中国人群CYP2C9和VKORC1基因指导华法林给药与常规给药的有效性和安全性的Meta分析

Efficacy and safety of CYP2C9 and VKORC1 genotype-guided warfarin dosing vs clinically guided dosing of warfarin in the Chinese population:Meta-analysis

目的:系统评价CYP2C9和VKORC1基因指导华法林给药与常规给药的有效性和安全性。方法:计算机检索PubMed、Embase、the Cochrane Library、CNKI、万方数据库等数据库,检索时限均为从建库至2019年7月。由两名评价者按照纳入标准与排除标准以及Cochrane协作网推荐的方法独立筛选文献,提取资料并评价文献质量,采用RevMan 5.3软件进行Meta分析。结果:共纳入25篇研究,6058例患者。Meta分析结果显示:①IWPC模型:与常规给药比较,根据CYP2C9和VKORC1基因型采用IWPC模型指导华法林给药能够减少达到华法林维持剂量所需时间[MD=-5.27,95%CI(-9.55,-0.99),P=0.02]、INR首次达标时间[MD=-1.54,95%CI(-2.19,-0.89),P<0.00001],增加达标率[OR=1.93,95%CI(1.18,3.15),P=0.009];降低不良反应发生[OR=0.43,95%CI(0.32,0.60),P<0.00001]。②多元线性回归模型:与常规给药比较,根据CYP2C9和VKORC1基因型采用多元线性回归模型指导华法林给药能够减少达到华法林维持剂量所需时间[MD=-7.24,95%CI(-7.79,-6.68),P<0.00001]、INR首次达标时间[MD=-3.52,95%CI(-4.63,-2.41),P<0.00001],增加达标率[OR=2.60,95%CI(1.58,4.28),P<0.00001];降低不良反应发生[OR=0.43,95%CI(0.24,0.76),P=0.004]。③基因型:与常规给药比较,根据CYP2C9和VKORC1基因型指导华法林给药能够减少达到华法林维持剂量所需时间[MD=-12.52,95%CI(-13.86,-11.18),P<0.00001]、INR首次达标时间[MD=-3.74,95%CI(-4.93,-2.54),P<0.00001],增加达标率[OR=4.35,95%CI(1.70,11.14),P=0.002];对不良反应发生影响差异无统计学意义[OR=0.42,95%CI(0.09,2.03),P=0.28]。结论:与常规给药比较,中国人群根据CYP2C9和VKORC1基因指导给药可减少达到华法林维持剂量所需时间和INR首次达标时间,增加达标率;根据CYP2C9和VKORC1基因型采用IWPC模型和多元线性回归模型指导给药可降低不良反应发生,但仅根据CYP2C9和VKORC1基因型指导给药不能降低不良反应发生。还需进一步研究基因指导华法林给药和常规华法林给药的成本效益。

OBJECTIVE To systematically review the efficacy and safety of CYP2 C9 and VKORC1 genotype-guided warfarin dosing and clinically guided dosing of warfarin.METHODS PubMed,Embase,the Cochrane Library,CNKI,Wanfang database,etc.were electronically searched for relevant studies from inception to July 2019.Two reviewers independently screened literature according to the inclusion and exclusion criteria as well as the methods recommended by the Cochrane Collaboration to extract data and assess the methodological quality included the study.Then,meta-analysis was performed using RevMan 5.3.RESULTS A total of 25 studies with 6,058 patients were included.Meta-analysis results showed:IWPC model:Compared with clinically guided dosing of warfarin,the use of IWPC model to guide warfarin dosing can reduce the time to reach a stable dose[MD=-5.27,95%CI(-9.55,-0.99),P=0.02],time to reach therapeutic INR[MD=-1.54,95%CI(-2.19,-0.89),P<0.00001],and increase compliance rate[OR=1.93,95%CI(1.18,3.15),P=0.009];reduced the occurrence of adverse reactions[OR=0.43,95%CI(0.32,0.60),P<0.00001].Multiple linear regression model:Compared with clinically guided dosing of warfarin,using multiple linear regression models to guide warfarin dosing can reduce the time to reach a stable dose[MD=-7.24,95%CI(-7.79,-6.68),P<0.00001],time to reach therapeutic INR[MD=-3.52,95%CI(-4.63,-2.41),P<0.00001],and increase compliance rate[OR=2.60,95%CI(1.58,4.28),P<0.00001];reduce the occurrence of adverse reactions[OR=0.43,95%CI(0.24,0.76),P=0.004].genotype:compared with conventional drug delivery,warfarin administration according to genotype can reduce the time to reach a stable dose[MD=-12.52,95%CI(-13.86,-11.18),P<0.00001],time to reach therapeutic INR[MD=-3.74,95%CI(-4.93,-2.54),P<0.00001],and increase compliance rate[OR=4.35,95%CI(1.70,11.14),P=0.002].There was no significant difference in the effect of adverse reactions[OR=0.42,95%CI(0.09,2.03),P=0.28].CONCLUSION Compared with conventional drug delivery,CYP2 C9 and VKORC1 genotype-guided warfarin dosing can reduce the time to reach a stable dose,time to reach therapeutic INR,and increase compliance rate in Chinese population.The adoption of IWPC model and multiple linear regression model to guide warfarin dosing can reduce the occurrence of adverse reactions,but CYP2 C9 and VKORC1 genotype-guided administration alone cannot reduce the occurrence of adverse reactions.Further studies are needed to investigate the cost-effectiveness of genotype-guided warfarin administration and conventional warfarin administration.