VKORC1及CYP2C9基因多态性对房颤射频消融患者华法林抗凝效果的影响研究
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摘要
研究背景
越来越多的心房颤动(Atrial fibrillation, AF)患者接受导管射频消融(Radiofrequency catheter ablation, RFCA)治疗, RFCA术出血及血栓栓塞(thromboembolic, TE)并发症多发生在术后早期2周之内,而在华法林初始抗凝阶段按照传统法给药(起始剂量固定,依据INR检测结果调整剂量),INR值经常波动较大。
细胞色素氧化酶P4502C9(cytochrome P4502C9, CYP2C9)和维生素K环氧化物降解酶复合物1(vitamin K epoxide reductase complex1, VKORC1)基因多态性被认为影响华法林剂量需求最主要的因素。目前研究多分别分析两个基因的多态性对患者敏感性的影响,而两种基因多态性以不同的方式组合对患者敏感性有抵消或叠加的混合效应,实际应用中更需要了解两种基因的共同影响。
国际华法林药物基因组学联合会CThe International Warfarin Pharmacogenetics Consortium, IWPC)依据不同国家和种族患者的临床和基因学资料,建立了遗传药理学运算模型,初始抗凝时预测患者的稳定剂量,提高初始给药的精准度,理论上可以使患者尽早达到所需要的抗凝目标,减少不良反应的发生,而临床试验比较传统法给药与运算模型法给药对抗凝初期INR控制效果,却得出矛盾的结果。运算模型未能取得预期效果,原因尚未明确,可能因为预测华法林稳定剂量的精准度不足,或者抗凝初始几周即使精准给药也难以控制好INR。此外,抗凝早期获得INR检测值后,遗传药理学给药模型的临床应用价值也未知。
第一部分VKORC1及CYP2C9基因多态性对房颤射频消融患者华法林抗凝效果的影响
1研究目的
探讨VKORC1及CYP2C9基因多态性对AF患者RFCA术前术后华法林抗凝效果的共同影响。
术前用传统法给药抗凝3周,术后用术前调整所得的剂量为起始剂量开始抗凝,探讨提高初始给药的精准度对AF患者RFCA术后华法林抗凝效果的影响。
2研究方法
1)研究对象及分组
选取接受RFCA术的AF患者287例,要求患者是初次使用华法林且接受我院随访。根据患者术前是否需要华法林抗凝治疗将患者分为A、B两组。
A组：CHA2DS2-VASC=0的阵发性AF患者125例,术前未予华法林抗凝。
B组：持续性AF患者或CHA2DS2-VASC≥1分的阵发性AF患者162例,术前需要华法林抗凝3周。
AB两患者均依据法林敏感指数(warfarin-responsive index WRI)分成WRI=0、WRI=1、WRI=2三个亚组。
2)基因检测
采用基于荧光染料的实时定量PCR法对患者进行VKORCl及CYP2C9基因的多态性检测。
WRI的计算方法：对华法林敏感的VKORCl-1639AA,CYP2C9*1/*3及*3/*3记为“0”,对华法林不敏感的VKORC1-1639AG及GG,CYP2C9*1/*1记为“1”,患者的WRI则等于两种基因型记分之和。WRI反映两种基因的不同基因型组合对华法林敏感性的的共同影响,WRI=0为极度敏感,WRI=1为中度敏感,WRI=2为不敏感。
3)抗凝方法及术后随访
B组患者术前用传统法给药抗凝3周,起始剂量3mg/d,术前4天改用低分子肝素“桥接”抗凝,术后起始剂量为术前调整好的剂量。A组患者术后传统法给药的起始剂量3mg/d。
所有患者在获得稳定抗凝剂量之前,每2-3天检测一次INR,获得稳定抗凝剂量之后,每1-2周检测一次INR。对每个患者随访3个月,详细记录每次INR值,华法林服用量及出血和TE并发症发生情况。
3研究结果
1)术后获得稳定华法林剂量的调整时间及各亚组的华法林稳定剂量
B两组患者术后获得稳定华法林剂量的平均调整时间比A组短4.4天,调整时间的HR(95%Confidence interval,CI)为1.58(1.23-2.02)。
A组中WRI=2比WRI=1亚组调整时间长6.8天,HR为0.60(0.39-0.91)。B组中不同亚组调整时间均无统计学差异。
各亚组华法林稳定剂量的平均值(mg/d)：A组WRI=1(3.44±0.68)、WRI=0(1.89±0.28).WRI=2(5.81±1.06)；B组WRI=1(3.29±0.71),WRI=0(1.83±0.36),WRI=2(5.53±1.15).
2)首次达到INR>2.0的时间
B组患者术前WRI=2比WRI=1亚组的平均时间延长2.4天,HR0.59(0.34-0.92)。B组患者术后比术前缩短1.1天,HR1.83(1.41-2.27),术后各亚组之间的平均时间及HR均无统计学差异。
A组患者术后WRI=2比WRI=1亚组平均时间延长2.5天,HR0.58(0.33-0.84)。A组患者术后的平均时间与B组患者术前相近,长于B组患者术后。3)首次达到INR>4.0的风险
B组患者术前WRI=0比WRI=1亚组发生率高(28.6%vs9.5%,P<0.05),首次达到INR≥4.0的时间的HR4.36(1.32-30.99)。术后发生率低于术前(4.3%vsl0.5%,P<0.05),HR0.43(0.19-0.95),且术后不同亚组之间的发生率及HR均无统计学差异。
A组患者术后WRI=0生率高于亚组WRI=1(36.4%vs8.9%,P<0.05),HR5.45(1.36-44.29))。A组患者术后风险与B组患者术前相近,高于B组患者术后。
所有患者术后的第2月和第3月,INR>4.0的发生率明显低于最初3周,且各个亚组之间的风险均无差异。
4)出血及TE并发症
B组患者术前发生小出血5例,术后发生大出血1例,TE并发症1例,A组患者术后发生大出血1例,无TE并发症。
术后A组小出血发生率高于B组(12.8%vs5.6%,P<0.05),HR为2.38(1.07-5.26)。A组及B组不同亚组之间小出血发生率均无统计学意义。
所有患者术后的第2月和第3月,小出血的发生率明显低于最初3周,且各个亚组之间的风险均无差异。
4研究结论
1)VKORC1及CYP2C9基因多态性相结合可以共同影响患者对华法林敏感性和初始抗凝阶段的抗凝效果。两基因均为对华法林敏感的基因型时,患者过度抗凝及出血并发症的风险增加,两基因均不敏感的基因型时,患者进入华法林治疗窗的时间及获得稳定剂量的调整时间延长。
2)提高起始剂量的精准度,可以缩短患者进入华法林治疗窗的时间及获得稳定剂量的调整时间,降低患者过度抗凝及出血并发症的风险,减少VKORCl及CYP2C9基因多态性对患者初始抗凝阶段带来的不利影响。
第二部分评价两种遗传药理学给药模型的临床应用价值
1研究目的
1)验证阜外医院建立的遗传药理学运算模型(阜外模型)及IWPC推荐的模型
(IWPC模型),比较两模型预测汉族AF患者华法林稳定剂量的精准程度。
2)探讨在获得INR检测结果以后,在不同时段遗传药理学运算模型的临床实用价值。
3)探讨基因多态性检测的性价比的影响因素。
2研究方法
287例患者中有16例患者因为在3个月随访结束时仍然未获得稳定剂量,不纳入本部分的研究。
分别用两种遗传药理学运算模型计算每位患者预期的稳定剂量。通过3个月的随访中获得每个患者实际的稳定剂量,比较的两组模型预测剂量与实际剂量的符合程度,得出较优的运算模型。评价预测值与实际值符合程度的3个指标：1)平均绝对误差(rnean absolute error, MAE);2)理想预测值的比例,理想预测值定义为与实际值相差在20%以内；3)相关系数(correlation coefficient, r)。
通过随访获得传统法给药第1周末、第2周末使用的华法林剂量,评价其与实际稳定剂量的符合程度,并与运算模型对比。
3研究结果
阜外模型预测精准度优于IWPC模型,MAE(0.38±0.16vs0.52±0.21mg,P<0.05)理想预测值的比例(46.1%vs34.7%,P>0.05)、r(0.72vs0.62)。
阜外模型预测剂量与实际剂量的符合程度近似于传统法第1周末剂量的符合程度。MAE(0.38±0.16vs0.32+0.13mg,P>0.05)、理想预测值的比例(46.1%vs50.2%,P>0.05)、r(0.72vs0.77)；劣于第2周末剂量的符合程度MAE(0.38+0.16vs0.12±0.05mg,P<0.05)、理想预测值的比例(46.1%vs84.1%,P<0.05)、r(0.72vs0.91)。
WPI≠1的患者,预测模型法预测剂量与实际剂量的吻合程度优于传统法第1周末剂量。
4研究结论
1)对于中国汉族患者,阜外模型预测华法林稳定剂量的精准程度优于IWPC推荐的模型。IWPC推荐的运算模型难以在所有国家和种族都获得最佳的预测效果。
2)抗凝开始1周以后,INR检测值所能提供的预测价值不逊于遗传信息,遗传药理学运算模型临床实用价值显著下降。
3)基因多态性检测性价比的影响因素：a.某种族各等位基因的频率分布,b.两种基因均出现突变的基因型时的平均稳定剂量与某种族华法林常用起始剂量的差异,c.患者出血及TE并发症的风险。
Background
The radiofrequency catheter ablation (RFCA) has been widely used in patients with atrial fibrillation (AF). RFCA related bleeding and thromboembolism (TE) usually occurs in2weeks, and at the initial phrase of administration of warfarin, the fluctuate of INR is usually large.
Cytochrome P4502C9(CYP2C9) and vitamin K epoxide reductase complex1(VKORC1) have been proved as the main factors attributed for the efficacy of warfarin. Previous studies investigated the associations between the polymorphisms of these two genes and the stabilized dose of warfarin separately, while the interaction between these two genes in terms of the effect on warfarin has rarely been investigated.
The International Warfarin Pharmacogenetics Consortium (IWPC) developed the pharmacogenetics algorithm to predict the stabilized dose of warfarin based on the clinical and genetic data of different countries and races, which may improve the accuracy of initial dose and theoretically shorten the time to reach the anticoagulation goal, resulting in less adverse events. However, the clinical utility of pharmacogenetics algorithm has been tested in clinical trials with equivocal results, a large number of patients did not improve anticoagulation control with the pharmacogenetics algorithm, which may be contributed to the poor accuracy of the algorithm. In addition, the value of the pharmacogenetics algorithm when the therapy of anticoagulation has been started is still to be described.
Section1The association between the polymorphisms of VKORC1and CYP2C9genes and the anticoagulation control of warfarin for patients with atrial fibrillation underwent radiofrequency catheter ablation
Objectives
1, To investigate the association between the polymorphisms of VKORC1and CYP2C9genes and the anticoagulation control of warfarin for patients with atrial fibrillation underwent radiofrequency catheter ablation.
2. Titrate the dose of warfarin based on INR from3weeks before operation, and start the administration of warfarin with the adjusted dose. Investigate the influence of improving the accuracy of administration on the anticoagulating effect in AF patients after RFCA. Methods
Two hundred and eighty-seven AF patients underwent RPCA who were not treated with warfarin was enrolled. Patients were divided to2grouped according to the indications for therapy of warfarin before operation. Patients in group A were with CHA2DS2-VASC score of0, and warfarin therapy was not administrated before operation. Patients in group B were with permanent AF or CHA2DS2-VASC score≥1, and pre-operational warfarin therapy was administrated. Patients in both groups were divided to three subgroups according to their warfarin-responsive index (WRI).
Real-time PCR was used to test the polymorphisms of VKORC1and CYP2C9genes. WRI was calculated based on the sensitivity of polymorphisms on warfarin. Warfarin-sensitive polymorphisms including VKORC1-1639AA, CYP2C9*l/*3and*3/*3were scored to0, and non-warfarin-sensitive polymorphisms including VKORC1-1639AG and GG, CYP2C9*1/*1were scored to1. The patient's WRI was the total scores of these two genotypes. WRI reflected the combined effect of the above genes on warfarin-sensitivity. Zero score of WRI indicates high sensitive,1for medium sensitive and2for non-sensitive.
Warfarin was administrated with the initial dose of3mg/day for3weeks before operation in group B, and low molecular weight heparin was used to replace warfarin4days before operation. The warfarin with the last dose before operation was administrated in the next day after operation. Warfarin was administrated with the initial dose of3mg/day after operation in group A. Patients were followed up for3months, and INR, dose of warfarin, and complications including bleeding and TE were recorded.
Results
The time to reach the stabilized dose of warfarin after operation was4.4days' shorter in group B than in group A. The HR of adjusting time was1.58(95%CI1.23-2.02).
In group A, the adjusting time of subgroup with WRI=2had6.8days'longer than the time of subgroup with WRI=1(HR=0.60,95%CI0.39-0.91). There was no difference of adjusting time between subgroups with different WRIs in group B.
The stabilized doses of warfarin in subgroups were:in group A, WRI=1(3.44±0.68), WRI=0(1.89±0.28), WRI=2(5.81±1.06); in group B, WRI=1(3.29±0.71), WRI=0(1.83±0.36), WRI=2(5.53±1.15).
Before operation, the time to reach the goal of INR≥2in subgroup of group B with WRI=2was2.4days'longer than the time in subgroup of group B with WRI=1(HR=0.59,95%CI0.34-0.92). The time to reach the goal of INR≥2in subgroup of group A with WRI=2was2.5days'longer than the time in subgroup of group A with WRI=1(HR=0.58,95%CI0.33-0.84).
The time of INR≥2in group B was1.1days'shorter than the time before operation (HR=1.83,95%CI1.41-2.27). No difference between subgroups in terms of the time after operation to reach the goal was observed.
The incidence of INR≥4.0in subgroup of group B with WRI=0was higher than the one in subgroup with WRI=1(28.6%vs9.5%, P＜0.05; HR=4.36,95% CI1.32-30.99). The incidence of INR≥4.0in subgroup of group A with WRI=0was higher than the one in subgroup with WRI=1(36.4%vs8.9%, P＜0.05; HR=4.36,95% CI1.32-1.36-44.29).
In group B, the after operation was lower compared with the incidence before operation (4.3%vs10.5%, P＜0.05; HR=0.43,95%CI0.19-0.95). No difference of incidence of INR≥4.0between subgroups was observed.
In2months and3months after operation, the incidence of INR≥4.0was lower compared with3weeks after operation.
In group B, minor bleeding was occurred in5patients, major bleeding in1patient, TE in1patient. In group A, major bleeding was observed in1patient, and no TE was observed.
Conclusions
In patient with both warfarin-sensitive genotype in VKORC1and CYP2C9genes, the risk of over-anticoagulation and bleeding was elevated. In contrast, in patient with neither warfarin-sensitive genotype in above two genes, the time to reach the therapeutic window and stabilized dose will be prolonged.
The improvement of accuracy of initial dose may shorten the time to reach the therapeutic window and stabilized dose, and reduce the risk of over-anticoagulation and bleeding, which may reduce the adverse effect of the polymorphisms in VKORC1and
CYP2C9genes.
Section2The assessment of two pharmacogenetics algorithms
Objectives
To evaluate the accuracy of the to predict the warfarin stabilized dose in Chinese Han population with AF.
To assess the clinical value of the pharmacogenetics algorithms when the therapy of anticoagulation has been started.
To investigate the factors affecting cost-effectiveness of genotype-guided warfarin dosing
Methods
The stabilized dose of warfarin was calculated with2pharmacogenetics algorithms. The realistic stabilized doses after3months follow-up was recorded and compared with the calculated doses. Three indices were used to assess the agreement:mean absolute error (MAE), the rate of acceptable predicting value which was defined as difference no more than20%compared with realistic value, and correlation coefficient. These indices were compared between algorithms in1and2weeks.16patients who fail to acquire stable dose during the follow-up were excluded.
Results
The algorithm developed by fuwaihospital was better than the algorithm of IWPC with higher MAE (0.38±0.16vs0.52±0.21mg, P＜0.05), higher rate of acceptable predicting value (46.1%vs34.7%, P>0.05), and higher correlation coefficient (0.72vs0.62).
Fuwai-algorithm was similar to realistic dose at1week follow-up in terms of MAE(0.38±0.16vs0.32±0.13mg, P>0.05), rate of acceptable predicting value(46.1%vs50.2%, P>0.05), and correlation coefficient (0.72vs0.77). However, the accuracy was not as well as the realistic dose at2weeks follow-up in terms of MAE(0.38±0.16vs0.12±0.05mg, P＜0.05)、rate of acceptable predicting value (46.1%vs84.1%, P＜0.05), and correlation coefficient (0.72vs0.91).
In patients who WRI≠1, the accuracy of our algorithmwas better thanrealistic dose at1week follow-up, but in patients who WRI=1, the accuracy was not as well as realistic dose at1week follow-up. Conclusions
Fuwai-algorithm has higher accuracy than the algorithm of IWPC. The algorithm of IWPC may not the best algorithm for every countries and races.
The pharmacogenetics algorithm should be considered in patients with high risk for bleeding and TE and patients after RFCA. However, when anticoagulation therapy has been started for more than1week, the information supplied by the algorithm adds little value beyond the INR monitor. Factors which affect cost-effectiveness of genotype-guided warfarin dosing:frequencies of genetic variant distribution; difference between the average stabilized dose when both genes were mutated and common starting dose of race;risk ofpatients with bleeding and TE complications.
越来越多的心房颤动(Atrial fibrillation, AF)患者接受导管射频消融(Radiofrequency catheter ablation, RFCA)治疗, RFCA术出血及血栓栓塞(thromboembolic, TE)并发症多发生在术后早期2周之内,而在华法林初始抗凝阶段按照传统法给药(起始剂量固定,依据INR检测结果调整剂量),INR值经常波动较大。
细胞色素氧化酶P4502C9(cytochrome P4502C9, CYP2C9)和维生素K环氧化物降解酶复合物1(vitamin K epoxide reductase complex1, VKORC1)基因多态性被认为影响华法林剂量需求最主要的因素。目前研究多分别分析两个基因的多态性对患者敏感性的影响,而两种基因多态性以不同的方式组合对患者敏感性有抵消或叠加的混合效应,实际应用中更需要了解两种基因的共同影响。
国际华法林药物基因组学联合会CThe International Warfarin Pharmacogenetics Consortium, IWPC)依据不同国家和种族患者的临床和基因学资料,建立了遗传药理学运算模型,初始抗凝时预测患者的稳定剂量,提高初始给药的精准度,理论上可以使患者尽早达到所需要的抗凝目标,减少不良反应的发生,而临床试验比较传统法给药与运算模型法给药对抗凝初期INR控制效果,却得出矛盾的结果。运算模型未能取得预期效果,原因尚未明确,可能因为预测华法林稳定剂量的精准度不足,或者抗凝初始几周即使精准给药也难以控制好INR。此外,抗凝早期获得INR检测值后,遗传药理学给药模型的临床应用价值也未知。
第一部分VKORC1及CYP2C9基因多态性对房颤射频消融患者华法林抗凝效果的影响
1研究目的
探讨VKORC1及CYP2C9基因多态性对AF患者RFCA术前术后华法林抗凝效果的共同影响。
术前用传统法给药抗凝3周,术后用术前调整所得的剂量为起始剂量开始抗凝,探讨提高初始给药的精准度对AF患者RFCA术后华法林抗凝效果的影响。
2研究方法
1)研究对象及分组
选取接受RFCA术的AF患者287例,要求患者是初次使用华法林且接受我院随访。根据患者术前是否需要华法林抗凝治疗将患者分为A、B两组。
A组：CHA2DS2-VASC=0的阵发性AF患者125例,术前未予华法林抗凝。
B组：持续性AF患者或CHA2DS2-VASC≥1分的阵发性AF患者162例,术前需要华法林抗凝3周。
AB两患者均依据法林敏感指数(warfarin-responsive index WRI)分成WRI=0、WRI=1、WRI=2三个亚组。
2)基因检测
采用基于荧光染料的实时定量PCR法对患者进行VKORCl及CYP2C9基因的多态性检测。
WRI的计算方法：对华法林敏感的VKORCl-1639AA,CYP2C9*1/*3及*3/*3记为“0”,对华法林不敏感的VKORC1-1639AG及GG,CYP2C9*1/*1记为“1”,患者的WRI则等于两种基因型记分之和。WRI反映两种基因的不同基因型组合对华法林敏感性的的共同影响,WRI=0为极度敏感,WRI=1为中度敏感,WRI=2为不敏感。
3)抗凝方法及术后随访
B组患者术前用传统法给药抗凝3周,起始剂量3mg/d,术前4天改用低分子肝素“桥接”抗凝,术后起始剂量为术前调整好的剂量。A组患者术后传统法给药的起始剂量3mg/d。
所有患者在获得稳定抗凝剂量之前,每2-3天检测一次INR,获得稳定抗凝剂量之后,每1-2周检测一次INR。对每个患者随访3个月,详细记录每次INR值,华法林服用量及出血和TE并发症发生情况。
3研究结果
1)术后获得稳定华法林剂量的调整时间及各亚组的华法林稳定剂量
B两组患者术后获得稳定华法林剂量的平均调整时间比A组短4.4天,调整时间的HR(95%Confidence interval,CI)为1.58(1.23-2.02)。
A组中WRI=2比WRI=1亚组调整时间长6.8天,HR为0.60(0.39-0.91)。B组中不同亚组调整时间均无统计学差异。
各亚组华法林稳定剂量的平均值(mg/d)：A组WRI=1(3.44±0.68)、WRI=0(1.89±0.28).WRI=2(5.81±1.06)；B组WRI=1(3.29±0.71),WRI=0(1.83±0.36),WRI=2(5.53±1.15).
2)首次达到INR>2.0的时间
B组患者术前WRI=2比WRI=1亚组的平均时间延长2.4天,HR0.59(0.34-0.92)。B组患者术后比术前缩短1.1天,HR1.83(1.41-2.27),术后各亚组之间的平均时间及HR均无统计学差异。
A组患者术后WRI=2比WRI=1亚组平均时间延长2.5天,HR0.58(0.33-0.84)。A组患者术后的平均时间与B组患者术前相近,长于B组患者术后。3)首次达到INR>4.0的风险
B组患者术前WRI=0比WRI=1亚组发生率高(28.6%vs9.5%,P<0.05),首次达到INR≥4.0的时间的HR4.36(1.32-30.99)。术后发生率低于术前(4.3%vsl0.5%,P<0.05),HR0.43(0.19-0.95),且术后不同亚组之间的发生率及HR均无统计学差异。
A组患者术后WRI=0生率高于亚组WRI=1(36.4%vs8.9%,P<0.05),HR5.45(1.36-44.29))。A组患者术后风险与B组患者术前相近,高于B组患者术后。
所有患者术后的第2月和第3月,INR>4.0的发生率明显低于最初3周,且各个亚组之间的风险均无差异。
4)出血及TE并发症
B组患者术前发生小出血5例,术后发生大出血1例,TE并发症1例,A组患者术后发生大出血1例,无TE并发症。
术后A组小出血发生率高于B组(12.8%vs5.6%,P<0.05),HR为2.38(1.07-5.26)。A组及B组不同亚组之间小出血发生率均无统计学意义。
所有患者术后的第2月和第3月,小出血的发生率明显低于最初3周,且各个亚组之间的风险均无差异。
4研究结论
1)VKORC1及CYP2C9基因多态性相结合可以共同影响患者对华法林敏感性和初始抗凝阶段的抗凝效果。两基因均为对华法林敏感的基因型时,患者过度抗凝及出血并发症的风险增加,两基因均不敏感的基因型时,患者进入华法林治疗窗的时间及获得稳定剂量的调整时间延长。
2)提高起始剂量的精准度,可以缩短患者进入华法林治疗窗的时间及获得稳定剂量的调整时间,降低患者过度抗凝及出血并发症的风险,减少VKORCl及CYP2C9基因多态性对患者初始抗凝阶段带来的不利影响。
第二部分评价两种遗传药理学给药模型的临床应用价值
1研究目的
1)验证阜外医院建立的遗传药理学运算模型(阜外模型)及IWPC推荐的模型
(IWPC模型),比较两模型预测汉族AF患者华法林稳定剂量的精准程度。
2)探讨在获得INR检测结果以后,在不同时段遗传药理学运算模型的临床实用价值。
3)探讨基因多态性检测的性价比的影响因素。
2研究方法
287例患者中有16例患者因为在3个月随访结束时仍然未获得稳定剂量,不纳入本部分的研究。
分别用两种遗传药理学运算模型计算每位患者预期的稳定剂量。通过3个月的随访中获得每个患者实际的稳定剂量,比较的两组模型预测剂量与实际剂量的符合程度,得出较优的运算模型。评价预测值与实际值符合程度的3个指标：1)平均绝对误差(rnean absolute error, MAE);2)理想预测值的比例,理想预测值定义为与实际值相差在20%以内；3)相关系数(correlation coefficient, r)。
通过随访获得传统法给药第1周末、第2周末使用的华法林剂量,评价其与实际稳定剂量的符合程度,并与运算模型对比。
3研究结果
阜外模型预测精准度优于IWPC模型,MAE(0.38±0.16vs0.52±0.21mg,P<0.05)理想预测值的比例(46.1%vs34.7%,P>0.05)、r(0.72vs0.62)。
阜外模型预测剂量与实际剂量的符合程度近似于传统法第1周末剂量的符合程度。MAE(0.38±0.16vs0.32+0.13mg,P>0.05)、理想预测值的比例(46.1%vs50.2%,P>0.05)、r(0.72vs0.77)；劣于第2周末剂量的符合程度MAE(0.38+0.16vs0.12±0.05mg,P<0.05)、理想预测值的比例(46.1%vs84.1%,P<0.05)、r(0.72vs0.91)。
WPI≠1的患者,预测模型法预测剂量与实际剂量的吻合程度优于传统法第1周末剂量。
4研究结论
1)对于中国汉族患者,阜外模型预测华法林稳定剂量的精准程度优于IWPC推荐的模型。IWPC推荐的运算模型难以在所有国家和种族都获得最佳的预测效果。
2)抗凝开始1周以后,INR检测值所能提供的预测价值不逊于遗传信息,遗传药理学运算模型临床实用价值显著下降。
3)基因多态性检测性价比的影响因素：a.某种族各等位基因的频率分布,b.两种基因均出现突变的基因型时的平均稳定剂量与某种族华法林常用起始剂量的差异,c.患者出血及TE并发症的风险。
Background
The radiofrequency catheter ablation (RFCA) has been widely used in patients with atrial fibrillation (AF). RFCA related bleeding and thromboembolism (TE) usually occurs in2weeks, and at the initial phrase of administration of warfarin, the fluctuate of INR is usually large.
Cytochrome P4502C9(CYP2C9) and vitamin K epoxide reductase complex1(VKORC1) have been proved as the main factors attributed for the efficacy of warfarin. Previous studies investigated the associations between the polymorphisms of these two genes and the stabilized dose of warfarin separately, while the interaction between these two genes in terms of the effect on warfarin has rarely been investigated.
The International Warfarin Pharmacogenetics Consortium (IWPC) developed the pharmacogenetics algorithm to predict the stabilized dose of warfarin based on the clinical and genetic data of different countries and races, which may improve the accuracy of initial dose and theoretically shorten the time to reach the anticoagulation goal, resulting in less adverse events. However, the clinical utility of pharmacogenetics algorithm has been tested in clinical trials with equivocal results, a large number of patients did not improve anticoagulation control with the pharmacogenetics algorithm, which may be contributed to the poor accuracy of the algorithm. In addition, the value of the pharmacogenetics algorithm when the therapy of anticoagulation has been started is still to be described.
Section1The association between the polymorphisms of VKORC1and CYP2C9genes and the anticoagulation control of warfarin for patients with atrial fibrillation underwent radiofrequency catheter ablation
Objectives
1, To investigate the association between the polymorphisms of VKORC1and CYP2C9genes and the anticoagulation control of warfarin for patients with atrial fibrillation underwent radiofrequency catheter ablation.
2. Titrate the dose of warfarin based on INR from3weeks before operation, and start the administration of warfarin with the adjusted dose. Investigate the influence of improving the accuracy of administration on the anticoagulating effect in AF patients after RFCA. Methods
Two hundred and eighty-seven AF patients underwent RPCA who were not treated with warfarin was enrolled. Patients were divided to2grouped according to the indications for therapy of warfarin before operation. Patients in group A were with CHA2DS2-VASC score of0, and warfarin therapy was not administrated before operation. Patients in group B were with permanent AF or CHA2DS2-VASC score≥1, and pre-operational warfarin therapy was administrated. Patients in both groups were divided to three subgroups according to their warfarin-responsive index (WRI).
Real-time PCR was used to test the polymorphisms of VKORC1and CYP2C9genes. WRI was calculated based on the sensitivity of polymorphisms on warfarin. Warfarin-sensitive polymorphisms including VKORC1-1639AA, CYP2C9*l/*3and*3/*3were scored to0, and non-warfarin-sensitive polymorphisms including VKORC1-1639AG and GG, CYP2C9*1/*1were scored to1. The patient's WRI was the total scores of these two genotypes. WRI reflected the combined effect of the above genes on warfarin-sensitivity. Zero score of WRI indicates high sensitive,1for medium sensitive and2for non-sensitive.
Warfarin was administrated with the initial dose of3mg/day for3weeks before operation in group B, and low molecular weight heparin was used to replace warfarin4days before operation. The warfarin with the last dose before operation was administrated in the next day after operation. Warfarin was administrated with the initial dose of3mg/day after operation in group A. Patients were followed up for3months, and INR, dose of warfarin, and complications including bleeding and TE were recorded.
Results
The time to reach the stabilized dose of warfarin after operation was4.4days' shorter in group B than in group A. The HR of adjusting time was1.58(95%CI1.23-2.02).
In group A, the adjusting time of subgroup with WRI=2had6.8days'longer than the time of subgroup with WRI=1(HR=0.60,95%CI0.39-0.91). There was no difference of adjusting time between subgroups with different WRIs in group B.
The stabilized doses of warfarin in subgroups were:in group A, WRI=1(3.44±0.68), WRI=0(1.89±0.28), WRI=2(5.81±1.06); in group B, WRI=1(3.29±0.71), WRI=0(1.83±0.36), WRI=2(5.53±1.15).
Before operation, the time to reach the goal of INR≥2in subgroup of group B with WRI=2was2.4days'longer than the time in subgroup of group B with WRI=1(HR=0.59,95%CI0.34-0.92). The time to reach the goal of INR≥2in subgroup of group A with WRI=2was2.5days'longer than the time in subgroup of group A with WRI=1(HR=0.58,95%CI0.33-0.84).
The time of INR≥2in group B was1.1days'shorter than the time before operation (HR=1.83,95%CI1.41-2.27). No difference between subgroups in terms of the time after operation to reach the goal was observed.
The incidence of INR≥4.0in subgroup of group B with WRI=0was higher than the one in subgroup with WRI=1(28.6%vs9.5%, P＜0.05; HR=4.36,95% CI1.32-30.99). The incidence of INR≥4.0in subgroup of group A with WRI=0was higher than the one in subgroup with WRI=1(36.4%vs8.9%, P＜0.05; HR=4.36,95% CI1.32-1.36-44.29).
In group B, the after operation was lower compared with the incidence before operation (4.3%vs10.5%, P＜0.05; HR=0.43,95%CI0.19-0.95). No difference of incidence of INR≥4.0between subgroups was observed.
In2months and3months after operation, the incidence of INR≥4.0was lower compared with3weeks after operation.
In group B, minor bleeding was occurred in5patients, major bleeding in1patient, TE in1patient. In group A, major bleeding was observed in1patient, and no TE was observed.
Conclusions
In patient with both warfarin-sensitive genotype in VKORC1and CYP2C9genes, the risk of over-anticoagulation and bleeding was elevated. In contrast, in patient with neither warfarin-sensitive genotype in above two genes, the time to reach the therapeutic window and stabilized dose will be prolonged.
The improvement of accuracy of initial dose may shorten the time to reach the therapeutic window and stabilized dose, and reduce the risk of over-anticoagulation and bleeding, which may reduce the adverse effect of the polymorphisms in VKORC1and
CYP2C9genes.
Section2The assessment of two pharmacogenetics algorithms
Objectives
To evaluate the accuracy of the to predict the warfarin stabilized dose in Chinese Han population with AF.
To assess the clinical value of the pharmacogenetics algorithms when the therapy of anticoagulation has been started.
To investigate the factors affecting cost-effectiveness of genotype-guided warfarin dosing
Methods
The stabilized dose of warfarin was calculated with2pharmacogenetics algorithms. The realistic stabilized doses after3months follow-up was recorded and compared with the calculated doses. Three indices were used to assess the agreement:mean absolute error (MAE), the rate of acceptable predicting value which was defined as difference no more than20%compared with realistic value, and correlation coefficient. These indices were compared between algorithms in1and2weeks.16patients who fail to acquire stable dose during the follow-up were excluded.
Results
The algorithm developed by fuwaihospital was better than the algorithm of IWPC with higher MAE (0.38±0.16vs0.52±0.21mg, P＜0.05), higher rate of acceptable predicting value (46.1%vs34.7%, P>0.05), and higher correlation coefficient (0.72vs0.62).
Fuwai-algorithm was similar to realistic dose at1week follow-up in terms of MAE(0.38±0.16vs0.32±0.13mg, P>0.05), rate of acceptable predicting value(46.1%vs50.2%, P>0.05), and correlation coefficient (0.72vs0.77). However, the accuracy was not as well as the realistic dose at2weeks follow-up in terms of MAE(0.38±0.16vs0.12±0.05mg, P＜0.05)、rate of acceptable predicting value (46.1%vs84.1%, P＜0.05), and correlation coefficient (0.72vs0.91).
In patients who WRI≠1, the accuracy of our algorithmwas better thanrealistic dose at1week follow-up, but in patients who WRI=1, the accuracy was not as well as realistic dose at1week follow-up. Conclusions
Fuwai-algorithm has higher accuracy than the algorithm of IWPC. The algorithm of IWPC may not the best algorithm for every countries and races.
The pharmacogenetics algorithm should be considered in patients with high risk for bleeding and TE and patients after RFCA. However, when anticoagulation therapy has been started for more than1week, the information supplied by the algorithm adds little value beyond the INR monitor. Factors which affect cost-effectiveness of genotype-guided warfarin dosing:frequencies of genetic variant distribution; difference between the average stabilized dose when both genes were mutated and common starting dose of race;risk ofpatients with bleeding and TE complications.
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