A Study On The Interaction Of Chinese And Western Medicines Based On Real-world Diagnosis And Treatment Data Of Patients With Atrial Fibrillation Against Warfarin

Background:Atrial Fibrillation(AF)is one of the most common arrhythmias with high morbidity and mortality in clinical practice.It has attracted great attention because of the occurrence of severe clinical events such as stroke and thromboembolism.Warfarin anticoagulant therapy is one of the main treatment methods for atrial fibrillation.Although warfarin is widely used in clinical practice due to its definite anticoagulant effect,its narrow therapeutic window makes it vulnerable to genetic and environmental factors(diet,drugs,diseases,etc.),which makes INR frequently monitored during medication.Adverse reactions,synergism and attenuation of drug interactions are common in the process of clinical application.With the increasing wide application of traditional Chinese medicine,the combination of traditional Chinese medicine and Western medicine has become common clinical medication regimen.However,there is still a lack of in-depth safety studies on the combination of traditional Chinese medicine and Western medicine.To analyze the herb-drug interaction on curative effect and explore the analysis method of herb-drug interaction based on real-world clinical data has become an international research hotspot and difficulty.In order to find possible herb-drug interaction which may affect the intensity of INR,a case-control study design was adopted based on real-world clinical data and combined analysis with a variety of statistical methods were employed in this study.The results might provide reference and clues for clinical medication safety and research strategies for herb-drug interaction.Study 1:Research on the herb-drug interaction based on real-world diagnosis and treatment data of atrial fibrillation patients with warfarin anticoagulationObjective:To explore the effect of herb-drug interaction on INR of atrial fibrillation patients with warfarin anticoagulation based on real-world clinical data.Methods:Through the Kaientai system of Xiyuan Hospital China Academy of Chinese Medical Sciences reviewed 848 clinical visits of atrial fibrillation patients with warfarin anticoagulant who were in our hospital from April 2009 to August 2018.According to the anticoagulation intensity INR level,the diagnosis times were divided into three groups:INR<2.0,2.0?INR?3.0 and INR>3.0.The sample sizes were 554 cases,214 cases and 80 cases respectively.The study was divided into 2 case-control studies,all of which were analyzed with the 2.0<INR<3.0 group as the control group.Binary logistic regression multiplication and addition model,MDR were used to analyze herb-drug interaction which might cause increase and decrease of INR intensity.Results:1.There was no significant difference between the baseline data of 2.0?INR?3.0 and INR>3.0;2.0?INR?3.0 and INR<2.0 groups in age,life history,warfarin stability and other factors,which were comparable(P>0.05),but there was a significant difference between the two groups in gender and valvular disease history(P<0.05).2.Analysis of herb-drug interaction that may cause changes in INR level2.1 Herb-drug interaction that may lead to decrease INR level,(1)Based on logistic regression multiplication model,it can be found that there are 17 kinds of first-order interactions such as fuling*jiaomu,fuling*haipiaoxiao,fuling*dansghen,and other 13 kinds of second-order interactions such as fuling*dangshen*zisu,chuanxiong*guizhi*dangshen,fuling*chuanxiong*dangshen.The significance of learning,P<0.05 and OR(95%Cl)<1,is the multiplicative interaction(antagonistic effect),suggesting that there is an interaction between the above drug combination and warfarin,which may cause the INR level decrease.The above-mentioned 46 drug-addition interaction indicators RERI and AP and their 95%CI were all less than 0 and the SI value and 95%CI were less than 1,indicating that there was no additive interaction between the variables.(2)Based on MDR,the 3-factor model(fuling,guizhi,and dazao)is the best model with higher cross-validation consistency(7/10)and test balance accuracy(0.59),P<0.0001.It can be concluded that there is an interaction between fuling,guizhi,and dazao,the value of OR is 2.03(1.46,2.82),it indicates that there is a positive synergy interaction between warfarin and the drugs,suggesting that the risk of INR level decrease caused by the combination of the above three drugs is 2.03 times that of not taking the three drugs.2.2 Herb-drug interaction that may lead to increase INR level,(1)Based on the results of logistic regression multiplication model analysis,the three first-order interactions of taoren*gancao,chuanxiong*gancao,estazolam*suanzaoren were statistically significant(P<0.05),and the OR rate respectively is(95%CI)>1,which is a synergistic multiplication interaction.The above-mentioned eight drug-addition interaction indicators RERI and AP and their 95%CI were all less than 0,the SI value and 95%CI were less than 1,indicating that there was no additive interaction between the variables.(2)It was found that the 3-factor model(gancao,chuanxiong,and taoren)is the best model based on MDR,which had higher cross-validation consistency(9/10)and test balance accuracy(0.60),P=0.0015,and the difference is statistically significant.It can be concluded that there is an interaction between gancao,chuanxiong,and taoren and OR:2.31(1.37,3.90),suggesting that the drugs are positive interaction between warfarin and the risk of INR level increase caused by the combination of the above three drugs is 2.31 times that of not taking the three drugs.Conclusion:The logistic regression multiplication model and MDR analysis indicated that fuling*jiaomu,fuling*haipiaoxiao,fuling*dangshen,fuling*dangshen*zisu,chuanxiong*guizhi*dangshen,fuling*chuanxiong*dangshen,and fuling*guizhi*dazao may interact with warfarin to cause a decrease in INR level.For the INR level increased group,there was synergistic interaction between taoren*gancao,gancao*chuanxiong,estazolam tablets*suanzaoren,and gancao*chuanxiong*taoren.Study 2:Exploring the active ingredients and mechanism of action of related drugs:on INR based on network pharmacologyObjective:The further study aimed to explore the main active components,targets and predict the action mechaism of traditional Chinese medicine for INR level changing by using network pharmacology.Methods:On the basis of the previous research,the main active components and mechnisms of TCM were explored by using the method of network pharmacology.Detailed steps for network pharmacology were as follows:the chemical composition and target of the TCM,which were obtained in BATMAN-TCM database.Then the relevant targets of the International Normalized Ratio were retrieved through PALM-IST and GeneCards databases.The composition-target and the INR targets were constructed in to component-target network by using Cytoscape 3.6.1 software to screem the core target and its active components and the relevant pathways were set up by using DAVID or Funrich 3.1.3 database.The potential active components and their molecular mechanisms were explored by means of networks and pathways.Results:1 fuling,guizhi,dazao ingredients-target results(1)Network was constructed based on TCM components and INR targets,and INR core targets were selected according to network characteristics.The research results show that the components of TCM can be used to achieve the effect of INR with core targets of AR,NR3C1,ATP1A1,PTGS1,PTGS2,TRPV1,NR3C2,and NR1H4.(2)The main active ingredient of high frequency Chinese medicine affecting INR changes are triterpenoids and organic acids.(3)The components of fuling,guizhi,dazao can regulate biological processes,such as cell signaling,blood pressure regulation,regulating blood circulation,and regulating neurological factors to decrease the INR lever.(4)The main pathways of TCM cause a decrease in INR levels is the neurohumoral regulation,calcium signaling pathway,cellular functional pathway.2gancao,chuanxiong,taoren ingredients-target results(1)Network was constructed based on TCM components and INR targets,and INR core targets were selected according to network characteristics.The research results show that the components of TCM can be used to achieve the effect of INR with core targets such as NR3C1,DRD2,AR,CNR1,CNR2,OPRK1,NR3C2,ATP1A1,CHRNB2,PRKCA,ANXA1,NR1I2,SOAT2,ZP3,SUMO1,CAV3,SEC14L3,SEC14L2,and PRKCB.(2)The main active ingredients of high frequency Chinese medicine affecting INR changes are flavonoids and volatile oil compounds.(3)The components of gancao,chuanxiong and taoren can regulate biological processes,such as cell signal conduction,cardiac systolic function regulation,molecular function regulation and ion balance regulation to increase the INR lever.(4)The main pathways of TCM cause an increase in INR levels is the cytokine pathway and smad2/3signaling protein pathway.Conclusion:The specific active components,targets and pathways of TCM for INR can be obtained by further analysis and prediction of network pharmacological methods.The influence of TCM on INR lever is characterized by multi-component,multi-target and multi-pathway.In conclusion,this research is based on real-world clinical data,application of case-control study design to study herb-drug interation on INR of atrial fibrillation patients by using the binary logistic regression and MDR.To explore the influence of TCM active ingredients and mechanism of action on INR,some potential effects of warfarin anticoagulation in patients with herb-drug interation was found by the method of network pharmacology.It has certain reference value for clinical safety medication,and provides clues and basis for further research.