Efficacy and Safety of Modified Banxia Xiexin Decoction (Pinellia Decoction for Draining the Heart) for Gastroesophageal Reflux Disease in Adults: A Systematic Review and Meta-Analysis

Modified Banxia Xiexin decoction (MBXD) is a classical Chinese herbal formula in treating gastroesophageal reflux disease (GERD) for long time, but the efficacy of it is still controversial. This study is to evaluate the efficacy and safety of MBXD for the treatment of GERD in adults. The search strategy was carried out for publications in seven electronic databases. RevMan software version 5.3 and the Cochrane Collaboration's risk of bias tool were performed for this review. Twelve RCTs were included for the analysis. The results of overall clinical efficacy and efficacy under gastroscope demonstrated that MBXD was superior to conventional western medicine. Meanwhile, the results of subgroup analysis showed clinical heterogeneity between the two groups. However, there was no statistically significant difference in acid regurgitation between the two groups. But in the improvement of heartburn and sternalgia, the results showed statistically significant differences for the comparison between two groups. In addition, the adverse reactions of the experiment groups were not different from those of the control groups. This systematic review indicates that MBXD may have potential effects on the treatment of patients with GERD. But because the evidence of methodological quality and sample sizes is weak, further standardized researches are required.


Introduction
Gastroesophageal reflux disease (GERD), which affects a substantial proportion of the world's population particularly in western countries, is defined as a gastroesophageal motility disorder that appears when the reflux of stomach contents causes troublesome gastroesophageal symptoms and/or complications [1]. Based on its clinical manifestation, GERD is subclassified into three types: nonerosive reflux disease (NERD), reflux esophagitis (RE), and Barrett esophagus (BE) [2].
According to epidemiological investigation [3], the prevalence of symptom-based GERD increased from 2.5-4.8% before 2005 to 5.2-8.5% from 2005 to 2010 in East Asia, and after 2005, the prevalence was 6.3-18.3% in Southeast and West Asia. Similarly, in East Asia, the prevalence of endoscopic reflux esophagitis increased from 3.4-5.0% to 4.3-15.7%. Thus, the incidence of GERD appears to be an increasing problem throughout Asia including China, causing substantial reductions in subjective wellbeing [4] and lower work productivity and involving substantial healthcare costs [5].
Proton pump inhibitors (PPIs) are currently the mainstay of treatment for GERD. To be better control of acid secretion, a substantial proportion of patients require twice-daily therapy with PPIs. In addition, decreasing transient lower esophageal sphincter relaxations (TLESRs) can reduce distal acid exposure and weakly acidic refluxate [6]. Despite the efficacy of these agents in healing and symptom relief, many Asian patients with GERD continue to experience symptoms [7]. Moreover, the long-term use of PPIs may cause some clinical risks, such as fracture [8][9][10], respiratory infection [11][12][13], spontaneous peritonitis [14], and clostridium difficile bacteria infection [15][16][17]. Due to chronicity and progressivity of GERD, many patients have turned their attentions to traditional Chinese medicine (TCM) [18,19]. Modified Banxia Xiexin decoction (MBXD), an ancient formula in treating GERD [20], is modified by different Chinese herbal additions based on Banxia Xiexin decoction according to TCM syndrome differentiation. However, in the past decades, although numerous studies have compared MBXD with conventional western medicine in the treatment of GERD, the comparability of treatment protocols and evaluation methodologies among these studies remains to be proven, which greatly limits their clinical applicability [21]. Furthermore, the current state of evidence of MBXD for GERD has so far been unknown. Therefore, we conducted this systematic review to evaluate efficacy and safety of MBXD in the treatment of GERD.

Eligibility Criteria.
The studies included in this review were randomized controlled trials (RCTs) in humans, without limitations on publication type. And all the included studies should present the efficacy of MBXD in comparison with conventional western medicine. Outcomes should contain at least one outcome, such as overall clinical efficacy, efficacy under gastroscope, or symptom scores. In addition, overall clinical efficacy was our primary outcome in this systematic review.

2.2.
Patients. GERD is diagnosed on the basis of published diagnostic criteria [22]. All patients in the included studies had confirmed diagnoses of it. In addition, pregnant women, juveniles, and patients with malignant tumour or severe cardiovascular diseases were excluded.

Databases and Search Strategy.
A literature search was comprehensively carried out for publications in the following 7 electronic databases from their inception through July 30, 2016: PubMed, Embase, Springer Link, CNKI (China National Knowledge Infrastructure), VIP (Chinese Scientific Journals Database), Wan-fang database, and CBM (Chinese Biomedicine Database). In the article search, the following general wordings of search terms were used individually or in combination: "gastroesophageal reflux disease", "reflux esophagitis", "nonerosive gastroesophageal reflux disease", "barrett's esophagus", "Banxia Xiexin decoction", "traditional Chinese medicine", "herbal formula", "herbs", "clinical application", "randomized controlled trials", and "clinical trial". No limit for publication was placed on language. Manual searches of relevant literatures supplemented the electronic searches.

Endpoint Indicators.
Dichotomous data in this systematic review contained overall clinical efficacy and efficacy under gastroscope. Both of them were graded into 3 or 4 categories according to the appropriate guiding principles and guidelines [22][23][24]: (cure), markedly effective, effective, and ineffective. Dai and  Yunzhan Zhang) independently extracted data from all  included publications, including the first author, publication  year, classification of GERD, sample size, age, course of  disease, duration, intervention, outcome measures, randomization, double blinding, withdrawal or dropout, allocation concealment, follow-up, and side effects. Data were extracted as intention-to-treat (ITT) analyses, in which dropouts were assumed to be treatment failures. One researcher (Yunkai Dai) extracted the initial data; the other (Yunzhan Zhang) subsequently reexamined each study and verified the results. Disagreements were resolved by discussion with another researcher (Danyan Li).

Study Identification. Two investigators (Yunkai
2.6. Quality Assessment. Evaluation of methodological quality in the included studies was performed independently by two reviewers (DYL and JTY), which used the Cochrane Collaboration's risk of bias tool [25], supplemented by Jadad score [26]. We could judge whether all the included literatures contained selection bias, performance bias, detection bias, attrition bias, reporting bias, and other bias from randomization, double blinding, and withdrawal or dropout. Literature with a Jadad score above 3 was regarded as a superior quality article; otherwise, it was viewed as a poor one. However, the final results of literature quality including the risk of bias evaluation were illustrated by the Cochrane tool.

Data Synthesis and
Analysis. This systematic review used Review Manager 5.3 software to pool effect sizes. Summary odds ratio (OR) or risk ratio (RR) and 95% confidence intervals (CI) were calculated for overall clinical efficacy, efficacy under gastroscope, and recurrence rate. Standardized mean difference (SMD) or mean difference (MD) and 95% CI were reported for symptom scores. Heterogeneity was evaluated statistically using the 2 test and inconsistency index statistic ( 2 ) [27]. If substantial heterogeneity existed ( 2 > 50% or < 0.05), a random effect model was applied. If there was no observed heterogeneity, fixed effect models were chosen [28]. A sensitivity analysis was done to explore potential sources of heterogeneity. Publication bias was evaluated using visual inspection with the aid of a funnel plot.

Risk of Bias Assessment.
All of the 12 included RCTs described no significant differences at baseline between experiment groups and treatment groups. However, only 5 studies [29,31,32,34,37] reported a randomization technique using random number table, while the other 7 [30,33,35,36,[38][39][40] did not report the specific randomization technique. Moreover, none of the 12 trials described double blinding and allocation concealment. Although only 1 trial [36] mentioned a single-blind design, and the specific implementation of this design was not reported. In addition, dropouts were described in 2 trials [29,36], but neither of them performed ITT analysis. In general, owing to the relative lacking of specific information (Figure 2), the validity of this metaanalysis was regarded as high risk. A description of the evaluation of methodological quality of the 12 trials can be found in Table 3.

Sensitivity Analysis.
Because of good homogeneity in primary outcome ( 2 = 0% for overall clinical efficacy), we did not conduct a sensitivity analysis for overall clinical efficacy.  (Figure 7). The asymmetrical funnel plot in Figure 8 presented potential publication bias.

Adverse Events.
Of all the included RCTs, three reported adverse reactions during the treatment period [36,38,39]. However, one trial mentioned no adverse events [40]; the other two mentioned the number of people in adverse effects (Zhu et    Heterogeneity: 2 = 7.20, df = 4 (P = 0.13); I 2 = 44% of waist. Although these side effects occurred in the period of treatment, they did not have impact on the experimental process.

Discussion
This meta-analysis included 12 studies with 1210 total participants comparing MBXD with conventional western medicine for the treatment of GERD. As for the overall clinical efficacy and efficacy under gastroscope, our analysis revealed that experiment groups showed better efficacy than control groups. Meanwhile, the results of subgroup analysis showed clinical heterogeneity between MBXD and conventional western medicine. However, as for the improvements of acid regurgitation, heartburn, and sternalgia, the result of metaanalysis in acid regurgitation had a similar efficacy when compared with the control groups. But the results of metaanalyses in heartburn and sternalgia showed better improvement than conventional western medicine. In addition, both recurrence rate and adverse events had no statistically significant difference between treatment groups and control groups. Moreover, weaknesses were identified in most trials using the Cochrane Collaboration's risk of bias tool, while the quality level of Jadad score evaluation indicated "poor." In a word, although MBXD had a positive therapeutic effect on overall clinical efficacy and efficacy under gastroscope, because of the high risk of bias of the included studies, the significant differences observed in this systematic review may be inaccurate. Therefore, further research must be required to acquire specific evidence for efficacy and safety of MBXD in treating GERD. The pathogenesis of GERD remains inadequately explained. Previous studies have demonstrated that numerous potential mechanisms are involved in the development of GERD, including histologic changes of esophageal inflammation [41], antireflux barrier dysfunction [42], obesity [43], psychological factors [44,45], hiatal hernia [46], and transient lower esophageal sphincter relaxation (TLESR) [47]. However, our studies, in modern pharmacological field, are consistent with the evidence for the effectiveness of MBXD for GERD. Experimental data have verified that MBXD can relieve esophageal mucosa injury and reduce the expression of intercellular adhesion molecule-1 and L-selectin in rats with RE [48]. Other data suggest that pungent dispersion bitter purgation (Xinkai Kujiang) method can present favorable treatment effect on RE model rats and the therapeutic   effect may be more obvious along with the treatment course that went by, possibly by achieving through good repair effect on damaged mucosa, increasing the pressure of esophageal sphincter, and inhibiting gastric acid [49]. In addition, a few studies have shown that MBXD can exert its preventive and protective effect on esophageal mucosa by downregulating mRNA expression for calponin and caldesmon, increasing the intracellular free calcium, lowering gastric acidity with modulation of calcitonin-gene-related peptide synthesis in rats with RE [50,51]. In a word, MBXD may be a multitargeting management in treating GERD. To better understand the herbal formulae mechanism, further studies in vitro and in vivo should be conducted. There was significant heterogeneity for secondary outcomes. We checked all of the included studies carefully and found that there was difference of scoring criteria for symptom scores among them. Furthermore, the scores of acid regurgitation, heartburn, and sternalgia were categorized into three different levels (0∼3 , 0∼6 , or 0∼9 ), which may be the main origin of the heterogeneity. In addition, in the included trials, five reported the improvement of acid regurgitation and heartburn [31,35,36,38,39], and two reported sternalgia improvement [31,38]. The quantity of the literatures in this systematic review was too small to yield reliable results, which may contribute to the heterogeneity.
Most evaluations of Chinese medicinal herbs have focused on the efficacy of diseases. And treatment based on syndrome differentiation is a characteristic of TCM. However, the information for TCM syndrome classification Heterogeneity: 2 = 0.40; 2 = 2.17, df = 1 (P = 0.14); I 2 = 54% Figure 12: Forest plot of recurrence rate (random effect model).
was taken into consideration only in five trials [29,32,33,37,38] and these trials presented variations in TCM syndrome classification. Furthermore, of the included twelve trials, although all the Chinese herbal formulae in treatment groups were based on Banxia Xiexin decoction, MBXD contained different additional herb(s). Moreover, the doses, frequencies, and methods of administration were different among these trials. In addition, discrepancies in the herbal medicines themselves including source and preparation were existent. In sum, all of them mentioned above could be a matter of heterogeneity among the evaluated studies. Several limitations of this systematic review were as follows: First, single center, small sample size, and low methodological quality resulted in poor quality of the included RCTs. Moreover, all of the participants in the included trials were Chinese. This geographically limited distribution and poor quality of studies were hard to apply in future large-scale trials. As for the evaluation of publication bias, the power of this systematic review was modest because of the small number of studies, resulting in the possible existence of publication bias for the analysis. Second, only four trials reported the follow-up visits and the follow-up periods were between 1 week and 6 months [31,32,39,40]. In addition, the treatment courses in the twelve studies ranged from 4 weeks to 8 months. Both the follow-up periods and treatment courses were not long enough to assess the longterm efficacy and safety of MBXD for GERD. Third, dropouts from the RCTs were reported only in two trials [29,36], and the missing data were not evaluated by ITT analysis, which produced deviation in assessment of the efficacy of interventions. Fourth, only two trials reported recurrence rate [31,39] and three trials reported side effects [36,38,39]. The minority of literatures reported recurrence rate and side effects, which potentially caused unreliable results and inability to truly reflect general trends. Fifth, discrepancies in interventions among control groups existed. Therefore, potential harm for all medical drugs should be taken into consideration.

Conclusion
Evidence from this systematic review shows that MBXD has a positive efficacy in the treatment of GERD. However, because of limitations of methodological quality and small number of the included studies, recommendations of specific MBXD for GERD cannot be made at present, and these results should be interpreted cautiously. Therefore, further standardized researches with multicenter, large-scale, and rigorous design are needed.