A meta-analysis of Banxia Xiexin decoction versus omeprazole in the treatment of gastroesophageal reflux disease

Xiao-Ting Ma,Jing-Na Zhou,Bin Hao

1School of traditional Chinese Medicine,Hebei University,Baoding,China.

Abstract Objective:To investigate the clinical efficacy and safety of Banxia Xiexin decoction and omeprazole in the treatment of gastroesophageal reflux disease(GERD).Methods:EMbase,Cochrane,PubMed,CNKI,Wan Fang and VIP database were searched from inception to November 2018 according to the search strategy.Eligible randomized controlled clinical trials related to the efficacy of omeprazole compared with Banxia Xiexin decoction in the treatment of GERD were included according to the inclusion and exclusion criteria.Total effective rate,pathological improvement rate,total symptom score,acid reflux symptoms,heartburn symptoms,improvement of post-sternal pain symptoms,and incidence of adverse reactions were evaluated.Data analysis was performed with RevMan5.3 software provided by Cochrane Collaboration.Results:A total of 15 studies were enrolled,including 1,532 patients.Meta-analysis results showed that the total effective rate of Banxia Xiexinfang was higher than that of omeprazole in the treatment of GERD(odds ratio(OR)=3.99,95% confidence intervals(CI)(2.58,6.15), P＜0.00001).Pathological improvement under endoscopy was not obvious(OR=1.98,95%CI(0.94,4.19),P=0.07)between the two groups.The total symptom score improved significantly,indicating that Banxia Xiexin decoction has an objective advantage over omeprazole in the treatment of GERD(standardised mean difference(SMD)=-2.56,95% CI(-3.86,-1.26), P=0.0001),The incidence of adverse reactions in patients treated with Banxia Xiexin decoction is lower than omeprazole group(OR=0.09,95% CI(0.02,0.39), P=0.001].In addition,total effective rate of Banxia Xiexin decoction combined with omeprazole was higher than omeprazole alone(OR=6.31,95% CI(2.86,13.92), P＜0.00001).Conclusion:Banxia Xiexin decoction is superior to omeprazole in total effective rate,total symptom score and adverse reaction rate in the treatment of GERD.The clinical efficacy of Banxia Xiexin decoction combined with omeprazole is better than that of omeprazole alone.However,due to the low quality of the included literatures,large-scale and high-quality RCTs are still needed for further confirmation.

Keywords:Banxia Xiexin recipe;omeprazole;gastroesophageal reflux disease;systematic evaluation;meta-analysis

Introduction

Gastroesophageal reflux disease(GERD)is a clinical syndrome characterized by the reverse flow of the contents of the stomach and the duodenum into the esophagus,which can be divided into non-erosive reflux disease,reflux esophagitis and Barrett's esophagus.The incidence of GERD has increased significantly in recent years.The disease is characterized by recurrent attacks,long course and lingering,seriously affecting the life quality of patients.At present,in view of the possible causes of GERD,the medical treatment of western medicine is mainly to inhibit gastric acid,promote gastric motility,protect gastric mucosa,anti-helicobacter pylori therapy and other symptomatic treatment.Although the condition can be partially relieved using the above mentioned therapies,the recurrence rate after the drug withdrawal is high and the treatment time is long with serious adverse reaction,making it difficult for some patients to insist on taking the medicine on time.Thus,the expected effect is hard to reach,causing the disease repeated and even aggravating the condition of the disease ultimately[1].

According to the clinical manifestations of GERD,it should be classified into the categories of acid ingestion,acid vomiting,chest arthralgia,stomachache and so on in the theory of traditional Chinese medicine(TCM).According to TCM,the disease is located in esophagus and stomach,which is closely related to liver,gallbladder,spleen,stomach and lung.The basic pathogenesis of the disease is the weakness of spleen and stomach,the disorder of Qi,marking the weakened body resistance as principal cause,stagnation of heat,dampness and heat,phlegm and turbid,and blood stasis as subordinate symptoms[2].Banxia Xiexin decoction,from Treatise on Febrile Diseases,has the function of reducing nausea and resolving masses,and is one of the representative prescription of Xinkai Kujiang method.The basic components of Banxia Xiexin decoction is as follows:Banxia(Rhizoma Pinelliae)12g,Huangqin(Radix Scutellariae)9g,Ganjiang(Rhizoma Zingiberis)9g,Dangsen(Radix Codonopsis)9g,Haunglian(Rhizoma Coptidis)3g,4 Dazao(Fructus Jujubae),Zhigancao(prepared Radix Glycyrrhizae)9g[3].In the prescription,Banxia(Rhizoma Pinelliae)is acrid and warm and returns to the lung,spleen,stomach meridians,making it has the effect of dispelling phlegm and depressing Qi.Ganjiang(Rhizoma Zingiberis),with acrid flavor,returns to the lung,spleen,stomach meridians.The two drygs can work together and relieve the fullness of stomach.Both Huangqin(Radix Scutellariae)and Haunglian(Rhizoma Coptidis)are bitter and cold,having the function of clearing heat and drying dampness.Dangsen(Radix Codonopsis),Dazao(Fructus Jujubae)and Zhigancao(preparedRadixGlycyrrhizae)can work together,strengthen the body resistance to eliminate pathogenic factors,and nourish the body with property of sweet and warm[4].Due to the function of Baixia Xiexin decoction and the clinical manifestations of GERD,Baixia Xiexin decoction is often used in clinic to treat GERD.However,the long-term efficacy of Banxia Xiexin decoction in the treatment of GERD is still worthy of attention.Therefore,this study intends to use meta analysis to evaluate the effectiveness and safety of Banxia Xiexin decoction in the treatment of GERD,in order to provide relevant reference and basis for clinicians.

Materials and methods

Inclusion criteria

(1)Random controlled trials(RCTs)or semi-random controlled trials,including blind and non-blind methods.(2)The participants were patients diagnosed as GERD clinically;the diagnostic criteria of western medicine referred to Expert Consensus on Gastroesophageal Reflux Disease in China(2014);the diagnostic criteria of TCM referred to Consensus on Diagnosis and Treatment of Gastroesophageal Reflux Disease with Iintegrated Traditional Chinese and Western Medicine(2010).(3)The intervention measures were Banxia Xiexin decoction or Banxia Xiexin decoction combined with omeprazole,and the control measures were omeprazole or omeprazole combined with other western drugs.(4)The outcomes included total effective rate,endoscopic pathological improvement rate,total symptom scores,acid regurgitation symptom,heartburn symptom,improvement of retrosternal pain symptom and incidence of adverse reactions.The basic characteristics of included literatures are shown in Table 1.

Exclusion criteria

(1)Non-randomized controlled trial;(2)animal experiment and tissue cell experiment;(3)review,experience and case report;(4)the content of the study does not match;(5)the repeated published literatures;(6)TCM external therapies and western medicine functional training therapies;(7)the literatures with obvious data error.

Literature search

According to the combination of "Banxia Xiexin recipe","Banxia Xiexin decoction","gastroesophageal reflux disease","GERD" and "random",EMbase,Cochrane,PubMed,,SinoMed,CNKI,Wanfang,and VIP were searched from inception to November 2018.RCTs related to the efficacy of omeprazole compared with Banxia Xiexin decoction in the treatment of GERD were included according to the inclusion andexclusion criteria.The flow chart of literature search is shown in Figure 1.

Table 1 Basic features of included literature

Data extraction and quality evaluation

The basic characteristics of patients in the two groups,intervention measures and outcomes were extracted.The quality of the literatures included in the study was evaluated according to the Cochrane Evaluation Manual.The following items were evaluated:the random sequence generation,the allocation concealment,the blinding of participants and personal,the blinding of outcome assessment,data integrity,the selective reporting and the other bias.Each item was judged on three levels such as low risk of bias,high risk of bias and unclear risk of bias(Figure 2).None of the studies mentioned sample size estimation methods.Taking into account the possible existence of other bias,the summary of the risk of bias in the included studies is shown in Figure 3.

Statistical analysis

RevMan5.3 software was used for Meta analysis.Categorical variables and continuous variables were in the results.So odds ratio(OR),standardised mean difference(SMD)and 95% confidence intervals(CI)was used.The chi-square test was applied to evaluate heterogeneity among studies,and I2 was used to show the magnitude of this heterogeneity.Results ofP≥0.1 and I2≤50% suggested a lack of significant heterogeneity;the fixed-effect model was used accordingly.For cases with P＜0.1 and I2＞50%,the random-effect model was adopted.The test level is α=0.05.Funnel plots were used to reveal the potential publication bias(Figure 4).

Results

Search results

Initially,273 potentially relevant articles were retrieved.After initial screening,According to the definite diagnostic criteria and strict inclusion criteria,a total of 15 RCTs[5-19],including 1,532 patients,were enrolled for this meta-analysis.

Outcomes

Total effective rate

A total of 644 cases of 13 RCTs were included.The heterogeneity analysis showed that the heterogeneity was small and the results were stable,and the fixed effect model was used.Meta-analysis results showed that:(1)the total effective rate of Banxia Xiexin recipe compared with omeprazole in the treatment of GERD(OR=3.99,95%CI(2.58,6.15),P＜0.00001);(2)the total effective rate of Banxia Xiexin recipe combined with omeprazole compared with omeprazole alone in the treatment of GERD(OR=6.31,95%CI(2.86,13.92),P＜0.00001).There was significant difference between the two groups(P＜0.05),which indicated that the total effective rate of the treatment group was better than that of the control group(Figure 5,6).

Figure 1 Flow chart of literature search

Figure 2 Methodological quality of included trials

The rate of pathological improvement under the endoscope

A total of 122 cases of 3 RCTs were included.There was statistical heterogeneity among the above 3 trials(P＞0.1)and the fixed effect model was performed.The results of Meta-analysis showed that the rate of pathological improvement under the endoscope(OR=1.98,95% CI(0.94,4.19),P=0.07)was not statistically significant(P＞0.05),which indicated that there was no significant difference between the treatment group and the control group under the endoscope(Figure 7).

The rate of improvement in symptom scores

Figure 3 The summary of the risk of bias in the included studies

Figure 4 The funnel plots of the meta-analysis

Among them,122 cases of 3 RCTs were included in the symptom of acid regurgitation and heartburn,and 76 cases of 2 RCTs were included in retrosternal pain.We made heterogeneity test and found that there was statistical heterogeneity among the trials(P＜0.1).Therefore,the random effect model was adopted.Meta-analysis showed that acid regurgitation(SMD=-2.90,95% CI(-5.14,0.66),P=0.01),heartburn(SMD=-2.39,95% CI(-4.80,0.01),P=0.005),posterior sternal pain(SMD=-2.34,95% CI(-6.49,1.81),P=0.27)and the total symptom scores(SMD=-2.56,95%CI(-3.86,≤1.26),P=0.0001),indicating that the treatment group was superior to the control group in improving the symptom scores(Figure 8).

Incidence of adverse reactions

Dizziness and elevation of liver transaminase were included in 85 cases of 2 RCTs.There was not statistical heterogeneity among the trials(P＞0.1)and the fixed effect model was performed.Meta-analysis showed that dizziness(OR=0.07,95%CI(0.01,0.52),P=0.010),elevated liver transaminase(OR=0.13,95% CI(0.02,1.10),P=0.06)and the incidence of adverse reactions(OR=0.09,95%CI(0.02,0.39),P=0.001),indicating that the incidence of adverse reactions in the treatment group was lower than that in the control group(Figure 9).

Discussion

Figure 5 Forest plot of total effective rate of Banxia Xiexin decoction compared with omeprazole

Figure 6 Forest plot of total effective rate of Banxia Xiexin decoction combined with omeprazole

Figure 7 Forest plot of pathological improvement rate of Banxia Xiexin decoction compared with omeprazole

GERD,as a common digestive system disease,has a great influence on the normal life of patients.The first-line drug commonly used in western medicine is proton pump inhibitor,which can achieve certain clinical therapeutic effect,but the recurrence rate after withdrawal is relatively high,and there is a possibility of increasing cardiovascular and cerebrovascular events,leading to osteoporosis,inducing colitis and intestinal flora disorder,and so on.Honghaidu[20]believes that GERD has certain repeatability and is difficult to be cured.The mechanism of western medicine is mostly to inhibit gastric acid secretion,so as to improve gastric motility and protect gastric mucosa.This treatment is easy to produce drug resistance and is prone to recurrence in the later stage.Therefore,the dialectical treatment of GERD with TCM highlights its unique advantages.Banxia Xiexin decoction,which comes from Zhang Zhongjing's classic book Treatise on Febrile Diseases,has the function of reducing nausea and eliminating ruffian and dispersing knot.It focuses on regulating the movement of Qi,calming stomach Qi and improving spleen Qi,so as to improve the symptoms of acid regurgitation and heartburn in patients.Clinical practice has proved that Banxia Xiexin decoction is effective in the treatment of GERD.

In recent years,a lot of researchers on the mechanism of Banxia Xiexin decoction in the treatment of GERD had been reported.Pan Shuang et al[21]found that Banxia Xiexin decoction could reduce the injury of esophageal mucosa and the expression of intercellular adhesion molecule-1 and L-selector in rats with reflux esophagitis.The mechanism may be related to increasing plasma motilin level and contraction amplitude of gastric fundus muscle strips,promoting gastric emptying and reducing the stimulation of reflux to esophageal mucosa.

Figure 8 Forest plot of improvement of GERD symptom scores by Banxia Xiexin decoction and omeprazole

Figure 9 Forest plot of incidence of adverse reactions treated by banxia xiexin fang and omeprazole

Our meta-analysis shows that there are many RCTs for the comparison of Banxia Xiexin decoction and western medicine,but there is a lack of multi-center and large sample researches with strict design.Meta analysis increases the possibility of bias because of the small number of RCT samples included in the analysis.In the course of the research,we also find that the existing RCTs has the following problems to be solved.(1)Outcomes were emphasized and designs were neglected.The description of the design of the trial is less or missing.The concept of blind methods and randomness is vague.Some schemes about selection in the implementation of the experiment are not standardized,such as the random mode.(2)The criteria for judging the curative effect are inconsistent,with more emphasis on the change of the intensity of symptom improvement and the lack of observation of improvement time.(3)Lack of long-term efficacy observation(such as recurrence rate)and comparison,making the sustained effect of drugs difficult to be analyzed[22].

In this study,the systematic evaluation and meta analysis of Banxia Xiexin decoction and omeprazole in the treatment of GERD are not deep enough,and there are few effective literatures included in this study.It is still necessary to further study the efficacy of Banxia Xiexin decoction in the treatment of GERD,so as to provide new ideas and methods for clinicians.

The efficacy of Banxia Xiexin decoction is superior to the control group in the treatment of GERD with or without omeprazole.The incidence of adverse reactions of Banxia Xiexin decoction is generally lower than that of omeprazole.The results of this system evaluation suggest that Banxia Xiexin decoction is effective and safe in the treatment of GERD,which is worthy of clinical promotion and application.

Abbreviations

GERD,gastroesophageal reflux disease;TCM,traditional Chinese medicine;OR,odds ratio;RCTs,random controlled trials;OR,odds ratio;SMD,standardised mean difference;CI,confidence intervals.

Acknowledgments

None.

Competing interests

The authors declare that there is no conflict of interests regarding the publication of this paper.