Introduction

Gastroesophageal reflux disease (GERD) is a common digestive system disease, mainly caused by the stomach, duodenum content reverse flow into the esophagus of inflammatory lesions, such as acid reflux,heartburn, retrosternal pain as the main clinical manifestations of, the world an attack more than once a week GERD symptom prevalence was 13%, differences in different countries or areas, The prevalence rate is high in western countries, with a significant trend of increase in the Asia-Pacific region [1–3].At present, the treatment of PPIs is mainly proton pump inhibitors (PPIs) or combined gastric motility drugs, gastric acid neutralizers, etc., but for some patients, the efficacy is not good, the recurrence rate is high, and maintenance treatment is needed, causing certain economic and psychological burden to patients.Xiaoxianxiong Decoction for Xiaoxianxiong syndrome and set up by Coptis, Trichosanthes and Pinellia, from

written by Zhang Zhongjing: “Xiaoxianxiong syndrome, is under the heart, it hurts when you press it, the pulse is smooth, treat with Xiaoxianxiong Decoction.” In recent years, more and more studies have shown that Xiaoxianxiong Decoction has good efficacy in the treatment of GERD, and the recurrence rate is low [4, 5].However, there is still a lack of evidence-based medical evidence supported by large sample, multicenter, randomized controlled trials(RCTS).Therefore, this study searched high-quality RCT studies published at home and abroad on the treatment of GERD with Xiaoxianxiong Decoction, conducted META analysis, and adopted Cochrane systematic evaluation method to evaluate the quality of the included literatures, in order to provide more objective evidence-based medical evidence for the clinical application of Xiaoxianxiong Decoction.

Data and methods

Literature retrieval strategy

Search the Databases of Pub Med, CNKI, Wan Fang, VIP, Sino Med and Cochrane Library with the computer for the literature related to Xiaoxianxiong Decoction in the treatment of GERD (Retrieve time:From the establishment of the database to December 2021), the search strategy is “(Xiaoxianxiong Decoction) and (gastroesophageal reflux disease)”, and the search is conducted by subject.The English strategy was “Xiaoxianxiong Decoction” and “Gastroesophageal disease”,retrieved by Title.

Literature inclusion criteria

(1) Subjects: GERD was confirmed to be diagnosed according to the diagnostic criteria of Multidisciplinary Diagnosis and Treatment consensus of GERD in China [6]; (2) Study type: randomized controlled trial; (3) Treatment measures: The control group received conventional western medicine therapy such as PPIs, H2RA or combined gastrointestinal dynamic drugs; The experimental group was treated with Xiaoxianxiong Decoction.(4) Outcome indicators:total response rate, recurrence rate, symptom score.

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Literature exclusion criteria

(1) Literatures that did not meet the diagnostic criteria of Gastroesophageal reflux disease; (2) The intervention measures of the experimental group were non-Xiaoxianxiong Decoction.(3)Self-control experiment before and after; (4) Non-clinical studies such as expert experience, conference papers, case reports and meta-analysis; (5) Literature with unreasonable test design scheme and incorrect data; (6) Repeated literature published in different journals.

Due to different intervention measures, the total effective rate was analyzed in subgroups, which were divided into subgroup 1 (flavored with Xiaoxianxiong Decoction vs PPI), subgroup 2 (flavored with Xiaoxianxiong Decoction VS PPI + Gastric motor drug), and subgroup 3 (flavored with Xiaoxianxiong Decoction VS H2RA + Gastric motor drug) (Figure 4).Fixed effect model was used for combination.Results:

= 0.99, I

= 0%, OR = 3.40, 95%CI [1.48, 7.80] (subgroup 1);

= 0.26, I

= 25%, OR = 3.12, 95%CI [1.49, 6.55] (subgroup 2);

= 0.95, I

= 0%, OR = 3.65, 95%CI [1.94, 6.89] (subgroup 3).There were statistically significant differences among the three groups(

＜ 0.05), indicating that Xiaoxianxiong Decoction was more effective in the treatment of Gastroesophageal reflux disease than conventional treatment in Western medicine.The inverted funnel plot of subgroup analysis showed basic symmetry, indicating no significant bias in the results (Figure 5).

Literature screening and data extraction

A total of 11 literatures were included, including 873 patients, 467 cases in the control group and 406 cases in the experimental group.The maximum sample size was 62 and the minimum was 17.In the control group, 3 interventions were proton pump inhibitors (PPI), 4 interventions were PPI plus gastrointestinal dynamic drugs, and 4 interventions were H2 receptor antagonists (H2RA) plus gastrointestinal dynamic drugs.The intervention measures of the experimental group were more or less Xiaoxianxiong depression Decoction.The specific information of the included literature is shown in Table 1.

Literature quality evaluation

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Statistics and data analysis

A total of 4 of the 11 studies reported comparison of TCM symptom scores before and after treatment, including acid reflux, heartburn, and retrosternal pain.Therefore, the 4 included studies were directly subgroup analysis.A forest map was drawn (Figure 6), subgroup 1 (Sour regurgitation)

=0.001, I

= 81%, subgroup 2 (Heartburn)

= 0.0002, I

= 88%, and subgroup 3 (Pain behind the sternum)

＜ 0.0001, I

= 94%,suggesting high literature heterogeneity within each subgroup and using a random effect model.Results: WMD = –0.30, 95%CI [–0.59, –0.01], Z = 2.06,

= 0.04 (subgroup 1); WMD = –0.17, 95%CI [–0.44, 0.11], Z = 1.18,

= 0.24 (subgroup 2); WMD = –0.14, 95%CI[–0.37, 0.08], Z = 1.23,

= 0.22 (subgroup 3).The differences in subgroup 1 were statistically significant, suggesting that Xiaoxianxiong Decoction could significantly improve the symptoms of acid reflux in patients with GERD compared with other conventional western medicine therapies.There was no statistical significance in subgroup 2 and subgroup 3 (

＞ 0.05), suggesting that there was no significant difference between the experimental group and the control group in improving heartburn and retrosternal pain.

Results

Literature retrieval results

A total of 10 literatures studied the total effective rate and were combined using a fixed-effect model.Results:

= 0.89, I

= 0%, OR = 3.48, 95%CI [2.29, 5.30], Z = 5.84,

＜ 0.00001, indicating that the difference was statistically significant, indicating that Xiaoxianxiong Decoction was superior to the control group in the treatment of Gastroesophageal reflux disease.(Figure 3).

Basic characteristics of the study were included

The researchers screened the literatures by reading the title and the full text, and two researchers negotiated to resolve the dissenting literatures.If there was any disagreement, the third researcher would discuss and make a decision.Data extraction included: author, age,sample size, gender, treatment measures, course of treatment,outcome indicators, etc.

Quality evaluation of included studies

RCT was used in all 11 literatures, among which random number table method was used in 4 literatures, the random number table method was only mentioned in 7 literatures but specific methods were not explained, selective reporting results were not clear in 9 literatures, 1 literatures were double-blind, 1 literatures were single-blind, and 1 literatures were detached.Other sources of bias cannot be determined.Overall, the quality of the included literature was low, and the risk bias was summarized in Figure 2.

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The quality of the included studies was evaluated by two researchers with reference to bias risk assessment criteria.Evaluation criteria:selective reporting, allocation hiding, data integrity and number of shedding cases, blind method, random method, publication bias.For each study, the researcher will evaluate the above content as low risk,high risk or unclear according to the evaluation criteria.If the results are inconsistent, the third researcher will discuss the decision together.

Meta-analysis

A total of 132 literatures were retrieved from CNKI, Wan Fang, VIP,Sino Med, Cochrane Library and Pub Med, and 42 literatures with low quality and non-RCTS and controls were screened out, including 64 duplicates, 13 reviews, 2 irrelevant articles, and 42 literatures with non-RCTS and controls.Finally, 11 literatures were included in this study.See Figure 1 for the literatures retrieval process.

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Statistical analysis was conducted by using Rev Man5.3 software, and the dichotomous variable was OR (95%CI) and continuous variable was MD (95%CI).The heterogeneity between studies was determined by I

value, and the fixed effect model (I

≤ 50%) or random effect model (I

＞ 50%) was selected.The factors with high heterogeneity were analyzed by subgroup.If a large number of studies were included in the analysis, an inverted funnel plot was drawn to judge the unbiased research results.

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Among the included literatures, 3 literatures studied the recurrence rate one year after drug withdrawal.Forest map (Figure 7) indicated

= 0.21 and I

= 36%, indicating large heterogeneity among studies.Random effect model was adopted for merger, OR = 0.13, 95%CI [0.05, 0.37], Z = 3.89,

＜ 0.0001.The results indicated that the recurrence rate of gastroesophageal reflux disease treated by Xiaoxianxiong decoction was lower than that treated by conventional Western medicine, and the difference was statistically significant.

Discussion

Gastroesophageal reflux disease belong to the motherland medicine“spit acid” “stomach against” “noisy” category, phlegm and dampness accumulate stagnation and transform heat is the basic pathogenesis,often because of food and drink not section, sentiment is not smooth,so that the stomach internal heat and humidity, or liver depression turns heat into the stomach, the stomach estrangement, gastric qi carries acid upwelling in the stomach, burn the esophagus, resulting in acid reflux, heartburn, chest pain and other clinical manifestations[18, 19].Therefore, the principle of treatment is to clear heat and cleanse phlegm, relieve chest stiffness to dissipate mass.Xiaoxianxiong Decoction for Xiaoxianxiong syndrome from

written by Zhang Zhongjing: “Xiaoxianxiong syndrome, is under the heart, it hurts when you press it, the pulse is smooth, treat with Xiaoxianxiong Decoction”.Most modern doctors think these symptoms are similar to GERD, especially the stagnation of liver and stomach heat and stagnation of phlegm-qi.Xiaoxianxiong Decoction has a cold coldness with a bitter taste, channel tropism include heart, spleen, stomach, liver, gallbladder and large intestine.It has the functions of clearing heat, dryness and dampness, eliminating fire and detoxification, and removing heat in the chest.Modern pharmacology shows that it has antibacterial, anti-inflammatory,antioxidant and gastric mucosal protection effects [20].Pinellia warm taste, go to the spleen, stomach, lung channel.It has the effect of lowering adverse qi and stopping vomiting, regulating the stomach and eliminating carbuncles, can eliminate stagnation in the chest;Modern pharmacological studies have shown that Pinellia ternata can regulate gastrointestinal function and promote mucosal repair [21].Trichosanthes cold taste sweet and bitter, channel tropism includes the lung, stomach, large intestine.It has the effect of clearing heat and cleansing phlegm, relieving chest stiffness to dissipate mass, can depress Qi in the chest; Modern pharmacological studies have shown that trichosanthes can act on the cardiovascular system, digestive system and respiratory system, and have dilate the coronary arteries,anti-myocardial ischemia, anti-tumor, antibacterial, immune promotion, anti-inflammatory, anti-ulcer, anti-aging and other effects[22].

The results of this meta-analysis showed that the treatment of GERD with Xiaoxianxiong Decoction was significantly superior to conventional western medicine in terms of total clinical effective rate,reduction of acid reflux symptom score and recurrence rate, but there was no significant difference between the treatment group and the western medicine group in terms of improving heartburn and retrosternal pain.Therefore, the clinical efficacy of Xiaoxianxiong Decoction in the treatment of GERD is better than that of conventional western drugs.There are also some limitations in this study: (1) the single-center design with multiple and small samples was included in the study, which was of low quality; (2) The course of treatment and control drugs included in the study were not uniform, and there was certain clinical heterogeneity; (3) Few studies on patient recurrence rate were included, and most literatures did not describe adverse reactions and safety evaluation, which may have a certain publication bias.The above factors can affect the credibility of the meta-analysis results to a certain extent.Therefore, in order to clarify the long-term efficacy of Xiaoxianxiong Decoction in the treatment of GERD,high-quality sample size can be expanded for further in-depth research, so as to provide a better research basis for clinical and experimental studies.

At present, as a basic drug for GERD, PPI also has significant disadvantages, such as frequent recurrence after drug withdrawal, and a variety of adverse reactions such as dry mouth, nausea, abdominal pain, osteoporosis and anemia after long-term use [23–25].Meanwhile, large doses of PPI for patients with refractory GERD, will increase the risk of these adverse reactions.For patients with extra-esophageal symptoms, the effect of PPI is not significant.TCM syndrome differentiation has shown great advantages in the treatment of such diseases, it grasps the etiology and pathogenesis as a whole,improves symptoms by removing the etiology, and at the same time adjusts the body's resistance to disease, so that it can tolerate the invasion of pathogenic factors and achieve treatment for the root causes.Therefore, Xiaoxianxiong Decoction can relieve acid reflux symptoms and reduce recurrence rate, so as to treat both symptoms and root causes, which has a sufficient theoretical basis of TCM.In addition, unlike the ancient periods of hunger and cold, with the improvement of living standards, especially diet, Gerd patients with the stagnation of liver qi and stomach heat and stagnation of phlegm-qi will be more and more common.Based on TCM syndrome differentiation and treatment, Xiaoxianxiong Decoction will achieve better clinical efficacy.Combined with the results of this meta-analysis and existing clinical evidence, it is confirmed that Xiaoxianxiong Decoction can be used to improve the clinical practice of GERD.

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