A peptic ulcer (PU) is a digestive disorder most commonly found in clinical practice. An oriental herbal formula, Xiao Chai Hu Tang (XCHT), has been used to treat PU for an extended period in China. The effectiveness and safety of XCHT in treating peptic ulcers was evaluated using a systematic review of randomized controlled trials (RCTs). Studies were systematically retrieved from CNKI, Embase, Medline, PubMed, SinoMed, VIP, Wanfang, and Web of Science. The following information was extracted from the relevant RCTs: the clinical efficacy rate, recurrence rate, clinical efficacy of traditional Chinese medicine, and the adverse effects. 13 RCTs, including 1334 patients, were included in this review. The meta-analysis showed that treatment with XCHT was superior to conventional pharmacotherapy (CPT) in improving the clinical efficacy rate (RR: 1.20, 95% confidence intervals (CIs): 1.08–1.34,
PU is defined as ulceration inside the gastrointestinal (GI) mucosa, which occurs due to erosion induced by peptic acid. Conversely, gastric ulcer (GU) and duodenal ulcer (DU) [
Furthermore, patients can be affected by several adverse reactions during WM treatment [
TCM interventions, including but not limited to Chinese Herbal Medicine (CHM) and treatments such as acupuncture, are commonly applied in Asia and are gradually being accepted worldwide [
This is the first meta-analysis and systematic review that aims to evaluate the effect of XCHT on clinical efficacy rate, recurrence rate, the clinical efficacy of traditional Chinese medicine, and the adverse effects. Comparison types in RCTs include XCHT alone or XCHT plus WM compared with WM. The patients with PU in the control group are treated with recommended conventional medicine (proton pump inhibitors (PPIs), histamine-2 receptor antagonists (H2RAs), protective agents for gastric mucosa, and drugs targeting
This meta-analysis and systematic review follows the Cochrane Handbook criteria [
This meta-analysis was registered on PROSPERO (CRD42020209106). A comprehensive electronic search was carried out using four Chinese databases and four English databases. The English databases were Cochrane, Embase, PubMed, and Web of Science. The four Chinese databases were the Wanfang Database, SinoMed, the VIP information database, and the Chinese National Knowledge Infrastructure. The included studies were collected by two team members and all were published before September 2020. The following search terms were used: (“Peptic Ulcer” [MeSH Terms] OR “peptic ulcers” [Title/Abstract] OR “ulcer peptic” [Title/Abstract] OR “ulcers peptic” [Title/Abstract] OR “gastroduodenal ulcer” [Title/Abstract] OR “gastroduodenal ulcers” [Title/Abstract] OR “ulcer gastroduodenal” [Title/Abstract] OR “ulcers gastroduodenal” [Title/Abstract] OR “marginal ulcer” [Title/Abstract] OR “marginal ulcers” [Title/Abstract] OR “ulcer marginal” [Title/Abstract] OR “ulcers marginal” [Title/Abstract] OR “PUD” [Title/Abstract] OR “PU” [Title/Abstract] OR “gastric ulcer” [Title/Abstract] OR “duodenal ulcer” [Title/Abstract]) AND (“xiao chaihu tang” [Title/Abstract] OR “xiao chaihu decoction” [Title/Abstract] OR “XCHT” [Title/Abstract] OR “sho saiko to” [Title/Abstract] OR “sho saiko to” [Title/Abstract] OR “sho” [Title/Abstract]) AND (“randomised controlled trial” [Title/Abstract] OR “clinical trial” [Title/Abstract] OR “clinical study” [Title/Abstract]). In addition, to identify other relevant research, a record of reclaimed article references was hand-searched. All included studies were comprehensively read. Each database was searched individually.
All the studies collected by our team members were added to Endnote. After removing duplicate articles, all the candidate articles were screened by two independent investigators (ML and HZ) based on the title and abstract. This review included all RCTs that investigated the outcome of XCHT among patients with PU. Comments, editorials, letters, methodological reports, observational studies, opinion pieces, and traditional literature reviews were excluded.
Adult subjects of any gender or ethnicity with PU were included. Two diagnostic criteria for PU were thoroughly applied for this research (first, the American International Health Alliance’s Protocol for Diagnosis and Treatment of PU in Adults (2002) and second the Guiding Principle of Clinical Research on New Drugs of TCM, issued by the Ministry of Public Health of China, in 1993 and 2002).
Only RCTs that evaluated the utility and reliability of XCHT to treat PU were eligible to be included. All blinded and non-blinded RCTs of both languages were included. Trials with a sample size of less than ten were excluded as well as any duplicated reports.
The patients in the treatment group were mainly treated with XCHT or XCHT combined with WM. The patients were treated with standard WM within the control group. Modified XCHT (MXCHT) prescribed based on syndrome-characterized TCM was acceptable. Practitioners stated that MXCHT merely joined the initial herbs, leading to a similar effect as the original XCHT.
The clinical efficacy rate was defined as the primary clinical endpoint. The total clinical efficacy rate of PU treatment would be calculated as (clinical cure + markedly effective + effective)/total number of participants. The efficacy of RCTs was assessed by Criteria for Diagnosis and Curative Effect of TCM Clinical Diseases [
The secondary results included the number of adverse events, recurrence rate, and clinical effect of TCM symptoms, including vomiting, stomachache, acid reflux, appetite loss, and abdominal distension.
All disagreements on data collection and report choice were explored and resolved through a discussion.
Relevant data from the RCTs was collected by two investigators separately with a data abstracted criteria sheet and then cross-checked. Each study’s information included the baseline equilibrium, blinded experiment, control groups, evaluation indicators, issued year, names of the authors, randomization method, research samples, results, treatment course, type of ulcers, and interventional measures and efficacy follow-up duration. Two investigators (WD and YY) separately rated the included RCTs and collected the data. All disagreements were resolved by a third author (QH).
The overall evidence rank was evaluated based on the measurement of the main results according to the methodological analysis in the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) [
Data from the included studies was summed to generate quantitative summaries using the Cochrane Collaboration Review Manager (RevMan 5.4). The results were gathered using mean differences with 95% CIs. The chi-squared test and the
The industrial classification of qualified research was assessed separately using the Cochrane Collaboration’s tool comprising the following seven domains: Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of the outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Other sources of bias
The following three types of bias risk were used across all domains: unclear risk of bias, low risk of bias, and high risk of bias. Based on the types mentioned above, the quality of each study was classified as follows: fair: low risk for two items; weak: low risk for fewer than two items; good: low risk for more than two items. The final scores were agreed upon by all the authors.
In total, 653 potentially eligible articles were collected, of which 321 duplicates were removed. From the remaining 332 studies assessed in detail, 186 studies were precluded for one or more of the following reasons. Case reports and reviews Summary of clinical classifications Not clinical trials Trials treated with non-drug therapy such as massage, acupuncture, and other non-drug therapy Not relevant to PU
Thus, 133 more studies were precluded by further evaluation due to the following: Not RCTs No relevant interventions No relevant outcome
Eventually, 13 studies [
PRISMA flowchart detailing the data identification, screening, eligibility, and inclusion.
Table
Characteristics of the 13 included RCTs.
ID | Sample size (T/C) | Mean age (years) (T/C) | Diagnostic standards | Type of ulcer (D/G/C) (T/C) | Intervention | Comparison | Course duration (days) | Outcome | Adverse effects |
---|---|---|---|---|---|---|---|---|---|
Li et al. | 112 | T: 42.62 ± 6.71 | The diagnostic methods and criteria for peptic ulcer disease (2010) | T: 30/26/0 | XCHT | Routine treatment | 60 | Clinical efficacy rate, the clinical efficacy of TCM symptoms | T: 3 |
(56/56) | C: 42.59 ± 6.56 | C: 32/24/0 | C: 9 | ||||||
Wang | 60 | T: 42.8 ± 3.7 | Guidance principle of clinical study on new drug of traditional Chinese medicine (1993) and criteria of diagnosis therapeutic effect of diseases and syndromes in traditional Chinese medicine (1994) | T: 11/19/0 | XCHT | Routine treatment | 75 | Clinical efficacy rate, recurrence rate | T: 0 |
(30/30) | C: 42.5 ± 3.4 | C: 10/20/0 | C: 6 | ||||||
Luo | 200 | T: 56.2 ± 3.4 | The practice of internal medicine (unclear) and guidance principle of clinical study on new drug of traditional Chinese medicine (1993) | NR | XCHT | Routine treatment | 28 | Clinical efficacy rate, the clinical efficacy of TCM symptoms | NR |
(100/100) | C: 53 ± 6.4 | ||||||||
Yang et al. | 166 | NR | Internal medicine teaching (unclear) and guidance principle of clinical study on new drug of traditional Chinese medicine (1993) | NR | XCHT | Routine treatment | 75 | Clinical efficacy rate | NR |
(83/83) | |||||||||
Wang | 100 | T: 42.24 ± 7.31 | Internal medicine (unclear) | T: 33/17/0 | XCHT | Routine treatment | 56 | Clinical efficacy rate, recurrence rate, the clinical efficacy of TCM symptoms | NR |
(50/50) | C: 41.86 ± 6.93 | C: 18/32/0 | |||||||
Zhang | 98 | T: 34.13 ± 2.13 | NR | NR | XCHT + routine treatment | Routine treatment | 28 | Clinical efficacy rate | NR |
(49/49) | C: 34.78 ± 2.12 | NR | |||||||
Zeng | 86 | T: 32 ± 2.5 | NR | NR | XCHT + routine treatment | Routine treatment | 30 | Clinical efficacy rate | NR |
(43/43) | C: 33 ± 2.3 | NR | |||||||
Zheng et al. | 68 | T: 37.52 ± 3.25 | Practice of internal medicine (unclear) | NR | XCHT + routine treatment | Routine treatment | 28 | Clinical efficacy rate | T: 5 |
(43/43) | C: 37.05 ± 3.12 | NR | C: 4 | ||||||
Zhang | 94 | T: 55.35 ± 7.24 | Guidance principle of clinical study on new drug of traditional Chinese medicine (2002) and practice of internal medicine (2010) | T: 19/25/3 | XCHT + routine treatment | Routine treatment | 28 | Clinical efficacy rate | NR |
(47/47) | C: 53.13 ± 6.68 | C: 25/15/7 | |||||||
Liu | 120 | T: 36.5 ± 3.9 | Guidance principle of clinical study on new drug of traditional Chinese medicine (2002) and internal medicine (unclear) | T: 19/30/11 | XCHT + routine treatment | Routine treatment | 75 | Clinical efficacy rate, recurrence rate | T: 3 |
(60/60) | C: 44.5 ± 2.6 | C: 21/29/10 | C: 10 | ||||||
Sun | 100 | T: 32 ± 2.5 | Guidance principle of clinical study on new drug of traditional Chinese medicine (1993) and practice of internal medicine (unclear) | T: 18/22/10 | XCHT + routine treatment | Routine treatment | 30 | Clinical efficacy rate, recurrence rate | NR |
(50/50) | C: 33 ± 2.4 | C: 19/23/8 | |||||||
Su et al. | 62 | T: 56.2 ± 5.4 | Guidance principle of clinical study on new drug of traditional Chinese medicine (2002) and practice of internal medicine (2002) | T: 9/20/2 | XCHT + routine treatment | Routine treatment | 28 | Clinical efficacy rate, the clinical efficacy of TCM symptoms | NR |
(31/31) | C: 53.4 ± 6.2 | C: 9/20/2 | |||||||
Ma | 68 | T: 35.2 | Guidance principle of clinical study on new drug of traditional Chinese medicine (2002) and practice of internal medicine (1997) | T: 12/20/6 | XCHT + routine treatment | Routine treatment | 28 | Clinical efficacy rate, recurrence rate | NR |
(36/32) | C: 37.3 | C: 11/17/4 |
T, treatment group; C, control group; XCHT, Xiao Chai Hu Tang; NR, not reported; D, duodenal ulcer; G, gastric ulcer; C, compound ulcer.
The Cochrane Collaboration assessment tool was applied to evaluate the risk of bias of the included studies. The evaluation outcomes were listed in Figures
Risk of bias summary.
Risk of bias graph.
Tables
Assessment of the study quality using GRADE (XCHT plus CPT compared to CPT).
Outcomes | Illustrative comparative risks | Relative effect (95% CI) | No. of participants (studies) | Quality of the evidence (GRADE) | |
---|---|---|---|---|---|
The assumed risk with the comparator | The corresponding risk with intervention | ||||
Clinical efficacy rate | 772 per 1000 | 941 per 1000 (887 to 1000) | RR 1.22 (1.15 to 1.3) | 696 (8 studies) | ⊕⊕⊕⊕ high |
Adverse events | 149 per 1000 | 91 per 1000 (22 to 374) | RR 0.61 (0.15 to 2.51) | 188 (2 studies) | ⊕⊕⊕⊕ high |
Recurrence rate | 303 per 1000 | 88 per 1000 (48 to 157) | RR 0.29 (0.16 to 0.52) | 288 (3 studies) | ⊕⊕⊕⊝ moderate |
∗The control risk is based on the median risk of the control group of each study. The intervention risk (and its 95% CI) is based on the control risk in the control group and the relative effect of the intervention (and its 95% CI).CI: confidence interval, RR: risk ratio. GRADE Working Group grades of evidence: (1) High certainty: we are very confident that the true effect lies close to that of the estimate of the effect; (2) Moderate certainty: we are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different; (3) Low certainty: our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect; (4) Very low certainty: we have very little confidence in the effect estimate ⊕⊕⊕⊕represents high-quality evidence; ⊕⊕⊕⊖represents moderate-quality evidence.
Assessment of the study quality using GRADE (XCHT compared to CPT).
Outcomes | Illustrative comparative risks | Relative effect (95% CI) | No of participants (studies) | Quality of the evidence (GRADE) | |
---|---|---|---|---|---|
The assumed risk with the comparator | The corresponding risk with intervention | ||||
Total effective rate | 781 per 1000 | 937 per 1000 (843 to 1000) | RR 1.2 (1.08 to 1.34) | 638 (5 studies) | ⊕⊕⊕⊕ high |
Adverse events | 150 per 1000 | 68 per 1000 (11 to 465) | RR 0.45 (0.07 to 3.1) | 160 (2 studies) | ⊕⊕⊕⊝ moderate |
Recurrence rate | 174 per 1000 | 40 per 1000 (12 to 120) | RR 0.23 (0.07 to 0.69) | 172 (2 studies) | ⊕⊕⊕⊕ high |
Vomiting | 245 per 1000 | 81 per 1000 (47 to 135) | RR 0.33 (0.19 to 0.55) | 400 (3 studies) | ⊕⊕⊝⊝ low |
Stomachache | 165 per 1000 | 59 per 1000 (31 to 112) | RR 0.36 (0.19 to 0.68) | 400 (3 studies) | ⊕⊕⊝⊝ low |
Acid reflux | 165 per 1000 | 125 per 1000 (78 to 203) | RR 0.76 (0.47 to 1.23) | 400 (3 studies) | ⊕⊕⊝⊝ low |
Abdominal distension | 205 per 1000 | 125 per 1000 (80 to 197) | RR 0.61 (0.39 to 0.96) | 400 (3 studies) | ⊕⊕⊝⊝ low |
Appetite loss | 200 per 1000 | 60 per 1000 (30 to 122) | RR 0.3 (0.15 to 0.61) | 300 (2 studies) | ⊕⊕⊝⊝ low |
∗The control risk is based on the median risk of the control group of each study. The intervention risk (and its 95% CI) is based on the control risk in the control group and the relative effect of the intervention (and its 95% CI).CI: confidence interval, RR: risk ratio. GRADE Working Group grades of evidence: (1) High certainty: we are very confident that the true effect lies close to that of the estimate of the effect; (2) Moderate certainty: we are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different; (3) Low certainty: our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect; (4) Very low certainty: we have very little confidence in the effect estimate. ⊕⊕⊕⊕ represents high-quality evidence; ⊕⊕⊕⊝ represents moderate-quality evidence; ⊕⊕⊖⊖ represents low-quality evidence.
A sensitivity analysis of the evaluation indicators (clinical efficacy rate, recurrence rate, and adverse events) that were heterogeneous among the studies was conducted after excluding studies one by one to verify the stability of the analysis results. The sensitivity analysis results of the clinical efficacy rate, recurrence rate, and adverse events did not detect significant differences, indicating that the analysis results were stable.
13 studies reported the clinical efficacy rate. The clinical efficacy rate was compared between those receiving XCHT and routine treatment in 5 studies [
Meta-analysis of the clinical efficacy rate of (a) XCHT and (b) XCHT + CPT.
The clinical efficacy rate was compared between those receiving XCHT plus CPT and CPT alone in 8 studies [
Comparing the recurrence rate between patients who received XCHT treatment and CPT was conducted on 160 subjects in 2 RCTs [
Meta-analysis of the recurrence rate of (a) XCHT and (b) XCHT + CPT.
Three studies [
3 trials [
Meta-analysis on the clinical efficacy of TCM symptoms. (a–e) show the comparisons and meta-analysis results on the clinical efficacy of TCM symptoms between the XCHT and CPT groups. (a) Poor appetite. (b) Distention. (c) Vomit. (d) Stomach pain. (e) Acid reflux.
Among the 13 studies, 4 studies [
Meta-analysis on adverse events of (a) XCHT and (b) XCHT + CPT.
However, the other 2 trial results [
Based on the Cochrane guidelines, publication bias was not fulfilled as the number of RCTs for meta-analysis purposes of every major result measure was no more than nine.
PU is related to diet, stress, and a hypersecretory acid environment. However, the epidemiology of PU is changing due to alcohol and smoking abuse, Hp contamination, and widespread application of non-steroidal anti-inflammatory drugs (NSAIDs). A small number of patients with Hp inflammation or those on aspirin or NSAIDs develop PU, suggesting that the specific sensitivity of drug toxicity and bacterial harm are significant to start mucosal damage [
WM has been predominately used to treat GU, but the drugs available are limited in their efficacy. For instance, proton pump inhibitors are considered efficient drugs for PU treatment [
13 RCTs of 1334 patients with PU, including GU and DU, were collected for analysis. Our study’s main finding is that XCHT therapy is superior to CPT, with a better clinical efficacy rate and fewer side effects. Similarly, XCHT therapy was excellent to CPT except in terms of acid reflux. XCHT could reduce PU symptoms in patients much more effectively. As an alternative medicine, XCHT appeared to be associated with an improved clinical efficacy rate and fewer adverse events. The included studies showed that XCHT combined with CPT seemed to be more effective at reducing the recurrence rate than CPT alone. Additionally, XCHT is safe to apply and is generally well-tolerated by patients. Therefore, XCHT could successfully treat patients with PU, improve the healing of the ulcer, and reduce the recurrence rate.
To the best of our knowledge, the present systematic review and meta-analysis is the first to assess the effects of XCHT on PU and provide a thorough synthesis of results from RCTs. However, the present study has some limitations. First, every trial selected was performed in Asia, which limits diversity and inclusion. Further research with multi-center RCTs of XCHT for PU is needed to expand the research worldwide. Second, some of the included RCTs were of low methodological quality. None of the RCTs detailed the proper distribution occultation clearly, which can cause selection bias.
Moreover, a lack of double-blinding of participants and personnel can result in detection and performance biases. However, it can be challenging to the blind in XCHT RCTs, as the smell, taste, and color of XCHT are apparent. A placebo with no medical reaction can imitate XCHT, which is not beneficial for improving the rationality or benefit of medical proof and lowering selective reporting bias. Third, the clinical efficacy rate, including clinical cure, markedly effective, effective, and noneffective, is generally considered result measurements. However, based on the clinical symptoms, the clinical efficacy rate assessment may be vague and subjective, limiting its usefulness. Finally, latent clinical heterogeneity can be caused by different XCHT medications being used and different doses.
XCHT treatment for patients with PU appears to be safe and efficacious. The essential pathogenic factors of PU include both excess and deficiency syndrome based on TCM theory. The actual pathological factors mainly include (i) Qi stagnation, (ii) cold coagulation, (iii) food accumulation, (iv) amp heat, and (v) blood stasis. The main pathological factors of deficiency are (i) Qi (yang) deficiency and (ii) Yin deficiency [
Moreover, PU is located in the stomach, closely related to the liver and spleen [
Sufficient patients should be included in future clinical trials with blinded, statistical, and proper randomization methods applied. Based on the limitations mentioned above, the latest international guidelines and a consistent, standard diagnosis method should be used to select patients in future RCTs.
The inclusion and exclusion criteria should be explicitly stated. Age groups should be clearly defined. A description of the outcome and baseline data for the control and treatment groups must be displayed. The adoption and application of efficacy rate scales should be in agreement with the latest updated global guidelines for future statistical investigation. Patients should undergo long-term follow-up to observe any potential adverse reactions. Medical research needs to be registered in advance and provide the trial date at the end of the experiment.
Modern medical research on PU treated with XCHT has progressed considerably. In modern pharmacology, it is well acknowledged that GU is caused by attack and defense factors of unbalanced mucosa [
This meta-analysis and systematic review supports the use of XCHT for PU as part of an alternative medicine approach to a certain extent. However, due to clinical heterogeneity, the results of this review should be treated cautiously. Furthermore, RCTs of specific XCHT, supervised with quality control for PU patients, are progressing.
Any data that were analyzed and extracted or supporting information is included in this manuscript. Detailed datasets or any other information are available on reasonable request from the corresponding author.
The authors declare that there are no conflicts of interest regarding the publication of this paper.
This work was supported by the Beijing-Tianjin-Hebei Basic Research Cooperation Project (No. J200020).