Efficacy and safety of Banxia Xiexin Decoction in the treatment of gastric ulcer ： a systematic review and meta-analysis of twenty-seven randomized controlled trials

Background: Banxia XieXin Decoction (BXD) is a traditional Chinese medicine decoction commonly used in the Chinese clinical treatment of gastric ulcer (GU). Although some people believe that it may have some advantages in this regard,There is no reliable evidence-based study demonstrating its effectiveness. This study aims to systematically evaluate the healing effect and security of BXD in the treatment of GU. Methods: PubMed, Cochrane Library, EMBASE, ScienceNet, China National Knowledge Infrastructure (CNKI), Wanfang database, Weipu database, and China biomedical literature service (CBM) database were systematically searched to obtain all randomized controlled trials (RCTs) evaluating the treatment GU of BXD published as of April 2022. Two researchers independently screened and extracted all research data, finally evaluated the bias risk of inclusion in the study using revman 5.4. Results: This meta-analysis included 27 randomized controlled trials and 1411 patients. The clinical effective rate, recurrence rate, HP eradication rate, adverse reaction rate, and visual analog score (VAS) of BXD combined treatment and standard treatment alone were compared. The results of the meta-analysis showed that BXD combined treatment improve the symptoms related to the gastric ulcers and reduce drug-related adverse reactions. Due to the low quality of the research included in this analysis, in-depth high-quality research is crucial for verifying these results.


Introduction
Gastric ulcer (GU) is one of the peptic ulcer (PU), which is closely related to the pathophysiological imbalance of gastric mucosa, chemical and psychological factors [1]. Ulcers mostly occur between the cardia and pylorus, and the depth of the lesions is more than the mucosal muscle layer. They often develop chronically and have a lingering course [2].
It has been reported that about 5%-10% of the global populations have suffered from GU in their lifetime [3]. Although the overall incidence rate is positively correlated with age, also gradually younger. An epidemiological survey in China shows that Helicobacter pylori infection and drug damage caused by long-term use of NSAIDs are the main factors inducing GU, of which the positive rate of GU complicated with HP is as high as 70% [4][5].
There are many kinds of drugs for the treatment of GU, mainly including reducing damage and enhancing protection [6]. In clinical practice, to avoid excessive, frequent, and unreasonable use of a single drug to make HP produce drug resistance and form "super bacteria" antibiotics are usually combined with other drugs to reduce liver and kidney damage and prevent the efficacy of antibiotics from being damaged by strong gastric acid [7]. For example, triple therapy and quadruple therapy in the treatment of HP are PPI drugs, gastric mucosal protective agents and antibiotics [8]. Although western medicine can alleviate symptoms in a timely manner, it has certain side effects, and with the prolongation of medication time, the effect becomes increasingly unsatisfactory [9].
In traditional Chinese medicine theory, the pathogenesis of GU is mainly a perennial high-fat diet or out-of-control diet, liver and spleen dysfunction, resulting in excessive pressure on the spleen and stomach [10]. Ban Xia Xie Xin Decoction(BXD)is a famous prescription for treating gastrointestinal diseases in China for thousands of years. It is composed of Ban Xia(Pinellia ternata), Huang Lian(Coptis chinensis ), Huang Qin(Scutellaria baicalensis), and Gan Jiang(dried ginger ), Gan Cao(licorice), Hong Zao(red jujube), and Ren Shen(ginseng ) [11].
BXD is widely used in GU diseases and effectively improves gastrointestinal mucosa. Some recent Clinical investigations have evaluated the potency of BXD in the treatment of GU [12]. A number of Randomized controlled trial (RCTs) found that BXD was surpassed the control treatment in improving the efficacy, relieving pain, combating helicobacter pylori (HP) and reducing the rate of Adverse drug reaction [13].
Up till the present moment, Although BXD has loads of clinical tests in the treatment of GU, there are many intervention forms and uneven literature quality, which hinders the clinical promotion of BXD in the treatment of GU to a certain extent. Therefore, this study collects the clinical tests of BXD in the remedy of GU for meta-analysis, compares the efficacy and safety of BXD in the remedy of GU, and provides a reliable evidential on fundamentals of clinical application of BXD in the remedy of GU patients.

Methods
This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) [14] and registered with PROSPERO (registration number CRD42022324263).

Search Strategy
Search each database according to the formulated search words, including PubMed, the Cochrane Library, EMBASE, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang database, Vip database, and China Biomedical Documentation Service System (CBM) databases. The search time limit is from the establishment of the database to April 1, 2022. The following keywords were searched: "Stomach Ulcer" OR "gastric ulcer" OR "Stomach Ulcers" OR "Gastrohelcosis" OR "Peptic Ulcer" AND "Banxia Xiexin Decoction" OR "Banxia Xiexin" OR "acrid opening and bitter down bearing".

Study Selection
Inclusion Criteria. Study type: RCTs to explore the application of BXD for the remedy of GU.
Diagnostic principles: standard remedy standard: confirmed by X-ray and gastroscopy, it meets the diagnostic criteria of gastric ulcer in "practical internal medicine" and "Chinese disease diagnostic efficacy standard" [15]; TCM standard: it meets the diagnostic standard of gastric ulcer of "consensus opinion of TCM diagnosis and remedy experts of peptic ulcer" [16] and "New Chinese Medicine Clinical Research Guidance Manual" [17].
Intervention measures: The patients in the experimental group used BXD combined with standard remedy, while the patients in the control group only used the same standard remedy as the experimental group. Among them, Standard treatment includes classic two combinations, three combinations, and four combination therapy.
Outcome indicators: Main achievement indicators of this research include: Clinical effective rate. Secondary outcome indicators included: recurrence rate, eradication rate of Helicobacter pylori, adverse reaction rates, symptom score, visual analog score(VAS).
Recurrence rate: After 6 months of remedy, follow-up visits will be conducted to determine if the patient's condition has recurred.
Hp eradication rate: Urea breath test was performed on all subjects before and after treatment to detect Hp. A positive result indicates ineffectiveness, while a negative result indicates eradication.
Adverse reaction rates: Observe the condition of two groups of patients during the medication period, If patients experience symptoms such as abdominal pain, vomiting and headache, they are considered to have adverse reactions. Exclusion Criteria. (1) Repeated studies were excluded, and the only complete and high-quality study was included in the summary analysis.
(2) Excluded studies with imperfect or obvious mistakes in data that cannot be corrected by contacting the corresponding author.
(3) Research that did not report observational indicators was excluded.
(4) In addition to BXD, the experimental group also used other traditional Chinese medicine formulas.
(5) The control group did not receive classical standard remedy. (6) Both the remedy group and the control group used other TCM treatment techniques (such as acupuncture and moxibustion and massage) in the treatment process.

Data Collection and Assessment
Two researchers independently screened for the above inclusion and exclusion criteria. If disagreements were encountered, they were resolved by discussion and consultation with a third researcher. Data extracted from the included studies included: (I) basic information, including title, first author, year of publication, number of patients per group, and baseline patient characteristics; The intervention measures and remedy process of the treatment group and the control group; (III) indicators of achievement; (IV) elements necessary for risk assessment of bias.

Quality Appraisal
Two researchers independently quantified the risk of bias of the included studies. If there was a disagreement, it was resolved through discussion with a third researcher. The risk of bias was measured using the RCT risk of bias assessment tool in Cochrane Handbook 5.1.0. [18].

Statistical Analysis
Using revman 5.4 software for meta-analysis. The risk ratio (RR) is used as the effective index for classified data and the weighted mean difference (WMD) is used as the effective index for measurement data. The point estimates and 95% confidence intervals of each effect quantity are given. The heterogeneity among the results was analyzed by chi-square test ( α = 0.1) and combined with I 2 quantitative analysis to judge the heterogeneity. If there is no statistical   heterogeneity, a meta-analysis will be conducted using the fixed effects of the model. If there is statistical heterogeneity, further analyze the sources of heterogeneity. After excluding the impact of significant clinical heterogeneity, a random effects model was used for meta-analysis (α = 0.05). If significant clinical heterogeneity is found, subgroup analysis or sensitivity analysis can be used, or only descriptive analysis can be used. If the number of literature is sufficient, an "inverted funnel" analysis can be used to test for publication bias.

Search Results
According to PRISMA's guidance, 749 references were extracted from databases mentioned above. However, there were 414 duplicate records, and after reviewing the abstracts, 258 studies were excluded because they were protocol, review, or observational studies that did not meet our registration criteria. By reviewing the full text of the remaining studies, 50 studies were excluded due to methodological deficiencies, such as non-randomization or incomplete data. Finally, 27 studies were included for further analysis (Figure 1).

Characteristics of the Included Studies
The characteristics of all included studies are shown in Table 1 and did not depict a unique grouping method and were estimated as indeterminate risk. 27 studies did not specify the specific allocation method and the risk assessment was unclear. 27 studies did not mention blinding, so we assessed it as an unclear risk. Furthermore, all included literatures did not describe the blinding method, so it was rated as an unclear risk. All 27 papers reported outcome indicators, so they were rated as low risk. In the selection report bias, only one study had case loss, so it was classified as high risk [38]. All of these studies have no other biases and are therefore assessed as unclear risks. The quality assessment of the literature is shown in Figure 2.

Clinical Effective Rate
As shown in Figure 3, all literature reported the total clinical effective rate. The heterogeneity test imply that the heterogeneity of the selected paper was minimal (I 2 = 0% < 50%, P < 0.0001), and the random effect model were selected. Meta result analysis shows that the clinical efficacy of BXD combination therapy is superior to that of western medicine alone, with a statistically significant difference (RR = 1.20, 95% CI (1.16, 1.23), P < 0.00001).
In this study, we used funnel plots to appraise whether there was publication bias in the included literature and tested 27 studies that recorded the effectiveness of Banxia Xiexin Decoction in treating gastric ulcers. The results show that although most studies are located at the upper part of the funnel plot, their distribution is asymmetric, indicating that there may be some publication bias (Figure 4).
Further exploration of therapeutic effects of BXD combined therapy and different standard treatments, we divided the control group into a dual therapy group, triple therapy group and quadruple therapy group, according to different Standard treatments in the control group. As shown in Figure 5, because the heterogeneity is reduced (I 2 = 0%), the random effect model is used for the meta-analysis of the data. Search results, the clinical effective rate of the treatment group was better than that of the dual therapy group [RR = 1.13; 95% CI: 1.02, 1.25; P = 0.02], the triple therapy group [RR = 1.20; 95% CI: 1.16, 1.24; P < 0.00001] and the quadruple therapy group [RR = 1.24; 95% CI: 1.14, 1.34; P < 0.0001], and the difference was statistically significant (P < 0.05, Figure 5).

Recurrence rate
14 studies reported recurrence rates. The heterogeneity test showed that there was almost no heterogeneity between studies (I 2 = 0%, P < 0.0001), which was analyzed by the random effect model. Search Results, the recurrence rate of BXD combined treatment was lower than that of oral treatment with standard treatment alone and the difference was statistically significant (RR = 0.26; 95% CI: 0.19, 0.35; P < 0.0001), Figure 6).

Hp eradication rate
14 studies reported Hp eradication rates. The heterogeneity test showed that there was almost no heterogeneity between studies (I 2 = 0%, P < 0.0001), which was analyzed by the random effect model. The results of the meta-analysis showed that the HP eradication rate of BXD combined treatment was lower than that of oral treatment with standard treatment alone, and the difference was statistically significant (RR = 1.22; 95% CI: 1.17, 1.27; P < 0.0001), Figure 7).

Adverse Event Rates(Safety analysis)
8 studies reported adverse reactions. The heterogeneity test showed that there was almost no heterogeneity between studies (I 2 = 0%, P < 0.0001), and the random effect model was used for analysis. The results of the meta-analysis showed that the incidence of adverse reactions of BXD combined treatment was lower than that of oral standard treatment alone, and the difference was statistically significant ([RR =0.33; 95% CI: 0.24, 0.45; P < 0.0001], Figure 8).

Symptom score
The relief of symptoms can not only reflect the improvement of the condition to a certain extent but also reflect the intuitive feeling of patients. 2 studies reported symptom scores of acid reflux, belching, stomach pain, retching, and nausea.In these symptom scores, we found significant heterogeneity [(a) P < 0.00001, I 2 = 96%]; [(b) P < 0.00001, I 2 = 99%]; [(c) P<0.00001, I 2 = 98%]. However, the confidence interval of forest plots is on the left side of the invalid row, it indicates that this heterogeneity will not affect the overall result. Therefore, the pooled data were analyzed using a random-effect model. Overall analysis shows that the symptom score of the BXD group is dramatically lower than that of the Western medicine group  Figure 9).
2 studies reported overall symptom scores. In these symptom scores, we found significant heterogeneity [P < 0.00001, I 2 = 96%]. However, the confidence interval of woodland was on the left of the invalid line, indicating that this heterogeneity did not affect the overall results. Therefore, the pooled data were analyzed using a random-effects model. Overall analysis shows that the symptom score of the BXD group is dramatically lower than that of the Western medicine group(d [MD = −4.02, 95% CI: −6.58, −1.47, P = 0.002] Figure 7).

Visual analog scale ( VAS)
Among the included studies, 6 papers used VAS as an evaluation indicator. The heterogeneity test between the two papers was significant Submit a manuscript: https://www.tmrjournals.com/ghr (I 2 = 98%, P < 0.00001). By analyzing the full text of the included papers, we found that although all patients in each study had a gastric ulcer, the degree of illness was different, and tolerance to pain was different, which may be the main reason for the heterogeneity. After the papers were excluded one by one, the comprehensive effect did not change dramatically, indicating that the results were stable.
Finally, we use the random effect model for analysis. The results of the meta-analysis showed that BXD combined therapy was better than standard treatment in the treatment of gastric ulcers, which could effectively alleviate the pain of patients. There was a significant difference between the two groups ([MD = -1.34 95% CI: -1.72, -0.97; P < 0.00001], Figure 10). Submit a manuscript: https://www.tmrjournals.com/ghr

Discussion
We conducted a meta-analysis of 27 RCTs of BXD combined with GU. The results of these analyses show that the clinical effective rate of BXD combined with conventional Standard treatment is better than that of Standard treatment alone. Subgroup analysis further showed that this effect was still obvious whether the control group was two combinations therapy, three combinations therapy, or four combinations therapy; Through later follow-up, we found that patients treated with BXD had less recurrence and better HP eradication effect; In addition, compared to patients receiving BXD treatment, the VAS score commonly used to evaluate pain is more pronounced than patients receiving standard treatment alone; In the comparison of Gu related symptom scores, the score of BXD combined treatment group was apparently lower than that of Standard treatment conventional treatment group, indicating that BXD was better in alleviating GU symptoms; In terms of the incidence of adverse events, compared with the conventional treatment of Standard treatment alone, the BXD combined treatment group reported fewer adverse reactions. At the same time, the data shows that taking BXD is safe and effective, and can reduces the adverse reactions related to drug treatment.
GU is a common gastrointestinal disease. Patients often suffer from it, which affects their normal life. In severe cases, it can also lead to gastric perforation or even cancer. And with the repetition and delay of the disease, also causes great harm to the body and mind [46][47]. GU has been put forward as early as ancient times in Chinese medicine and has provided corresponding treatment strategies. BXD is one of the classic Chinese medicine therapies. The clinical research on such diseases shows that most chronic gastric ulcer diseases that have not been cured for a long time have the common pathogenesis characteristics of cold heat deficiency and excess, and the prescription compatibility of Banxia Xiexin Decoction is directly aimed at the pathogenesis characteristics. It has a significant curative effect and small side effects for the treatment of common and refractory chronic gastric ulcers The advantage of a low recurrence rate is more and more widely used in the clinical treatment of GU [48].
As a classic prescription for the treatment of gastric ulcers, BXD has been proved by basic experiments many times. The research of Liu Jiacheng et al. [49] suggests that Banxia Xiexin Decoction affects and blocks the occurrence and development of gastric ulcers by affecting three key links of microenvironment changes of rat gastric mucosa, namely promoters, regulators, and effectors in PI3K/Akt/mTOR signal pathway. Studies have shown that [50] Banxia Xiexin Decoction may increase superoxide dismutase (SOD) and the expression of Nrf2 by reducing malondialdehyde (MDA), MPO, and 8-oxoguanine, to have an obvious protective effect on chronic gastric ulcer induced by dextran sulfate sodium. Among all herbs in BXD, Coptis Chinensis, Scutellaria baicalensis and dried ginger has the effect of inhibiting HP [51][52][53][54][55]. Pinellia ternata and Coptis chinensis can protect the gastric mucosa from erosion [56][57][58].
There are some limitations in this study: (1) the quality of the 27 works of literature included in this study is insufficient. In most studies, the random method used for grouping is not specifically defined, and the blind method is not used in the process of research, implementation, and evaluation, so various biases may occur; (2) BXD is a traditional Chinese medicine made of two or more ingredients and the included studies are all from China. There is limited research in other countries, so it will also affect the conclusion of meta-analysis to a certain extent; (3) There may be some differences in the efficacy of different medication period of treatment and doses included in the study.

Conclusions
The current research shows that BXD ally to or with standard treatment can more effectively relieve the pain symptoms of patients, diminish the recurrence rate of GU, against HP and the incidence of medican tun toward reaction. In our summary and analysis, the overall effect of BXD combination therapy on gastric ulcer is very significant. In the future, to verify these findings, we need more large-scale, multicenter, high-quality clinical trials, which are crucial for providing a foundation for patient treatment.