Overview of systematic evaluation of efficacy of Tongxie Yaofang in treating diarrhea-predominant irritable bowel syndrome

Introduction

Diarrhea-predominant irritable bowel syndrome (IBS-D) is a functional gastrointestinal disease characterized by abdominal pain, diarrhea, and relief of abdominal pain after defecation. It is the most common type of IBS, accounting for about 40–65% of IBS patients (1,2). At present, the pathogenesis of IBS-D is unclear, with Western medicine compartmentalizing the treatment of diarrhea, spasmolysis, and pain, regulation of intestinal flora, or addressing anxiety and depression; however, it lacks specific drugs for the treatment of IBS-D (3). Although there is no record of IBS-D in traditional Chinese medicine (TCM), it can be classified as “diarrhea” and “abdominal pain” according to its symptoms (4). There is a cloud in the “Medical Prescription Examination”: “The spleen of diarrhea, the liver of pain, the reality of liver responsibility, and the deficiency of spleen responsibility; Spleen deficiency is solid, so it causes pain and diarrhea”. Therefore, IBS-D is often treated with modified Tongxie Yaofang (TXYF), which soothes the liver and strengthens the spleen. Formerly known as Baizhu Shaoyao Powder, TXYF was derived from the Liu Caochuang prescription in the text Jing Yue Quan Shu, which was called “Tongxie Yaofang” by the herbalist Zhang Jingyue, and it has retained this name to date. Due to its wide clinical application, the number of clinical studies on TXYF is increasing, with several systematic evaluations already having been published. Results have shown that TXYF has significant efficacy and safety in treating IBS-D. However, systematic evaluation is commonly problematic, including research program design defects, incomplete retrieval, publication bias, low evidence of outcome evaluation indicators, and so on, which can not provide a good reference for clinical practice. Systematic evaluation and re-evaluation can provide more integrated and reliable documentation for those looking for quality evidence (5). However, systematic evaluation and re-evaluation of TXYF in treating IBS-D has not yet been performed. With this in mind, this study aimed to evaluate the quality of methodology and grade the evidence of outcome indicators for the related systematic evaluation of TXYF in treating IBS-D in order to provide more and more reliable evidence base for the clinical application of TXYF.

We present the following article in accordance with the PRISMA reporting checklist (available at https://dx.doi.org/10.21037/apm-21-1612).

Methods

Eligibility criteria

The inclusion criteria were as follows: (I) type of research: Chinese and English language meta-analysis or systematic evaluation based on randomized controlled trial (RCT) or quasi-RCT; (II) research subject: published systematic evaluation or meta-analysis on the efficacy and safety of TXYF in the treatment of IBS-D; (III) type of intervention: experimental group was treated with TXYF alone or in combination or with TXYF as the basic prescription, control group was given routine Western medicine, blank control, or placebo; (IV) type of outcome measures: the main outcome indicators were total effective rate, cure rate, recurrence rate, adverse reactions, and various symptom indicators.

The exclusion criteria were as follows: (I) duplicate literature; (II) conference papers, letters, and so on; (III) control group received treatment containing TXYF; (IV) documents with incomplete data, obvious errors, or there was inability to obtain data to be extracted.

Search strategy

The databases of Web of Science (SCI), PubMed, Embase, Cochrane Library, Chinese Biomedical Literature (CBM), Chinese National Knowledge Infrastructure (CNKI), VIP, Wanfang, and others, were searched online by 2 researchers in order to collect relevant systematic reviews of TXYF in treating IBS-D. The main search methods were combination of subject words and free words. The Chinese search words were Tongxie Yaofang, diarrhea irritable bowel syndrome, irritable bowel syndrome, systematic review, and meta-analysis. English search terms included Tongxieyaofang, Tong Xie Yao Fang, Tongxie Yaofang, TXYF, diarrhea preponderant irritable bowel syndrome, irritable bowel syndrome, IBS-D, systematic review, and meta-analysis. The search deadline was January 2021.

Selection process

Firstly, the 2 researchers collected articles according to their titles and abstracts, and then obtained the full text to ensure consistency with the literature. They then imported them into NoteExpress (Aegean Software, Beijing, China) to eliminate duplicate literature according to the inclusion and exclusion criteria. Studies that met the inclusion criteria were selected and cross-checked. Next, the 2 researchers extracted and collated information included in the literature, and cross-checked them again. Any disagreements between the investigators were resolved through consultation with a third researcher.

Quality evaluation

Methodological quality evaluation

The 2 researchers applied the A MeaSurement Tool to Assess systematic Reviews-2 (AMSTAR-2) scale (6-8) to evaluate the methodological quality of the included studies. The AMSTAR-2 scale has a total of 16 items (the key items are 2, 4, 7, 9, 11, 13, and 15), which can be divided into “yes”, “partial yes”, and “no” according to the degree of satisfaction of evaluation criteria, and the methodological quality of systematic evaluation can be divided into high quality (none or only 1 non-critical item does not conform) and medium quality (more than 1 non-critical item does not conform), low quality (1 key item does not conform), and extremely low quality (more than 1 key item do not conform).

Evaluation of evidence quality

The 2 researchers used the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) scale (9,10) to grade the evidence quality of the outcome indicators included in the literature, and divided the evidence quality of systematic evaluation into 4 grades: high, medium, low, and extremely low.

Results

Description of the screening process

A total of 56 Chinese documents, 17 English documents, and 39 Chinese documents were obtained through the preliminary search. A total of 10 documents were finally included after removal of duplicates and exclusion of documents that did not meet the inclusion criteria (11-20). The document retrieval process is shown in Figure 1.

Figure 1 PRISMA 2009 flow diagram.

Study characteristics

All 10 of the included systematic reviews evaluated the methodology of the original studies, among which 6 documents were evaluated by the risk of bias (RoB) tool recommended by the Cochrane Collaboration, 2 were evaluated by Jadad scale, 1 was evaluated by both Cochrane RoB and Jadad scale, and 1 was evaluated by the literature quality evaluation standard issued by the National Health Service (NHS). A total of 3 papers were funded by the National Natural Science Foundation of China, and the basic characteristics of the included studies are shown in Table 1.

Table 1 Basic characteristic of included studies
Full table

Methodological quality evaluation

The AMSTAR-2 scale was used to evaluate the methodological quality of the included studies. The results showed that there were 5 items reported completely, which were item 1 (100%), item 3 (100%), item 11 (100%), item 13 (100%), and item 14 (100%). There were 5 items, namely, item 2 (10%), item 7 (0), item 10 (0), item 12 (0), and item 16 (2%), which were less completely reported, among which item 7 was the key item. The overall methodological quality included in the study was low, and the methodological quality evaluation was high and medium, with 0 systematic evaluations, 1 low (12), and 9 extremely low (11,13-20). A total of 10 papers did not mention the formulation of research scheme, 1 (12) paper was registered in PROSPERO (CRD42018105307), and the other nine papers did not mention a search test registry. There were 5 (11,14,18-20) documents that did not provide screening flow charts, 1 (17) document did not explain the reasons for excluding articles after reading of the full text, 10 documents did not provide a list of excluded documents, 1 (18) document did not provide a list of included research characteristics, and 3 (12,13,16) documents did not assess the bias of the original research. None of the 10 papers reported the source of funding for the included studies. Eight papers (11,14-20) did not describe whether there was a conflict of interest. See Table 2.

Table 2 Methodological quality evaluation of AMSTAR-2
Full table

Evaluation of evidence quality

The quality of outcome indicators of the 10 included studies was evaluated by the GRADE system. In terms of total effective rate, 3 studies (12,17,19) were of low quality, and the rest were of extremely low quality. Another study (14) showed that the effective rate, ineffective rate, and recurrence rate were of low quality, and other indexes were of extremely low quality. All outcome indicators were degraded in the quality of included research methodology, and other degradation factors, such as inconsistency, inaccuracy, and publication bias, also had a great impact on the quality of research evidence. The GRADE quality grade evaluation is shown in Table 3.

Table 3 GRADE grading
Full table

Efficacy evaluation

A summary report of quantitative analysis results of 10 systematic evaluations is displayed in Table 4. Only 1 article (12) reported the incidence of adverse reactions, which was significantly lower than that of the control group (P=0.03).

Table 4 Efficacy results included in the systematic reviews
Full table

Discussion

The etiology and pathogenesis of IBS have not been fully elucidated. Most academics (21-23) believe that the pathogenesis of IBS is mainly related to psychosocial factors, abnormal gastrointestinal motility, abnormal brain-intestinal axis function, visceral hypersensitivity, intestinal infection and inflammation, and destruction of intestinal mucosal barrier function. As IBS patients often display emotional disorders such as tension, anxiety, depression, and so on, the influence of psychological and mental disturbance on intestinal motor function and visceral sensitivity has been supported, upholding the modern medical belief that IBS-D is a psychosomatic disease (24). In TCM, it is held that the liver governs emotion, so IBS-D is closely related to liver. Dysfunction of liver-qi or stagnation of liver-qi, insult to the spleen, impaired temper, and disordered transportation and transformation result in abdominal pain and diarrhea. Therefore, liver stagnation and spleen deficiency is a common syndrome type of IBS-D, and TXYF is a common basic prescription for treating IBS-D. The TXYF prescription should be composed of Atractylodes macrocephala Koidz, Paeonia lactiflora Pall., Pericarpium Citri Reticulatae, and Saposhnikovia divaricate. Among the ingredients, Atractylodes macrocephala Koidz strengthens the spleen by taking advantage of imperial wood, and dries up dampness to stop diarrhea, white peony nourishes the blood and softens the liver, and relieves pain as a minister's medicine (the monarch and the minister match each other, which can “shed wood in the soil”). Dampness is easily generated in te presence of spleen deficiency, so it is an adjuvant medicine to use dried tangerine peel to regulate qi and dryness, invigorate the spleen and stomach; with the small amount of Saposhnikovia divaricata, one function is Xin San to regulate the liver, so that the liver qi can no longer invade the spleen; the second is to soothe the clear the spleen, and to overcome dampness and stop diarrhea. Saposhnikovia divaricata is also a medicine for inducing the spleen meridian and an assistant. The combination of the 4 drugs can tonify the spleen and overcome dampness to stop diarrhea, soften the liver and regulate qi to relieve pain, make the spleen nourish the liver, and stop pain and diarrhea. Compared with western medicine, TXYF is more suitable for the treatment of irritable bowel syndrome with complex pathogenesis (25). All 10 of the literatures included in this study showed that TXYF is effective in treating D-IBS with low recurrence rate and few adverse reactions. Clinical and animal experiments also show that Tongxie yaofang can regulate the intestinal movement of IBS (26-27), regulate brain gut interaction (28), reduce inflammatory reaction (29), regulate intestinal flora (30), regulate metabolism (31), and protect intestinal mucosal barrier function (32). However, Tongxie Yaofang also has some limitations, such as bad taste and inconvenient decoction.

This study evaluated the methodological and evidence quality of each systematic evaluation, summarized the efficacy and safety of TXYF in treating IBS-D, and provided an evidence-based medicine reference for its clinical application. However, from the results of AMSTAR-2 scale evaluation, there were some methodological deficiencies remained in the 10 systematic evaluations included in this study. As only 1 study was registered on the relevant platform, its transparency and credibility are not high; the literature search and screening was not satisfactorily comprehensive, which was limited to published literature, so there was serious publication bias, and the influence of individual research bias risk on meta-analysis results was not evaluated. The general information included in the literature was unknown, such as the research subject, research location, usage and dosage of control drugs, and so on. All studies did not provide a list of excluded literatures and none of the published literatures in China detailed their conflicts of interest. There were also many problems in the evaluation of GRADE’s evidence quality: for example, there was a great bias in randomization, distribution concealment, and blind method of clinical trials; less research was included; asymmetry of funnel diagram; literature without negative results, and so on. Therefore, the evidence quality of outcome indicators of TXYF in treating IBS-D is low, and its credibility is doubtful.

Conclusions

From the 10 studies included in this research, TXYF can improve the total clinical effective rate, improve abdominal pain, diarrhea and other symptoms, and does not increase adverse reactions. However, due to the low quality of research methodology and evidence, the reliability of research results is not strong. Therefore, it is necessary for clinicians to design more rigorous and high-quality RCT, and concurrently, it is necessary to improve the systematic evaluation methodology and the quality evaluation level of outcome evidence, so as to provide more reliable evidence-based medicine substantiation.

Acknowledgments

Funding: This project was supported by the Key Projects of Jiangsu Province Science and Technology Development Plan of Traditional Chinese Medicine, China (ZD201911).

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://dx.doi.org/10.21037/apm-21-1612

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/apm-21-1612). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: J. Jones)