| Objective:This study is a comprehensive study of the RVO of traditional Chinese medicine interventions based on evidence-based medical theory,and the following objectives were achieved by conducting a four part study including a systematic review,literature quality report,randomized controlled trial,and network pharmacology of traditional Chinese medicine interventions for RVO:1 Based on the theory of evidencebased medicine,a systematic review of traditional Chinese medicine(TCM)for the treatment of RVO and a report on the literature quality of RCTs were conducted to evaluate the clinical efficacy,research level,existence deficiency and improvement measures of TCM for the treatment of RVO;2.To combine the characteristics of traditional Chinese medicine(TCM)and optimize the brvo-me randomized controlled trials for the intervention of expectorant Tongluo formula,which will provide a highquality evidence-based basis for evaluating the efficacy and safety of expectorant Tongluo formula for the intervention of BRVO-ME;3.Use network pharmacology to explore the action targets and pharmacological mechanisms of expectorant Tongluo recipe for the pre-treatment of brvo-me and provide ideas for experimental research.Methods:Part Ⅰ:Systematic review and meta analysis of randomized controlled trials of traditional Chinese medicine for the treatment of RVO:The retrieval of data years began from January 1,2019,to December 31,2021.Chinese literatures were searched with CNKI,VIP,Chinese medical journal full text database(yiige),and Wanfang medical network.Foreign literature literature search web of science,PubMed,EMBASE and Cochrane library were searched to focus on RCTs of pharmaceutical therapies for RVO.RCTs comparing traditional Chinese medicine with western medicine or placebo for the treatment of BRVO-ME were included.RCTs comparing the combination of traditional Chinese medicine with western medicine alone were also included.Data were extracted independently by two systematic reviewers,and the Cochrane Handbook risk of bias tool was used for bias assessment.For BCVA,CMT and response rate,revman5 was used 5 software performed metaanalysis,examined heterogeneity,and selected the corresponding effect model according to the heterogeneity results.Effect measures for outcomes were RR or mean difference,all presented with 95%CI.Part Ⅱ:methodological and reporting quality assessment of randomized controlled trials of traditional Chinese medicine for the treatment of RVO:The retrieval of data years began from January 1,2019,to December 31,2021.Chinese literatures were searched with CNKI,VIP,Chinese medical journal full text database(yiige),and Wanfang medical network.Foreign literature literature search web of science,PubMed,EMBASE and Cochrane library were searched to focus on RCTs of pharmaceutical therapies for RVO.RCTs with oral traditional Chinese medicine treatments as intervention methods were reviewed for reporting quality by using CONSORT(2010),CONSORT Chinese herbal standard,and stricta criteria for acupuncture as intervention methods.All three evaluation tools were registered with yes,no,and N/A as final evaluation results.Partial entries were not included in the overall analysis of quality when applicable.Based on the corresponding entries,Excel 2022 was finally used to calculate the reporting rate of included articles in each entry and field,the completeness of reporting of single articles,the reporting rate of single entries,and the number of reported entries as a proportion of the number of evaluation tool entries.Part Ⅲ:randomized controlled trial of Quji Tongluo Prescription for intervention of macular edema secondary to Sputum Stasis junction type of retinal branch vein obstruction:A total of 60 patients(60 eyes)with nonischemic brvo-me were enrolled in this trial in a randomized,controlled,double-blind fashion,30 patients(30 eyes)were each enrolled in a 1:1 ratio of control to test group using a random number table method,and the test group was treated with intravitreal injection of an anti VEGF drug(conifercept ophthalmic injection)in combination with oral expectorant Tongluo formula granules,The control group received intravitreal injections of anti VEGF agents(conbercept ophthalmic injection)combined with oral placebo pellets for 1 month.The visual acuity index BCVA,macular edema index CRT and other examinations were performed at baseline,1 month after baseline,respectively,and the data of the collected patients were recorded into a computer by Excel 2022 software with SPSS 24 statistical analysis of patients’ BCVA,CRT,and other data was performed using statistical software.The measurement data were tested for normality first,such as obeying normal distribution,using t-tests,such as not obeying normal distribution,using non parametric tests.Count data were obtained using χ2 test.Analysis of covariance was used when baseline was not homogeneous.Hypothesis testing was uniformly performed using two-sided tests,giving test statistics and their corresponding p-values,with P<0.05 considered statistically significant.Part Ⅳ:explores the mechanism of Quji Tongluo Prescription for the treatment of retinal vein obstruction based on network pharmacology:Using tcmsp platform,tcmid database and combined with Chinese Pharmacopoeia to collect the pharmacological active ingredients related to expectorant collaterals as potential active ingredients and targets,RVO disease targets were screened using several databases including PubChem,Swiss target prediction,and then the disease targets were intersected with the drug predicted targets with the aid of Cytoscape 3.07.2 software to construct the intersection target network as well as the protein-protein interaction network,utilizing R3 6.0 software for go and KEGG enrichment analysis.Finally,the active ingredients of drugs were subjected to molecular docking with disease targets.Result:Part I Systematic review and Meta analysis of randomized controlled trials of traditional Chinese medicine for the treatment of RVO:① Retrieval after reading titles and abstracts yielded 537 articles,and 24 were finally included after reading full-text rescreening.A total of sample size was included:2059 eyes with 1115 males and 944 females,1156 RVO patients,308 CRVO patients,and 594 BRVO patients with the oldest at 79 years and the youngest at 22 years,with a maximum follow-up of 18 months.② Risk of bias assessment was performed for 24 articles,13 of which were rated as low risk of bias with fair quality in at least 4 of the 7 risk of bias assessment entries;Seven literatures with less than three out of seven review entries for risk of bias were rated as low risk of bias with low quality.③ A total of six items(n=585)from the decimal method of recording BCVA condition after 1 month of intervention were included in the study,and the results showed that the effect of the test group in improving BCVA was better than that of the control group,with high heterogeneity in the results(I2=83%,P<0.00001).④ A total of nine studies(n=615)that recorded LogMAR visual acuity 1 month after the intervention were included,and the results showed that the test group improved BCVA better than the control group,with statistically significant heterogeneity in the results(I2=89%,P<0.00001).⑤ A total of 9 studies(n=797)that recorded the intervention for 3 months after decimal recording method showed that the effect of the test group in improving BCVA was better than that of the control group,and the difference was statistically significant,with high heterogeneity in the results(I2=89%,P<0.00001).⑥ A total of nine studies(n=674)documenting LogMAR visual acuity 3 months after the intervention were included,and the results showed that the test group improved BCVA better than the control group with statistically significant differences,resulting in high heterogeneity(I2=91%,P<0.00001).⑦ A total of 13 studies(n=1067)documenting CMT after 1 month of intervention were included,and the results showed high heterogeneity(I2=98%,P<0.00001)between trial and control groups for improving CMT outcomes.Sensitivity analysis of the meta results by excluding single studies one by one,after removing the source of heterogeneity,the heterogeneity of the results decreased(I2=92%,P<0.00001),and the effect of CMT improvement in the test group was better than that in the control group,with statistically significant differences.⑧ A total of 18 studies(n=1604)documenting CMT improvement 3 months after the intervention were included,and the results showed that the test group improved CMT better than the control group,with a statistically significant difference,resulting in high heterogeneity(I2=96%,P<0.00001).⑨ A total of 18 studies(n=1600)were included to document efficacy,which was higher in the postintervention trial arm than in the control arm,with low heterogeneity of results(I2=50%,P=0.009).⑩ Using the effectiveness rate as the outcome measure to compare traditional Chinese medicine with western medicine,integrated traditional Chinese and Western medicine with western medicine,the results of the inverted funnel plot in the included 18 studies indicated that the graphic presented asymmetry and there may be publication bias.Part II:Methodological and reporting quality assessment of randomized controlled trials of traditional Chinese medicine for the treatment of RVO① Retrieval after reading titles and abstracts yielded 537 articles,and 44 were finally included after reading full-text rescreening.② Of these,29 studies reported the random sequence generation method,35 studies fully reported prespecified outcome measures and adverse effect measures,and 37 studies were considered not to be at additional risk of bias.③ In terms of completeness of reporting of individual RCT studies,43 reports of included studies were judged to be overall incompletely reported according to the 2010 version of the CONSORT statement,with an average reporting completeness of 47.3%(18/37),of which the lowest was 24.3%and the highest was 64.9%,and 12 studies achieved reporting completeness of 50%and above(19/37).The 43 reports of the included studies rated the overall reporting completeness according to the CONSORT statement-Chinese herbal medicines less than the overall reporting completeness according to the CONSORT statement 2010 version,with an average reporting completeness of only 38.6%(4/10),a minimum of 10%and a maximum of 80%,and the entries of 15 studies reported completeness of 50%and above(5/10).There was only 1 RCT report of acupuncture included in this study,and the completeness of this study’s reporting according to the standards for reporting interventions in clinical trials of acupuncture was 71%(12/17).④ In terms of completeness of reporting of individual entries for all RCT studies,the highest completeness of reporting according to the 2010 version of the CONSORT statement was achieved for structured abstracts(97.67%),sites and locations of data collection(97.67%),and outcomes measures(97.67%).High levels of completeness of reporting were the explanation of the scientific background and rationale for the trial(86.05%),the trial specific purpose or hypothesis(90.70%),the design of the trial specific methods(93.02%),the subject inclusion criteria(93.02%),how the specific interventions were implemented(93.02%),when the outcome measures were measured(90.70%),statistical methods(93.02%),the number and proportion of individuals included in each group(95.35%)For the scientific interpretation of trial results and the reliability and usefulness of their external promotion(93.02%).The least frequently reported entries for Title Identification were the randomized clinical trial(2.33%),the method of sample size determination(2.33%),the principle of trial discontinuation termination(4.65%),the specific qualification of the randomized method(2.33%),the concealment of the randomized method(2.33%),the specific generation and implementation of the randomized method and the person performing the allocation concealment(0%),etc.⑤ In terms of completeness of reporting of individual entries in all RCT studies,the reviews according to the CONSORT statement Chinese herbal medicine are more heterogeneous,the proportion of reports in each section and the reported entries fluctuates,and the overall reporting ratio is low.The highest of these is explained by traditional Chinese medicine theory in the discussion section,with a reported rate of about 80%;Explanations based on biomedical theory and/or traditional Chinese medicine theory were made in the preface section,the reporting rate was only about 60%,and specific descriptions of interventions were mostly reported,however,there was not a single literature that fully reported all the entries in detail according to the CONSORT statement Chinese herbal medicine.The least reported entries for the title,abstract,and keywords sections describe the trials targeting a certain TCM pattern and can be identified as randomized clinical trials.Part Ⅲ:Randomized controlled trial of an Quji Tongluo Prescription for intervention of macular edema secondary to sputum stasis junction type of retinal branch vein obstruction① Baseline data and efficacy measures were compared between the two groups.There were no significant differences in clinical basic data such as gender or age between the two groups(P>0.05);There were no significant differences(P>0.05)in BCVA measured by standard log visual acuity scale,CRT measured by OCT examination and vision related quality of life scores among the outcome measures,which were comparable.The difference in BCVA measured by ETDRS was statistically significant(P=0.005).There were no significant differences(P>0.05)in homocysteine and lipids(total cholesterol,triglycerides,HDL,LDL)between the two groups,which were comparable.② The ETDRS scores of the two groups of subjects were separately compared within the group,and the ETDRS scores of the test group after treatment were better than those of the pretreatment group,the difference was statistically significant(P<0.0001);There was no significant difference between the ETDRS scores of the control group after treatment and those of the patients before treatment(P=0.717).Between groups,ETDRS scores were compared before and after intervention using analysis of covariance,as the difference between the test group and the control group in ETDRS scores before intervention was statistically significant(P=0.005)(P=0.117)③ The BCVA obtained by standard log visual acuity chart examination was separately compared between the two groups of subjects,and the visual acuity of the test group after treatment was better than that before treatment,with significant differences(P<0.0001;The visual acuity of the control group after treatment was better than that before treatment,and the difference was statistically significant(P<0.0001).There was no significant difference in visual acuity after treatment between groups(P>0.05)④ The intra group comparison of CRT values between the two groups was performed separately,and the post-treatment CRT of the test group was superior to the pretreatment,with a statistically significant difference(P<0.0001;In the control group,post-treatment CRT was superior to pre-treatment,with a statistically significant difference(P<0.0001).There was a significant difference in CRT post-treatment between the two groups(P=0.018).⑤ The visual acuity related quality-of-life questionnaire scores of the subjects in the two groups were compared separately within groups,and the visual acuity related quality-of-life scores of the test group after treatment were better than those of the pretreatment group,with significant differences(P<0.0001);The visual acuity related quality-of-life scores in the control group after treatment were better than those before treatment,and the difference was statistically significant(P<0.0001).The visual acuity related quality-of-life scores did not differ between the two groups after treatment(P=0.494).⑥ For the intragroup comparison of homocysteine values between the two groups,respectively,there was no significant difference between the post-treatment and pretreatment homocysteine values of the test groups(P=0.216);There was no significant difference between the post-treatment homocysteine values of the control subjects and those of the pre-treatment subjects(P=0.493).When compared between groups,there was no significant difference in homocysteine values between the two treatment groups(P=0.586).⑦ When intragroup comparisons of blood lipids(total cholesterol,triglycerides,HDL,LDL)were made between the two groups,respectively,there were no significant differences in the blood lipids(total cholesterol,HDL,LDL)of the test group after treatment compared with those of the test group before treatment(Ptotal cholesterol=0.553,Ptriglycerides=0.066,p-HDL=0.395,p-LDL=0.504);There were no significant differences in the serum lipids(total cholesterol,triglycerides,HDL,LDL)between the control subjects and the subjects before treatment(Ptotal cholesterol=0.055,Ptiglycerides=0.629,P HDL=0.054,PLDL=0.060).When comparing the groups,there was no significant difference in the values of blood lipids(total cholesterol,triglycerides,HDL,LDL)between the two treatment groups(Ptotal cholesterol=0.957,Ptriglycerides=0.595,PHDL=0.633,PLDL=0.494).⑧ No adverse effects were observed in either group of subjects during the course of the study,and no blood routine,coagulation abnormalities were observed in either group of subjects after treatment.Part Ⅳ:Explores the mechanism of Quji Tongluo Prescription for the treatment of retinal vein obstruction based on network pharmacology:135 active ingredients in the expectorant collaterals formula,which can treat RVO through 156 potential targets,involve HIF-1 signaling pathway,MAPK signaling pathway and other related signaling pathways.Docking of PTGS2 with wogonin,ESR1 with naringenin,and MMP3 with baicalein suggested good binding activity.Conclusions:① The systematic review of RCTs from recent years shows that traditional Chinese medicine(TCM)therapies are effective for both CRVO and BRVO in improving visual acuity and improving macular edema,and that TCM combined with intravitreal anti VEGF drug injection has stable efficacy and is superior to anti VEGF and laser alone,however,the results of the studies based on the factors of low methodological quality,varying criteria of subjects,and different interventions among the included studies which make some limitations.② The methodological and research reporting quality of RCTs of traditional Chinese medicine interventions for RVO are low,and should start with improving the aspects of study writing specifications,trial registration,sample size calculation,randomization methods,blinding,TCM related outcomes,and safety outcome reporting.③ This study was conducted in a randomized,controlled,double-blind,placebocontrolled manner and provided a high-grade evidence-based basis for demonstrating the efficacy of Quji Tongluo Prescription for visual function improvement and promoting macular edema resolution in patients with BRVO-ME.④ To preliminarily reveal the potential mechanism of action of Quji Tongluo Prescription in treating RVO with multiple targets and multiple pathways,and to provide ideas for subsequent studies. |
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