Evidence-based Evaluation Of The Efficacy Of Tongxie Yaofang In The Treatment Of Diarrhea-predominant Irritable Bowel Syndrome And Exploration Of Influencing Factor

BackgroundDiarrhea-predominant Irritable Bowel Syndrome(IBS-D)is a prevalent,chronic,and refractory functional gastrointestinal disease characterized by recurrent abdominal pain,diarrhea,and increased stool frequency.It significantly impacts patients’ academic,occupational,and social activities while reducing their quality of life.Furthermore,it adversely affects patients’ mental health and imposes economic and medical burdens on them as well as their families and society at large.The pathogenesis of this disease remains incompletely elucidated,albeit closely linked to brain-gut axis dysfunction,leading some studies to classify it as a psychosomatic disorder.While drugs recommended by current guidelines may offer partial efficacy,they fail to address all clinical challenges associated with IBS-D.Tongxie Yaofang(TXYF)is a classical formula with a long history of use in traditional Chinese medicine,and it remains a common prescription for IBS-D in modern clinical practice.Although previous studies have initially validated the efficacy of TXYF in treating IBS-D,conflicting results and common issues such as short treatment periods and poor study designs have caused confusion for clinical practitioners,guideline/consensus makers,public health policymakers,and others who use relevant evidence.Furthermore,no further studies have investigated the factors that influence the efficacy of TXYF for IBS-D.Exploring these influencing factors is crucial in improving clinical diagnosis and treatment programs as well as designing related experimental research to enhance the clinical efficacy of IBS-D and improve the quality and value of research.ObjectiveTo systematically and comprehensively evaluate the efficacy of TXYF in the treatment of IBS-D and influencing factors of efficacy based on evidence-based medical research methods,and further to provide high-level and high-quality evidence for the application of TXYF treating IBS-D in clinical practice.MethodsStudy 1:Systematic review and meta-analysis of Chinese herbal formula TXYF for IBS-DPubMed,Embase,Web of Science,SinoMed,the Cochrane Library,CNKI,VIP and Wanfang Database were searched from their inception to 25 December 2021 for randomized controlled trials(RCTs)comparing TXYF with placebo,Western medications or no treatment for IBS-D.The primary outcome was the global improvement of IBS-D symptoms.Outcomes were analyzed using Revman 5.4 software to derive the risk ratio(RR)and its 95%confidence interval(95%CI),or mean difference(MD)and its 95%CI.For dichotomous outcomes,the incidence of events in each group and the Number Needed to Treat(NNT)were also calculated.Evidence certainty of the primary outcome was assessed by using the Grading of Recommendations Assessment,Development and Evaluation criteria(GRADE).Study 2:Chinese herbal formula TXYF granules for IBS-D:a randomized,multi-blind,placebo-controlled trialA randomized,multi-blind,placebo-controlled trial was conducted at the outpatient of Fangshan Hospital,Beijing University of Chinese Medicine,China.Participants were randomized in a 1:1 ratio to receive TXYF granules in one bag(3.7 g/bag)twice daily(orally before meals)or matched placebo granules through 8 weeks,followed by a 3-month follow-up.The primary outcome was the response rate of global symptom severity remission in IBS-D at week 8 of treatment(determined by changes in disease severity level based on the IBS Severity Scoring System(IBS-SSS)score).The trial was approved by the Medical Ethics Committee(ref:FZY LK-2021-002).The trial’s protocol has been registered in the UK’s ISRCTN registry(ref:ISRCTN12453166).Study 3:The factors influencing the efficacy of TXYF for the treatment of IBS-D:an interview studyUsing maximum variation purposive sampling following the principle of information saturation,interviewees were selected from the patients participating in the RCT(Study 2)for one-on-one semi-structured in-depth interviews,which were audio-recorded and transcribed in text.Based on the grounded theory,the transcriptional data were analyzed inductively using a six-step thematic analysis using NVIVO 12.0 software to derive possible factors influencing the clinical efficacy of IBS-D.The interview was conducted in strict compliance with the ethical requirements of the Declaration of Helsinki and received ethical approval(ref:FZY LK-2021-002).Study 4:Exploratory study of the correlation between treatment expectations and IBS-D outcomesThe Stanford Expectations of Treatment Scale(SETS)was translated to develop the Chinese SETS(C-SETS)through direct translation and back-translation.The feasibility,validity and reliability of the C-SETS were examined based on the C-SETS scores assessed by the patients in Study 2.Logistic regression and linear regression were conducted to assess the correlation between treatment expectations and IBS-D outcomes when the C-SETS demonstrated adequate feasibility and reliability.ResultsStudy 1:Systematic review and meta-analysis of Chinese herbal formula TXYF for IBS-DEleven RCTs involving 985 participants with IBS-D were included.For global improvement of symptoms,TXYF was superior to Western medication(83.41%vs.72.25%,RR=1.12,95%CI[1.12,1.22],NNT=9,10 RCTs,moderate certainty of evidence)and placebo(57.5%vs.37.5%,RR=1.53,95%CI[1.09,2.16],NNT=5,1 RCT,moderate certainty of evidence).The results of subgroup analysis for this outcome showed that TXYF was superior and statistically different than Western medication for IBS-D patients with liver depression and spleen deficiency(80.68%vs.67.74%,RR=1.17,95%CI[1.07,1.29],NNT=8,8 RCTs).Regarding the improvement of stool consistency,reduction of stool frequency and abdominal pain,TXYF was significantly more effective than the placebo.In addition,TXYF was superior to Western medication in improving the quality of life and relieving anxiety.Six trials reported adverse events:five of them reported no adverse events occurred in either group,and one trial reported that 3 cases with adverse events(constipation,elevation in liver-enzyme,nausea)occurred in the TXYF group and 3 cases with adverse events(abdominal distension,nausea)occurred in the placebo group.Study 2:Chinese herbal formula TXYF granules for IBS-D:a randomized,multi-blind,placebo-controlled trialThe TXYF group and the placebo group comprised 48 patients,respectively.Although the response rate was not significantly different at week 8 between the two groups(RR=1.12,95%CI 0.89 to 1.41,P=0.348;intention-to-treat analysis),each group had a high response rate where the TXYF group had a little bit higher[79.2%(38/48)vs.70.8%(34/48)].There were no statistically significant differences between the two groups on secondary endpoints(stool frequency,stool consistency,quality of life,anxiety and depression).The number of adverse events in the TXYF and placebo groups was 1(sinus arrhythmia)and 2(elevated transaminases,weakly positive faecal occult blood),respectively.No serious adverse events occurred in either group.Study 3:The factors influencing the efficacy of TXYF for the treatment of IBS-D:an interview studyTwenty-three patients with IBS-D were involved in this interview with the time ranging from 8 to 43 min.After analyzing the interview data,211 original codes were obtained,which could be categorized into 15 sub-themes and further categorized into 5 themes:disease factors,patient factors,physician factors,medication factors,and environmental factors.Among them,disease factors involve the nature,severity and duration of the disease;patient factors can be divided into psychosomatic factors that include physical quality and mental psychology,and behavioral factors including diet,lifestyle habits and medication compliance;physician factors include physician experience and doctor-patient communication;drug factors include drug quality,taste,dosage form and dosage;and environmental factors are mainly reflected in climate.Study 4:Exploratory study of the correlation between treatment expectations and IB S-D outcomesThe C-SETS had strong feasibility,reliability(Cronbach’s α=0.845 or 0.854)and validity(both structural and content validity).The results of the correlation analysis between treatment expectations and IBS-D outcomes suggested that the correlation coefficients were not statistically significant,except for the statistically significant correlation between positive treatment expectancy and quality of life scores(|b|=10.610～14.580,P<0.05),SAS scores(|b|=1.625,P<0.05)and SDS scores(|b|=1.435～2.050,P<0.05)at the end of 8 weeks treatment.ConclusionA combination of quantitative and qualitative methods was employed to systematically and comprehensively evaluate the efficacy of TXYF for IBS-D,as well as the influencing factors of efficacy.The results suggest that compared with the placebo,both TXYF and placebo can achieve a certain therapeutic effects in treating IBS-D,including alleviating the overall severity of IBS-D symptoms,improving stool consistency,reducing stool frequency,relieving abdominal pain,improving the quality of life of patients,and reducing the tendency/degree of anxiety and depression.The use of TXYF is relatively safe throughout the study.Meanwhile,the RCT results also showed that there was no statistical difference between the efficacy of TXYF and placebo for IBS-D.As the positive treatment expectancy is correlated with the quality of life in IBS-D patients,the results suggested that the placebo effect may play an important role in the treatment of IBS-D,and the specific effect of TXYF is not significant.In addition,the efficacy of IBS-D may be influenced by numerous other complex factors from the disease,the patient,the physician,the drug,and the environment,which partly explains the necessity of IBS-D requires comprehensive treatment to improve clinical efficacy.