学杂志,2011,91(48):3421-3425.
[12]马心超,缪丽燕.华法林个体化抗凝剂量多元回归方程临床验证研究[C].苏州:苏州大学,2009.
[13]黄盛文.VKORC1和CYP2C9基因型对中国人华法林个体化用药剂量影响的前瞻性研究[D].2008:南方医科大学.
[14]Anderson JL,Home BD,Stevens SM,et al.Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral antcoagulation[J].Circulation,2007,116(22):2563-2570.
[15]Wang M, Lang X, Cui S, et al. Clinical application of pharmacogenetic-based warfarin-dosing algorithm in patients of Han nationality after rheumatic valve replacement: a randomized and controlled trial[J]. Int J Med Sci, 2012, 9(6):472-479.
[16]Caraco Y, Blotnick S, Muszkat M. CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study[J].Clin Pharmaacol Ther,2007,83(3):460-470.
[17]Kaminsky LS,Zhang ZY.Human P450 metabolism of warfarin[J].Pharmacol Ther,1997,73(1):67-74.
[18]Wadelius M, Chen LY, Eriksson N, et al. Association of warfarin dose with genes involved in its action and metabolism[J]. Hum Genet , 2007,121(1): 23-34.
[19]Geisen C, Watzka M, Sittinger K, et al.VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation[J]. Thromb Haemost, 2005,94(4):773-779.
[20]Gao L, He L, Luo J, et al. Extremely low warfarin dose in patients with genotypes of CYP2C9*3/*3 and VKORC1-1639A/A[J]. Chin Med J (Engl), 2011,124(17) :2767-2770.
[21]Kovacs MJ, Rodger M, Anderson DR, et al. Comparison of 10 mg and 5 mg warfarin initiation nomograms together with low-molecular-weight heparin for outpatient treatment of acute venous thromboembolism: a randomized, doubleblind, controlled trial[J]. Ann Intern Med, 2003,138(9):714-719.
[22]Carlquist JF, Horne BD, Muhlestein JB, et al. Genotypes of the cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: a prospective study[J]. Thromb Thrombolysis, 2006,22(3):191-197.
[23]Sconce EA,Khan TI,Wynne HA,et al. The impact of CYP2C9 and VKORCl genetic polymorphism and patient characteristics upon warfarin dose requirements:proposal for a new dosing regimen[J].Blood, 2005,106(7):2329-2333.
[24]Veenstra DL,You JH,Rieder MJ,et al.Association of Vitamin K epoxide reductase complex I(VKORCl)variants with warfarin dose in a Hong Kong Chinese patient population[J]. Pharmacogenet Genomics, 2005,15(10):687-691.
[25]Chan SL,Suo C,Lee SC,et a1.Translational aspects of genetic factors in the prediction of drug response variability:a case athdy of warfarin pharmacogenomics in a multi-ethnic cohort from Asia[J].Pharmacogenomics J,2012, 12(4):312-318.
[26]郑绮姗,赵立子,曾武涛,等.NR1I2基因多态性对华法林维持剂量个体差异的影响[J]. 中国药理学与毒理学杂志,2012,26(2):219-224.
[27]Shikata E ,Leiri I ,Ishiguro S ,et al . Association of pharmacokinetic (CYP2C9) and pharmacodynamic (factorsII , VII , IX ,and X;proteins S and C;and r-glutamyl (carboxylase) gene variants with warfarin sensitivity[J] . Blood , 2004 , 103(7) :2630-2635.