The Association Between The Polymorphisms Of VKORC1and CYP2C9Genes And The Efficacy Of Warfarin For Patients With Atrial Fibrillation Underwent Radiofrequency Catheter Ablation

BackgroundThe 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 ablationObjectives1, 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. MethodsTwo 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.ResultsThe 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.ConclusionsIn 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 VKORC1andCYP2C9genes.Section2The assessment of two pharmacogenetics algorithms ObjectivesTo 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 dosingMethodsThe 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.ResultsThe 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. ConclusionsFuwai-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.