Study On The Oral Anticoagulant Dosage And Bleeding Prediction Of Patients With Pulmonary Embolism In A Top Tertiary Hospital In Xinjiang Based On Gene Guidance

Objective: 1.To systematically review the efficacy and safety of genotype-guided warfarin doing in patients with pulmonary embolism;2.To validate and evaluate the predictive accuracy of 12 warfarin stable dose prediction algorithms for pulmonary embolism patients in the First Affiliated Hospital of Xinjiang Medical University;3.To investigate the correlation between ABCB1 gene polymorphism,non-genetic factors and bleeding in patients with pulmonary embolism after taking rivaroxaban.Methods: 1.Pub Med,EMbase,The Cochrane Library,CBM,Wan Fang Data and CNKI databases were electronically searched to collect randomized controlled trials(RCTs)on the efficacy and safety of genotype-guided warfarin doing versus traditional doing in patients with pulmonary embolism from inception to July,2019.Then,literature was screened,data extracted,quality evaluation was conducted,and meta-analysis was performed by using Rev Man 5.3 software.2.The complete clinical data of 131 patients with stable Warfarin dose were collected.2 m L of peripheral blood was collected from each patient,and the VKORC1 and CYP2C9 genotypes were detected by polymerase chain reation-microarray hybridization technology.The actual stable dose with differences between different genotypes were analyzed.12 stable dose prediction algorithms of Warfarin were selected through previous publications,the prediction accuracy of each algorithm was evaluated by mean absolute error and prediction percentage.3.Complete data of 70 patients diagnosed with pulmonary embolism and receiving rivaroxaban were collected.2 m L of peripheral blood of each patient was collected and their ABCB1 genotype was detected by PCR direct sequencing method.The risk factors that may cause adverse reactions of bleeding were screened out by univariate analysis,and the risk factors were further identified by multivariate Logistic regression analysis Results: 1.A total of 12 RCTs involving 2 307 patients were included.The results of meta-analysis showed that: compared with traditional doing for pulmonary embolism,genotype-guided warfarin doing increased international normalized ratio of time within therapeutic range(TTR)[MD=6.22,95%CI(1.27-11.16),P=0.01],decreased time to first therapeutic INR[MD=-2.75,95%CI(-3.26-2.24),P< 0.00001],increased patients with stable dose[RR=1.33,95%CI(1.18-1.51),P< 0.00001],decreased the rates of adverse events[RR=0.62,95%CI(0.50-0.77),P<0.0001].2.The CYP2C9 and VKORC1 gene frequencies of 139 volunteers were in line with Hardy-Weinberg balance.There were significant differences in the actual stable dose of Warfarin among VKORC1 AA,AG and GG genotype(P < 0.001).Except for the genotype of only 1 patient in CYP2C9,CYP2C9*1/*1 type was higher than *1/*3 type in 136 patients with stable dose of warfarinda,with significant differences(P < 0.05).Among the 12 warfarin stable dose prediction algorithms,the MAE of Du Li-ping,Sconce and Wu Chao-jun in algorithms were lowest,and the ideal percentage of Du Li-ping,Wu Chao-jun and Ohno in algorithms were highest.The ideal prediction percentage of 8 algorithms was greater than40%,and the sensitivity analysis showed that the accuracy of stable dose prediction model for high,medium and low dose patients declined in turn.3.Among the included patients,25 cases(35.71%)had bleeding adverse reactions,3 cases(12%)had clinically unrelated major bleeding,and 22 cases(88%)had minor bleeding.ABCB1 gene frequency of 70 subjects was in line with Hardy-Weinberg equilibrium.Univariate analysis showed that previous bleeding history,hemoglobin,PT,APTT,ABCB1A1236G(AA/AG+GG),ABCB1 A2677C/T(AA/AC+AT+CC+CT+TT),and ABCB1rs4148738(CC/CT+TT)had statistically significant differences in the incidence of ADR of rivaroxaban hemorrhage in patients with pulmonary embolism(P < 0.05).Multivariate Logistic regression analysis showed that Lower hemoglobin [P = 0.047,OR = 0.930,95%CI(0.866,0.999)] and higher PT [P = 0.046,OR = 1.718,95%CI(1.009,2.926)] were the main risk factors for adverse bleeding reactions in patients with pulmonary embolism after taking rivaroxaban.Conclusion:1.Current evidence shows that,compared with traditional doing,genotype-guided warfarin doing in patients with pulmonary embolism may improve efficacy and safety of warfarin doing;2.Du Liping model has a good prediction accuracy for patients with pulmonary embolism in Xinjiang with high and medium doses,and Wu Chaojun model has better predictive accuracy than other models for patients with low doses;3.Lower Hemoglobin(HGB<115 g·L-1)and higher PT(PT>15s)are independent risk factors for bleeding adverse reactions in patients with pulmonary embolism after rivaroxaban administration;ABCB1 A1236 G,ABCB1A2677C/T and ABCB1 rs414873 may be potential protective factors for the occurrence of adverse reactions of rivaroxaban hemorrhage in patients with pulmonary embolism.