Clinical Evidence And Network Pharmacology Mechanism Of Qishen Yiqi Dropping Pill In Treating Heart Failure With Reduced Ejection Fraction

Objective1.To evaluate the clinical efficacy and safety of oral Chinese patent medicine in the treatment of heart failure（HF）with reduced ejection fraction based on Bayesian network meta-analysis method;2.To observe the clinical efficacy of Qishen Yiqi Dropping Pills in the treatment of patients with heart failure with reduced ejection fraction;3.To explore the network pharmacological mechanism of Qishen Yiqi Dropping Pill in the treatment of heart failure with reduced ejection fraction.Methods1.Search Chinese full-text journal database,Wanfang database,VIP Chinese science and technology journal database,Sino Med,PubMed,Embase,Cochrane Library and other databases for oral Chinese patent medicine in the treatment of heart failure with reduced ejection fraction Heart failure with reduced ejection fraction（HFrEF）clinical randomized controlled trial（RCT）,the literature search time was from the establishment of the database to December 2020,and the data was extracted after literature screening and quality evaluation;Yeas’s principle,using R language to conduct network meta-analysis on the clinical efficacy of less intervention measures,and perform visual analysis（drawing network diagrams,area under the curve diagrams,etc.）for different outcome indicators,so as to rank oral Chinese patent medicines.2.According to the inclusion and exclusion criteria,a total of 20 patients with chronic heart failure with an admission blood fraction（LVEF）<40%were screened and randomly divided into the control group and the treatment group,10 cases in each group.With placebo and Qishen Yiqi Dropping Pills,the course of treatment was 24 weeks.The general condition,TCM syndrome score,Lee’s heart failure score,Kansas city cardiomyopathy questionnaire（KCCQ）score,Minnesota living quality of life scale for heart failure（Minnesota living）before and after treatment were observed.with heart failure questionnaire,MLHFQ)score,New York Heart Association（NYHA）cardiac function classification,6-minute walk distance（6MWD）,echocardiography,plasma NT-proBNP,Heart failure rehospitalization time,heart failure rehospitalization events,blood routine,biochemical total items,adverse reactions,etc.3.Screen the active components and action targets of Qishen Yiqi Dropping Pills through the Traditional Chinese Medicine System Pharmacology Analysis Platform（TCMSP）,and use the Cytoscape 3.9.1 software to construct a network of"TCM-chemical components-action targets"and do topological analysis;Gene Cards,OMIN,and Drugbank databases were used to screen the targets for reducing ejection fraction in heart failure,and R language was used to screen the common targets of the two,and the common targets were imported into the STRING database to construct a protein-protein interaction network;Cytoscape 3.9.1 software was used to construct traditional Chinese medicine compounds Regulatory network;GO function enrichment and KEGG pathway enrichment analysis of common targets through the Bioconductor database to predict the mechanism of Qishen Yiqi Dropping Pills in the treatment of ejection fraction and heart failure.Results1.A total of 95 RCT,including 11,278 patients,involving a total of 5 kinds of oral Chinese patent medicines.The results of network Meta analysis based on Bayesian principle showed that:in improving 6MWD:Qishen Yiqi Dropping Pills（MD=64.17,95%Cl:49.62,78.71）>Qili Qiangxin Capsules（MD=47.23,95%Cl:37.74,56.64）>Shenfu Qiangxin Pill（MD=40.73,95%Cl:5.63,76.13）>Buyiqiangxin Tablet（MD=36.11,95%Cl:3.45,68.75）>Xinbao Pill（MD=31.28,95%Cl:3.37,59.28）;in improving MLHFQ score:Tonic Qiangxin Tablet（MD=-10.78,95%Cl:-18.34,-3.78）>Shenfu Qiangxin Pill（MD=-7.01,95%Cl:-17.82,3.94）>Qili Qiangxin Capsules（MD=-4.88,95%Cl:-9.93,-0.31）>Qishen Yiqi Dropping Pills（MD=-2.27,95%Cl:-12.47,8.02）;in improving NYHA cardiac function classification:Qishen Yiqi Dropping Pills（MD=4.46,95%Cl:2.33,8.82）>Shenfu Qiangxin Pill（MD=4.45,95%Cl:1.85,11.49）>Tonic Qiangxin Tablets（MD=4.15,95%Cl:0.89,22.3）>Xinbao Pill（MD=3.9,95%Cl:1.75,9.13）>Qili Qiangxin Capsules（MD=3.22,95%Cl:2.58,4.05）;in reducing plasma BNP level:Xinbao Pill（MD=-274,95%Cl:-575.4,29.48）>Qishen Yiqi Dropping Pills（MD=-148.01,95%Cl:-235.14,-62.33）>Shenfu Qiangxin Pill（MD=-146.42,95%Cl:-732.27,432.5）>Qili Qiangxin Capsules（MD=-109.17,95%Cl:-182.38,-41.42）;in reducing plasma NT-proBNP:Qili Qiangxin Capsules（MD=-491.18,95%Cl:-664.18,-322.62）>Shenfu Qiangxin Pill（MD=-455.53,95%Cl:-928.58,17.71）>Xinbao Pill（MD=-409.96,95%Cl:-897.89,73.55）>Qishen Yiqi Dropping Pills（MD=-297.73,95%Cl:-623.5,22.12）;in improving LVEF:Qishen Yiqi Dropping Pills（MD=7.55,95%C l:5.51,9.59）>Xinbao Pill（MD=5.99,5%C l:1.49,10.47）>Shenfu Qiangxin Pill（MD=5.48,95%Cl:9.94,9.92）>Qili Qiangxin Capsules（MD=5.7,95%Cl:4.46,6.95）.In terms of safety,a total of 53 RCTs reported adverse events,mainly manifested as digestive and neurological symptoms.Among them,the incidence of adverse events of Shenfu Qiangxin Pill was 5/54,the incidence of adverse events of Xinbao Pill was 7/108,the incidence of adverse events of Qili Qiangxin Capsule was 28/1526,and the incidence of adverse events of Qishen Yiqi Dropping Pill was 7/108.The rate of adverse events was3/1433.Compared with the control group,there was no significant difference in the incidence of adverse events between the above drug treatment groups（P>0.05）.2.A total of 20 patients were included in the clinical study,and no patients were dropped or excluded during the treatment cycle.In the end,10 patients were in the treatment group and 10 in the control group.There was no significant difference in baseline data between the two groups of patients at the time of enrollment,and they were comparable（P>0.05）.2.A total of 20 patients were included in the clinical study,and no patients were dropped or excluded during the treatment cycle.In the end,10 patients were in the treatment group and 10 in the control group.There was no significant difference in baseline information between the two groups of patients at the time of enrollment,and they were comparable(P_inter<0.05).（1）Heart failure syndrome/symptom score（1）Traditional Chinese Medicine Syndrome Score After treatment,the TCM syndrome score of the control group decreased compared with that before treatment(P_intra=0.001),and the net difference within the TCM syndrome score group was 7.00 points（95%CI:3.63-10.37 points）;The TCM syndrome scores in the treatment group decreased compared with those before treatment(P_intra<0.001),and the net difference within the TCM syndrome scores was 14.20 points（95%CI:10.18-18.22 points）;the TCM syndrome scores in the treatment group The net difference within the group was better than that of the control group(P_inter=0.006).（2）Lee’s Heart Failure Score Before treatment,there was no significant difference in Lee’s heart failure score between the two groups(P_inter>0.05),and after treatment,there was a statistically significant difference in Lee’s heart failure score between the two groups(P_inter=0.039),after treatment,the Lee’s heart failure score in the treatment group was lower than that in the control group;after treatment,there was no significant change in the Lee’s heart failure score between the two groups(all P_intra>0.05).（2）Quality of life questionnaire/scale survey（1）Kansas City Cardiomyopathy Questionnaire The KCCQ score of the control group before and after treatment had no significant difference(P_intra>0.05);the KCCQ score in the treatment group decreased after treatment,with statistical significance(P_intra<0.01).（2）The Minnesota Heart Failure Quality of Life Scale control group had no significant difference in the MLHFQ score after treatment compared with before treatment(P_组内>0.05);the MLHFQ score in the treatment group decreased after treatment,with statistical significance(P_intra<0.05).（3）New York Heart Association cardiac function classificationAfter treatment,the total effective rate of improvement of NYHA cardiac function classification in the control group was 60%,and the total effective rate of improvement in NYHA cardiac function classification in the treatment group was 80%,between the two groups have no significant difference(P_inter>0.05).（4）Six-minute walking distancebefore and after treatment in the control group(P_intra>0.05);the 6MWD in the treatment group increased after treatment,with statistical significance(P_intra=0.001),and the net difference in the 6MWD group was-32.80 meters（95%CI:-48.32～17.27 meters）;there were differences in the 6MWD increase distance between the two groups before and after treatment,and the increase distance in the treatment group was higher than that in the control group(P_inter=0.022).（5）Cardiac color Doppler ultrasound indicatorsno significant difference in cardiac color Doppler related indexes between the two groups before and after treatment(all P_intra>0.05,all P_inter>0.05).（6）Plasma level of N-terminal pro-B-type natriuretic peptidecontrol group before and after treatment(P_intra>0.05);the NT-proBNP in the treatment group was significantly lower than that before treatment(P_intra=0.013),and there was a net difference in the level of NT-proBNP within the group.was 538.50pg/ml（95%CI:192.25～884.75pg/ml）.（7）Heart failure rehospitalization eventsDuring the 24-week treatment period,there were 6 cases of heart failure rehospitalization events in the control group,and 1 case of heart failure rehospitalization events in the treatment group;there was no statistical significance between the two groups P_inter>0.05),but the P trend The test was significant(P_trend=0.022).（8）Safety evaluationThere was no statistical difference in general vital signs,blood routine,and blood biochemical indexes between the two groups before and after treatment(all P_组内>0.05,all P_inter>0.05).There was no significant difference in the incidence of adverse reactions between the two groups(P_inter>0.05).3.125 active ingredients of Qishen Yiqi Dropping Pills and 228 effective targets corresponding to the ingredients were screened from the TCMSP database,and 640 targets were obtained based on Gene Cards database,OMIM database,and Drugbank database to reduce ejection fraction and heart failure.Taking the intersection,77 common targets of Qishen Yiqi Dropping Pills in the treatment of heart failure with reduced ejection fraction were obtained.GO function and KEGG pathway enrichment analysis obtained 2194 GO function enrichment entries and 145 signaling pathways,which were mainly involved in biological processes such as oxidative stress and inflammatory response;many targets were enriched in AGE-RAGE,P13-Akt,MAPK,HIF-1,TNF,and other signaling pathways.Conclusion1.The results of network meta-analysis show that for different outcome indicators of HFrEF,five kinds of oral Chinese patent medicines,Qishen Yiqi Dropping Pill,Buyiqiangxin Tablet,Qili Qiangxin Capsule,Shenfu Qiangxin Pill,and Xinbao Pill,each have their own characteristics.The efficacy advantage of Qishen Yiqi Dropping Pills is more sufficient in improving 6MWD,LVEF and NYHA cardiac function classification,and the incidence of adverse reactions is lower.2.The results of clinical research suggest that the addition of Qishen Yiqi Dropping Pills on the basis of conventional western medicine treatment can reduce the plasma NT-proBNP level in HFrEF patients,improve clinical symptoms,and improve exercise tolerance and quality of life.3.The chemical constituents such as quercetin,luteolin,kaempferol,tanshinone IIA,β-sitosterol,and carrageenone in Qishenyiqi Dropping Pills may act on STAT3,HSP90AA1,JUN,AKT1,MAPK1,MAPK,etc.Key targets regulate AGE-RAGE,P13-Akt,MAPK,HIF-1,TNF and other signaling pathways,thereby exerting a therapeutic effect on HFrEF.