| Objective: 1.To evaluate the benefits and harms of traditional Chinese medicine(TCM)Xiao Chai Hu Tang formula and acupuncture therapies(manual needle acupuncture,electroacupuncture,laser acupuncture,moxibustion,acupoint injection,herbal patching,and acupoint pressure)separately intervening chronic hepatitis B,and to provide recommendations for clinical decision makers.2.To evaluate the research methodology quality of Xiao Chai Hu Tang formula and acupuncture therapies separately intervening chronic hepatitis B,and to light direction for future clinical trial research inChinese medicine.3.Taking Xiao Chai Hu Tang formula and acupuncture therapies seprately intervening chronic hepatitis B as examples,we constructed a visual tool,the three-dimensional error evidence matrix,to evaluate the quality of clinical evidence body for TCM through three dimensions of errors: systematic errors,random errors and design errors,to supplement the defects of the commonly used evidence quality assessment methods,which are insufficient attention to design errors,to make suggestions for TCM clinical research design from the three dimensions,to improve the TCM clinical evidence quality,and to further promote clinical implementation of Chinese medicine therapies.Material and method: 1.Evidence-based evaluation of Xiao Chai Hu Tang formula for chronic hepatitis B We searched clinical studies of Xiao Chai Hu Tang formual for chronic hepatitis B worldwide.We conducted Cochrane systematic reviews to evaluate the benefits and harms of Xiao Chai Hu Tang formual for chronic hepatitis B.We used the Trial Sequential Analysis(TSA)to explore the required information(IS)for “sufficient evidence”,and we test the statistical significance and invalidity of the retrieved clinical evidence to determine whether further clinical trials are needed,and to light the direction for future clinical research.We assessed the overall quality of the retrieved evidence by GRADE.2.Evidence-based evaluation of acupuncture therapies for chronic hepatitis BWe searched clinical studies of acupuncture therapies(manual needle acupuncture,electroacupuncture,laser acupuncture,moxibustion,acupoint injection,herbal patching,and acupoint pressure)for chronic hepatitis B worldwide.We conducted Cochrane systematic reviews to evaluate the benefits and harms of acupuncture therapies for chronic hepatitis B.We used the Trial Sequential Analysis(TSA)to explore the required information(IS)for “sufficient evidence”,and we test the statistical significance and invalidity of the retrieved clinical evidence to determine whether further clinical trials are needed,and to light the direction for future clinical research.We assessed the overall certainty of the retrieved evidence by GRADE.3.Exploratory Analysis of the Application of Three-Dimensional Error Evidence Matrix in the Evaluation of TCM Clinical EvidenceTaking Xiao Chai Hu Tang formula and acupuncture therapies(manual needle acupuncture,electroacupuncture,laser acupuncture,moxibustion,acupoint injection,herbal patching,and acupoint pressure)seperately intervening chronic hepatitis B as examples to evaluate the quality of retrieved evidence body.We evaluate the internal and external vality by systematic errors,random errors,and design errors.We uses evidence level to rank evidence body from the view of systematic errors,and we use the 'Risk of bias tool' to assess the specific systematic errors of retrieved evidence.We used standard error to assess the risk of random errors.We rank the evidence from the view of the risk of design errors according to the importance of outcomes,and we described other risk factors of design errors in details.We contucted a visualised ‘three-dimensional error evidence matrix'(error matrix)from three dimentiaons of systematic errors,random errors and design errors.We ranked retrieved evidence by the error matrix,and we make suggestions improving the quality of clinical evidence.Results: 1.Evidence-based evaluation of Xiao Chai Hu Tang formula for chronic hepatitis B We included ten randomised clinical trials with 926 participants randomised.All the trials compared Xiao Chai Hu Tang formula combined with conventional therapies withconventional therapies.The trials assessed heterogenous forms of Xiao Chai Hu Tang formula,administered for 3 to 8 months.One trial included participants with hepatitis B and comorbid tuberculosis,and one trial included participants with hepatitis B and liver cirrhosis.The remaining trials included participants with hepatitis B only.All the trials were assessed at high risk of bias,and the certainty of evidence for all outcomes was very low.None of the trials aimed at assessing all-cause mortality,serious adverse events,health-related quality of life,hepatitis B-related mortality,or morbidity.We are uncertain whether Xiao Chai Hu Tang formula has an effect regarding adverse events considered 'not to be serious'(RR 0.43,95% CI 0.02 to 11.98;I2 = 69%;two trials;240 participants;very low certainty).Xiao Chai Hu Tang formula showed a reduction of the proportion of people with detectable HBV-DNA(RR 0.62,95% CI 0.45 to 0.85;I2 = 0%;three trials;222 participants;very low certainty).We are uncertain whether Xiao Chai Hu Tang formula has an effect regarding the proportion of people with detectable HBeAg(RR 0.72,95% CI 0.50 to 1.02;I2 = 38%;two trials;160 participants;very low certainty).For seperately reported adverse events considered 'not to be serious',the intervention effect was not statistically significant in Xiao Chai Hu Tang group compared with the no intervention group: proportion of participants with nausea(RR 5.00;95% CI 0.24 to 102.53;P>0.05;only one trial),proportion of participants with nausea and vomiting(RR 2.00,95% CI 0.19 to 21.18;P>0.05;only one trial),proportion of participants with dizziness and sleep disorders(RR 0.11,95% CI 0.01 to 2.03;P>0.05;only one trial),proportion of participants with dizziness and fatigue(RR 1.00,95% CI 0.06 to 15.44;P>0.05;only one trial),proportion of participants with a dry feeling or bitter taste in the mouth(RR 1.00,95% CI 0.06 to 15.44;P>0.05;only one trial),proportion of participants with bloating and belching(RR 1.00,95% CI 0.06 to 15.44;P>0.05;only one trial),proportion of participants with loss of appetite(RR 1.00,95% CI 0.06 to 15.44;P>0.05;only one trial).There were no significant differences in the subgroup analysis of the composition,treatment duration,dosage form,and dose of Xiao Chai Hu Tang formula(P>0.05).Xiao Chai Hu Tang formula showed a reduction of ALT serum level of participant(MD-18.94,95% CI-29.42 to-8.45;I2 = 97%;seven trials;633 participants;very low certainty).Xiao Chai Hu Tang formula showed a reduction of AST serum level of participant(MD-22.75,95% CI-44.64 to-0.85;I2 = 99%;six trials;867 participants;very low certainty).Two of the included 10 randomised clinical trials received academic funding from government or hospital.The remaining eight trials provided no information on funding.Additionally,47 trials lacked the necessary methodological information needed to ensure the inclusion of these trials in our review.2.Evidence-based evaluation of acupuncture therapies for chronic hepatitis BWe included eight randomised clinical trials with 552 participants randomised.All the included trials compared acupuncture(manual needle acupuncture,electroacupuncture,laser acupuncture,moxibustion,acupoint injection,herbal patching,and acupoint pressure)versus no intervention.The included trials assessed heterogeneous acupuncture interventions.All trials used heterogeneous co-interventions applied equally in the compared groups.Seven trials included participants with chronic hepatitis B and one trial included chronic hepatitis B with comorbid tuberculosis.The treatment duration ranged from 14 days to 12 months.All the trials were assessed at high risk of bias,and the certainty of evidence for all outcomes was very low.None of the trials aimed at assessing all-cause mortality,serious adverse events,health-related quality of life,hepatitis B-related mortality,and hepatitis B-related morbidity.We are uncertain whether acupuncture has an effect regarding adverse events considered not to be serious(RR 0.67,95% CI 0.43 to 1.06;I2 = 0%;three trials;203 participants;very low certainty)and detectable HBeAg(RR 0.79,95% CI 0.69 to 0.91,I2 = 98%;two trials;158 participants;very low certainty).Manual needle acupuncture,compared with no intervention,showed a reduction in detectable HBV-DNA(a non-validated surrogate outcome;RR 0.45,95% CI 0.27 to 0.74;one trial,58 participants;very low certainty).For seperately reported adverse events considered 'not to be serious',the intervention effect was not statistically significant in acupuncture therapies group compared with the no intervention group: proportion of participants with fatigue(RR 0.67,95% CI 0.12 to 3.78;P>0.05;only one trial),proportion of participants with loss of appetite(RR 0.60,95% CI 0.15 to 2.34;P>0.05;only one trial),proportion of participants with flank pain(RR 0.67,95% CI 0.26 to 1.70;P>0.05;only onetrial),proportion of participants with bradycardia(RR 2.81,95% CI 0.12 to 66.77;P>0.05;only one trial).The meta-analysis showed that acupuncture was associated with a higher proportion of participants with bloating(RR 4.50,95% CI 1.04 to 19.54;P<0.05;only one trial).There were no significant differences in the subgroup analysis of different acupuncture therapies,treatment duration,diagnostic criteria,and participants with complications(P>0.05).Manual needle acupuncture,moxibustion,accupoint herbal patching showed a reduction of ALT serum level of participant(MD-21.35,95% CI-33.60 to-9.09;I2 = 81%;four trials;275 participants;very low certainty).Manual needle acupuncture,moxibustion,accupoint herbal patching showed a reduction of AST serum level of participant(MD-18.31,95% CI-35.44.64 to-1.18;I2 = 94%;four trials;275 participants;very low certainty).Three of the eight included randomised clinical trials received academic funding from government or hospital.None of the remaining five trials reported information on funding.Additionally,79 trials lacked the necessary methodological information that could have ensured their inclusion in this review.3.Study of clinical research quality assessment and clinical research design improvement methods for Xiao Chai Hu Tang formula and acupuncture therapies seprately intervening chronic hepatitis BTaking Xiao Chai Hu Tang formula and acupuncture therapies(manual needle acupuncture,electroacupuncture,laser acupuncture,moxibustion,acupoint injection,herbal patching,and acupoint pressure)seperately intervening chronic hepatitis B as examples,we contructed evidence matrix to evaluate the quality of retrieved evidence body.There were two meta-analyses and 52 randomized controlled trials to investigate the effect and safety of Xiao Chai Hu Tang formula for chronic hepatitis B.Through the visual error matrix,we found out that due to high risk of systematic errors and design errors,and the small risk random errors,the two meta-analyses are rated as low-quality research,and none of them is systematic review.17%(9/54)of the evidence showed high risk of random errors.100% of the evidence showed high-risk of systematic errors.About design errors,no evidence reported all-cause mortality,2%(1/54)of the evidence reported serious adverse events,and 20%(11/54)of the evidencereported non-serious adverse events,72%(39/54)of the evidence only reported surrogate outcomes,43%(23/54)of the evidence clearly defined the diagnostic criteria,inclusion criteria,and exclusion criteria,57%(31/54)of the evidence clearly reported the implementation of the combined intervention,19%(10/54)of the vidence reports the composition of Xiaochaihutang,0% of the evidence can be assessed as a practical study,and 4%(2/54)of the evidence was designed as multicenter trials.Evidence at the very northwest corner of the evidence matrix represents the highest quality evidence,which is a low-quality meta-analysis.Two meta-analyses,77 clinical randomized controlled trials,and two case series report studies explored he effect and safety of acupuncture therapies for chronic hepatitis B.Through the visual error matrix,we found out that due to high risk of systematic errors and design errors,and the small risk random errors,the two meta-analyses are rated as low-quality research,and none of them is systematic review.22%(18/81)of the evidence showed high risk of random errors.100% of the evidence showed high-risk systematic errors.About design errors,no studies reported all-cause mortality,1%(1/81)of the evidence reported both all-cause mortality and hepatitis B-related complications,19%(15/81)of the evidence reported serious adverse events,36%(29/81)of the evidence reported non-serious adverse events,12%(10/81)of the evidence reported health-related quality of life,7%(6/81)reported hepatitis B-related complications,58%(47/81)of the evidence clearly defined the diagnostic criteria,inclusion criteria,and exclusion criteria,44%(36/81)of the evidence clearly reported the implementation of the joint intervention,9%(3/33)reported the acupuncture Individualized treatment protocal,0% of the evidence reported eligibility criteria for medicine care practitioners,0% of studies can be assessed as superiority studies or practical studies,and 4%(3/81)of evidence was designed as multicenter trials.Evidence at the very northwest corner of the evidence matrix represents the highest quality evidence,which is a low-quality meta-analysis.Conclusion: 1.The evidence for Xiao Chai Hu Tang formula for chronic hepatitis B lacks assessment andreport of patient-centred outcomes(i.e.all-cause mortality,health-related quality of life,serious adverse events,hepatitis B-related mortality,and hepatitis B-related morbidity).By evaluating low-quality evidence,we found that Xiao Chai Hu Tang formula compared with no intervention may reduce the proportion of participants with detectable HBV-DNA,ALT serum level of participant,AST serum level of participant.We are uncertain whether Xiao Chai Hu Tang formula compared with no intervention has an effect on non-serious adverse events and HBeAg.Because of the high risk bias of the retrieved studies,the proportion of HBV-DNA positive participants,ALT serum level of participant,AST serum level of participant were unvalidated surrogate outcomes,and the certainty of retrieved evidence is very low,the conclusions were not confirmed.2.The evidence for acupuncture therapies for chronic hepatitis B lacks assessment and report of patient-centred outcomes(i.e.all-cause mortality,health-related quality of life,serious adverse events,hepatitis B-related mortality,and hepatitis B-related morbidity).By evaluating low-quality evidence,we found that manual needle acupuncture compared with no intervention may reduce the proportion of participants with detectable HBV-DNA,and manual needle acupuncture,moxibustion,acupoint herbal patching may reduce ALT serum level of participant,AST serum level of participant,and moxibustion may induce the proportion of participants with bloating.We are uncertain whether acupuncture therapies compared with no intervention has an effect on non-serious adverse events and HBeAg.Because of the high risk bias of the retrieved studies,the proportion of HBV-DNA positive participants,ALT serum level of participant,AST serum level of participant were unvalidated surrogate outcomes,the certainty of retrieved evidence is very low,and the limited number of included studies for each analysis,the conclusions was not confirmed.3.The included studies are all assessed as high risk bias,and the quality of the studies is very low.Future studies should define diagnostic criteria of participants and concomitant diseases more strictly and clearly,and should be stratified and randomized for different concomitant diseases.We should design RCT with longer follow-up and patient-centered outcomes(e.g.mortality,serious adverse events,and health-related quality of life).We should conduct more clinical randomized controlled trials to validate the relationship between surrogate outcomesand patient-centered outcomes.For RCT on Xiao Chai Hu Tang formula for chronic hepatitis B: we should carry out more trials for different composition,doses,and different treatment duration of Xiao Chai Hu Tang formula.We should design trials comparing Xiao Chai Hu Tang formula to placebo for chronic hepatitis B.For RCT on acupuncture therapies for chronic hepatitis B: we should carry out more trials on different acupuncture therapies such as laser acupuncture,moxibustion,or the combinaiton of different acupuncture therapies.We should design trials comparing acupuncture therapies to sham acupuncture for chronic hepatitis B.4.We recommend that in clinical practice,before implementing any interventions,to obtain evidence from a high-quality systematic review to minimize errors and to use Trial Sequential Analysis and GRADE to assist to evaluate the quality of evidence body.5.Using the visualised 'three-dimensional evidence matrix' established by our research,we found that clinical evidence of Xiao Chai Hu Tang formula and acupuncture therapies seperately intervening hepatitis B has serious problems in system errors,random errors and design errors.We proposed relevant recommendations for improving the quality of clinical evidence in TCM: we should strictly design,perform,and report important factors of systematic errors(eg,randomized,blinded,randomized allocation,incomplete outcomes,selective reports).We should design adequate sample size and diversity participants to minimise random errors.We should clearly define and report the diagnostic criteria,inclusion criteria,and exclusion criteria of participants.We should design more multi-center clinical trials,superiority studies,and pragmatic studies.For clinical research of TCM therapy,we should clearly define and report the details of individualization and the eligibility criteria for the implemen Ters of medical interventions.6.The ‘Three-dimensional evidence matrix' can be applied to the visualization of evidence quality and evidence evaluation in clinical research of Chinese medicine.Evidence matrix is cosistent with commonly used evidence quality assessments methods(i.e.'Risk of bias tool' and GRADE assessment),and the evidence matrix may work as a good supplement to put enough attention on random errors and design errors. |
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