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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.

1. 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 [8-10], respiratory infection [11-13], spontaneous peritonitis [14], and clostridium difficile bacteria infection [15-17].

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.

2. Materials and Methods

2.1. 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.

2.3. 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", "BanxiaXiexin 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.

2.4. 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 [22-24]: (cure), markedly effective, effective, and ineffective.

2.5. Study Identification. Two investigators (Yunkai 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).

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 couldjudge 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.

2.7. 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 test and inconsistency index statistic ([I.sup.2]) [27]. If substantial heterogeneity existed ([I.sup.2] > 50% or P < 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.

3. Results

3.1. Description of Studies. A total of 1516 records were obtained based on the search strategy. After further screening, 12 RCTs (N = 1210) satisfied the inclusion criteria and were included in this meta-analysis [29-40]. The flowchart of search process and study selection was shown in Figure 1. In addition, 12 studies were published in Chinese. Sample sizes ranged from 60 [34] to 150 [39]. The ages of patients are from 18 to 72 years. The courses of disease were between 2 days and 30 years apart from 2 studies [35, 37] without mention. The therapeutic sessions ranged from 4 weeks [33, 36,38] to 8 months [39]. In addition, as for classification of GERD, NERD was reported by 1 study [29], RE was reported by 7 studies [31, 35-40], and the remaining four studies [30, 32-34] did not mention the classification of GERD. The characteristics of the included studies were presented in Table 1. The constituents of herbal formulae were listed in Table 2.

3.2. 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, 38-40] 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.

3.3. Primary Outcome: Comparison of Overall Clinical Efficacy. Among the included studies, eleven including 1071 patients (553 in the experiment groups versus 518 in the control groups) evaluated overall clinical efficacy [29, 30, 3240]. On subgroup meta-analysis, 4 trials [30, 32-34] reported GERD, 1 trial [29] reported NERD, and 6 trials [31, 35-40] reported RE, and all of them showed statistically significant differences between MBXD and conventional western medicine (OR 3.25; 95% CI: 2.15 to 4.94; P < 0.00001). In addition, because of good homogeneity ([chi square] = 4.60, P = 0.92, [I.sup.2] = 0%), a fixed effect model was adopted to estimate pooled effect size for the analysis (Figure 3). The symmetrical funnel plot showed no potential publication bias in Figure 4.

3.3.1. Subgroup Analysis. Because of variability in evaluating point of the efficacy, we conducted subgroup analysis among studies using different conventional western medicines of PPIs, PPIs + 5-H[T.sub.4] receptor agonists (5-H[T.sub.4]RA), PPIs + [D.sub.2] receptor antagonists ([D.sup.2]RA), and [D.sup.2]RA + [H.sub.2] receptor antagonists ([H.sub.2]RA). In the included studies, PPIs contained omeprazole, lansoprazole, pantoprazole, and rabeprazole; 5H[T.sub.4]RA contained mosapride and cisapride; [D.sup.2]RA contained domperidone; [H.sub.2]RA contained ranitidine. Compared with the control groups, the results of subgroup analysis showed clinical heterogeneity between MBXD and PPIs (OR 3.07; 95% CI 1.15,8.19; P = 0.02) in three trials [29,36,39], between MBXD and PPIs + 5-H[T.sub.4]RA (OR 3.11; 95% CI 1.69, 5.73; P = 0.0003)infourtrials[30,33,38,40], between MBXD andPPIs + [D.sup.2]RA (OR 3.92; 95% CI 1.70,9.07; P = 0.001) in three trials [32, 34, 37], between MBXD and [D.sup.2]RA + [H.sub.2]RA (OR 2.74; 95% CI 0.75,10.06; P = 0.13) in one trial [35], and an overall clinical efficacy (OR 3.25; 95% CI 2.15, 4.94; P < 0.00001) in Figure 5. A funnel plot analysis of the 11 trials [29, 30, 3240] suggested possible publication bias and inclusion of low quality studies because of a significant asymmetry as shown in Figure 6.

3.3.2. Sensitivity Analysis. Because of good homogeneity in primary outcome (7 = 0% for overall clinical efficacy), we did not conduct a sensitivity analysis for overall clinical efficacy.

3.4. Secondary Outcomes

3.4.1. Comparison of Efficacy under Gastroscope. Five of twelve studies reported the efficacy under gastroscope [31, 32, 34, 35, 39]: of 525 patients, 278 were assigned to the groups of MBXD, whereas 247 were assigned to the groups of conventional western medicine. A model of fixed effect was performed to pool estimates because the meta-analysis indicated that [I.sup.2] = 44%. The treatment groups showed moderate heterogeneity in efficacy under gastroscope compared to the control groups (OR 1.96; 95% CI: 1.21 to 3.18; P = 0.006) (Figure 7). The asymmetrical funnel plot in Figure 8 presented potential publication bias.

3.5. Improvement of Symptom Scores. Of all the included trials, eight reported the improvement of symptom scores [30, 31, 33-36, 38, 39]. Although eight studies evaluated the improvement of acid regurgitation [30, 31, 33-36, 38, 39], three were excluded because of different scoring criteria compared with the remaining five studies [30, 33, 34]. Moreover, six studies evaluated the heartburn improvement [31, 34-36, 38, 39], but due to differences in scoring criteria, one was excluded [34]. In addition, six studies described the improvement of sternalgia [30, 31, 34-36, 38], but four were excluded because of being different from the remaining two studies in scoring criteria [30, 34-36]. As for other improvements of symptom scores, these were analyzed qualitatively because only one study respectively described them. However, although the improvements of acid regurgitation, heartburn, and sternalgia were scored by the appropriate guiding principle [23], the scores of them were classified as 0~ 3', 0~6', or 0~9'. Therefore, subgroup analysis was conducted for each symptom score.

3.5.1. Acid Regurgitation. For the reduction of the scores of acid regurgitation, five trials [31, 35, 36, 38, 39] adopted random effect models to estimate pooled effect size for significant heterogeneity ([chi square] = 209.26, P < 0.00001, [I.sup.2] = 98%) (Figure 9). Furthermore, we can conclude from Figure 9 that acid regurgitation improvement had no statistically significant difference for the comparison between experiment groups and control groups (SMD 0.51; 95% CI: -0.90 to 1.92; P = 0.48).

3.5.2. Heartburn. The five studies as mentioned above also reported heartburn [31, 35, 36, 38, 39]. But because of significant heterogeneity in heartburn score ([chi square] = 39.92, P < 0.00001, [I.sup.2] = 90%), a random effect model was performed. Meanwhile, the reduction of heartburn score showed statistically significant difference between treatment groups and control groups (SMD -0.68; 95% CI: -1.25 to -0.12; P = 0.02) (Figure 10).

3.5.3. Sternalgia. For the improvement of sternalgia, two trials used a model of random effect for the existence of significant heterogeneity ([chi square] = 2.60, P = 0.11, [I.sup.2] = 62%) [31, 38]. Moreover, the forest plot of sternalgia presented statistically significant difference between MBXD and conventional western medicine (SMD -0.48; 95% CI: -0.93 to -0.03; P = 0.04) (Figure 11).

3.5.4. Recurrence Rate. In the included studies, although four reported the follow-up after treatment (Yang et al. for 6 months, Wang et al. for 1 week, Chen et al. for 12 weeks, and Huang and Wu for 3 months) [31, 32, 39, 40], only two trials mentioned recurrence rate during the period of follow-up [31, 39]. Furthermore, the forest plot of recurrence rate using random effect models showed no statistically significant differenceinFigure 12(RR0.35; 95%CI: 0.11to 1.16; P = 0.08).

3.5.5. 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 al. for 8 cases and Chen et al. for 14 cases) [36, 39]. Furthermore, the Zhu et al. study reported that 3 cases suffered from diarrhea and 5 cases suffered from abdominal distention. The Chen et al. study reported that 4 cases developed nausea, 7 cases developed headache, 2 cases developed abdominal pain, and 1 case developed soreness of waist. Although these side effects occurred in the period of treatment, they did not have impact on the experimental process.

4. 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, possiblyby 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 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.

5. 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.

http://dx.doi.org/10.1155/2017/9591319

Additional Points

Supporting Information. S1 PRISMA Checklist (DOC). Competing Interests

The authors declare that they have no competing interests.

Authors' Contributions

Ling Hu conceived and designed the experiments. Yunkai Dai and Yunzhan Zhang performed the article search. Yunkai Dai, Danyan Li, and Jintong Ye analyzed the data. Yunzhan Zhang, Danyan Li, Jintong Ye, and Weijing Chen contributed reagents/materials/analysis tools. Yunkai Dai wrote the paper. Yunkai Dai, Yunzhan Zhang, Danyan Li, Jintong Ye, Weijing Chen, and Ling Hu read and approved the final manuscript. Ling Hu contributed to the study supervision. Yunkai Dai and Yunzhan Zhang contributed equally to this work.

Acknowledgments

This study was supported by National Natural Science Foundation of China (no. 81373563); Construction of high-level university of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine (2016) (no. 64); innovation team to foster scientific research projects of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine (2016) (no. 7, no. 2016KYTD07).

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[42] C. Xie, J. Wang, Y. Li et al., "Esophagogastric junction contractility integral reflect the anti-reflux barrier dysfunction in patients with gastroesophageal reflux disease," Journal of Neurogastroenterology and Motility, vol. 23, no. 1, pp. 27-33,2017.

[43] B. F. Nadaleto, F. A. M. Herbella, and M. G. Patti, "Gastroesophageal reflux disease in the obese: pathophysiology and treatment," Surgery, vol. 159, no. 2, pp. 475-486, 2016.

[44] C. E. Wright, M. Ebrecht, R. Mitchell, A. Anggiansah, and J. Weinman, "The effect of psychological stress on symptom severity and perception in patients with gastro-oesophageal reflux," Journal of Psychosomatic Research, vol. 59, no. 6, pp. 415424, 2005.

[45] L. H. Baker, D. Lieberman, and M. Oehlke, "Psychological distress in patients with gastroesophageal reflux disease," The American Journal of Gastroenterology, vol. 90, no. 10, pp. 17971803, 1995.

[46] M. P. Dore, G. M. Pes, G. Bassotti, M. A. Farina, G. Marras, and D. Y. Graham, "Risk factors for erosive and non-erosive gastroesophageal reflux disease and Barrett's esophagus in Nothern Sardinia," Scandinavian Journal of Gastroenterology, vol. 51, no. 11, pp. 1281-1287, 2016.

[47] P. Banovcin Jr., J. Halicka, M. Halickova et al., "Studies on the regulation of transient lower esophageal sphincter relaxations (TLESRs) by acid in the esophagus and stomach," Diseases of the Esophagus, vol. 29, no. 5, pp. 484-489, 2016.

[48] S. Pan, Q. Q. Lan, S. N. Lin, Y. P. Zhu, and Z. F. Xu, "Research of pinelliae decoction for purging stomach-fire on immune function of Esophagus Mucous membrane in rat model of reflux esophagitis," Shanxi Journal of Traditional Chinese Medicine, vol. 28, no. 4, pp. 49-51, 2012.

[49] Y.-P. Tang, S.-M. Liu, W. Wei et al., "Effect of pungent dispersion bitter purgation method on the esophageal mucosal intercellular space of reflux esophagitis model rats," Chinese Journal of Integrated Traditional and Western Medicine, vol. 34, no. 11, pp. 1335-1341, 2014.

[50] X. N. Liu, X. D. Jin, Y. Z. Li, G. L. Liu, and W. Sun, "Influence of BX decoction on mRNA expression for calponin and caldesmon and intracellular free calcium," Chinese Journal of Experimental Traditional Medical Formulae, vol. 14, no. 11, pp. 60-63, 2008.

[51] X. N. Liu, X. D. Jin, Y. Z. Li, G. L. Liu, and W. Sun, "Study on the treatment effect of BX decoction on rat models of reflux esophagitis," Journal ofRadioimmunology, vol. 21, no. 4, pp. 312314, 2008.

Yunkai Dai, Yunzhan Zhang, Danyan Li, Jintong Ye, Weijing Chen, and Ling Hu

Institute of Gastroenterology, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China Correspondence should be addressed to Ling Hu; hl.cn@139.com

Received 17 October 2016; Revised 7 January 2017; Accepted 16 January 2017; Published 19 February 2017

Academic Editor: Kieran Cooley

Caption: Figure 1: Flowchart of the process for literature retrieval.

Caption: Figure 2: Risk of bias summary and graph.

Caption: Figure 4: Funnel plot of overall clinical efficacy.

Caption: Figure 6: Funnel plot of subgroup analysis.

Caption: Figure 8: Funnel plot of efficacy under gastroscope.
Table 1: Characteristics of the studies included in the meta-analysis.

Study ID (first   Classification            Type of syndrome
author, year)         of GERD

He and Han             NERD           Stagnated heat in liver and
2016 [29]                                   stomach syndrome

Shou 2015 [30]          N/A                       N/A

Yang et al.             RE                        N/A
2015 [31]

Wang et al.             N/A             Cold and heat mixed type
2013 [32]

Chen 2013 [33]          N/A             Stagnation of liver and
                                     stomach Qi, stomachache due to
                                      cold, deficiency of stomach,
                                     yin, hyperactivity of stomach,
                                     heat, syndrome of retention of
                                            food in stomach

Sun et al.              N/A                       N/A
2013 [34]

Cao 2013 [35]           RE                        N/A

Zhu et al.
2012 [36]               RE                        N/A

Shen 2012 [37]          re              Cold and heat mixed type

Lu et al.
2010 [38]               re                 Stomach Qi rising

Chen et al.             re                        n/a
2009 [39]

Huang and Wu
2007 [40]               re                        n/a

Study ID (first      Sample size                        Age
author, year)       EG (M/F)      CG (M/F)            (years)

He and Han         45 (26/19)    45 (29/16)            21-68
2016 [29]

Shou 2015 [30]     43 (24/19)    43 (23/20)    E: 51.7 [+ or -] 12.9
                                               C: 52.6 [+ or -] 12.9

Yang et al.        70 (38/32)    69 (35/34)    E: 41.89 [+ or -] 5.67
2015 [31]                                      C: 40.31 [+ or -] 6.98

Wang et al.        56 (30/26)    56 (32/24)            22-64
2013 [32]

Chen 2013 [33]                E:C 58/58
                              M:F 70/46
                                                       21-68

Sun et al.         30 (17/13)    30 (14/16)            21-61
2013 [34]

Cao 2013 [35]      32 (26/6)     32 (22/10)          Mentioned

Zhu et al.
2012 [36]          60 (32/28)    60 (29/31)            19-72

Shen 2012 [37]     43 (27/16)    40 (26/14)            26-70

Lu et al.
2010 [38]          39 (20/19)    39 (19/20)            20-65

Chen et al.        90 (56/34)    60 (39/21)            18-69
2009 [39]
Huang and Wu
2007 [40]          60 (35/25)    60 (38/22)            18-61

Study ID (first          Course of          Duration
author, year)             disease

He and Han            2 days-102 days       8 weeks
2016 [29]

Shou 2015 [30]        1 year-10 years       60 d

Yang et al.        E: 4.56 [+ or -] 1.23    3 months
2015 [31]          C: 4.09 [+ or -] 1.68

Wang et al.           1 year-12 years       8 weeks
2013 [32]

Chen 2013 [33]

                     0.5 year-13 years      4 weeks

Sun et al.            1 year-6 years        30 d
2013 [34]

Cao 2013 [35]               N/A             8 weeks

Zhu et al.
2012 [36]            3 months-12 years      4 weeks

Shen 2012 [37]              N/A             56 days

Lu et al.
2010 [38]                1-6 years          4 weeks

Chen et al.             2-10 weeks          8 months
2009 [39]

Huang and Wu
2007 [40]            2 months-30 years      8 weeks

Study ID (first                      Intervention
author, year)
                                          EG

He and Han        Modified Banxia Xiexin decoction, 100 mL, b.i.d
2016 [29]

Shou 2015 [30]    Banxia Xiexin decoction, 100 mL, t.i.d

Yang et al.       Modified Banxia Xiexin decoction plus Sini Powder,
2015 [31]         b.i.d

Wang et al.       Modified Banxia Xiexin decoction, b.i.d + point
2013 [32]         injection (vitamin B6), q.o.d

Chen 2013 [33]    Modified Banxia Xiexin decoction, b.i.d

Sun et al.        Modified Banxia Xiexin decoction
2013 [34]

Cao 2013 [35]     Modified Banxia Xiexin decoction, 1 dose/d

Zhu et al.        Banxia Xiexin decoction plus Xuanfu Daizhe
2012 [36]         decoction, 250 mL, b.i.d

Shen 2012 [37]    Modified Banxia Xiexin decoction, 100 mL, b.i.d

Lu et al.         Modified Banxia Xiexin decoction, b.i.d
2010 [38]

Chen et al.       Modified Banxia Xiexin decoction, 150 mL, b.i.d
2009 [39]

Huang and Wu      Modified Banxia Xiexin decoction, b.i.d
2007 [40]

Study ID (first            Intervention                Outcome
author, year)                                         measures
                                CG

He and Han                     PPIs                   (1)(4)(5)
2016 [29]

Shou 2015 [30]        PPIs + 5- H[T.sub.4]RA           (1)(6)

Yang et al.             PPIs + [D.sub.2]RA            (2)(3)(6)
2015 [31]

Wang et al.             PPIs + [D.sub.2]RA            (1)(2)(7)
2013 [32]

Chen 2013 [33]        PPIs + 5- H[T.sub.4]RA           (1)(6)

Sun et al.              PPIs + [D.sub.2]RA          (1)(2)(6)(8)
2013 [34]

Cao 2013 [35]       [D.sub.2]RA + [H.sub.2]RA         (1)(2)(6)

Zhu et al.
2012 [36]                      PPIs                    (1)(6)

Shen 2012 [37]          PPIs + [D.sub.2]RA             (1)(9)

Lu et al.             PPIs + 5-H[T.sub.4]RA           (1)(2)(6)
2010 [38]

Chen et al.                    PPIs                (1)(2)(3)(6)(9)
2009 [39]

Huang and Wu          PPIs + 5-H[T.sub.4]RA
2007 [40]                                                (1)

[C]: overall clinical efficacy; [C]: efficacy under gastroscope; [C]:
recurrence rate; [C]: RDQ, SAS, and SDS grading; [C]: SF-36 dimensions
of grading; [R]: symptom integrals; [C]: plasma GAS level; [R]:
pathological effect; [C]: RE classification in gastroscopy; GERD:
gastroesophageal reflux disease; NERD: nonerosive reflux disease;
RE: reflux esophagitis; M: male; F: female; EG: experiment group;
CG: control group; N-A: not applicable; RDQ: reflux disease
diagnostic questionnaire; SAS: self-rating anxiety scale; SDS: self-
rating depression scale; PPIs: proton pump inhibitors; 5-H[T.sub.4]RA:
5- H[T.sub.4] receptor agonists; [D.sub.2]RA: [D.sub.2] receptor
antagonists; [H.sub.2]RA: [H.sub.2]
receptor antagonists.

Table 2: The ingredients of each formula.

Author                  Ingredients of each formula

He and Han 2016        Scutellaria baicalensis Georgi
[29]                          (Huang Qin) 15 g
                       Trichosanthes kirilowii Maxim.
                            (Quan Gua Lou) 10 g
                             Santalum album L.
                              (Tan Xiang) 5 g

Shou 2015 [30]         Scutellaria baicalensis Georgi
                              (Huang Qin) 10 g
                         Zingiber officinale Rose.
                              (Gan Jiang) 6 g
                      Pinellia ternata (Thunb) Breit.
                            (Jiang Ban Xia) 15 g

Yang 2015 [31]            Coptis chinensis Franch.
                              (Huang Lian) 3 g
                            Citrus aurantium L.
                               (Zhi Shi) 10 g
                      Evodia rutaecarpa (Juss.) Benth.
                              (Wu Zhu Yu) 3 g

Wang 2013 [32]            Coptis chinensis Franch.
                              (Huang Lian) 6 g
                        Radix Glycyrrhizae preparata
                             (Zhi Gan Cao) 6 g
                        Fritillaria thunbergii Miq.
                             (Zhe Bei Mu) 10 g

Chen 2013 [33]        Pinellia ternata (Thunb) Breit.
                             (Qing BanXia) 12 g
                         Zingiber officinale Rose.
                              (Gan Jiang) 9 g
                        Radix Glycyrrhizae preparata
                             (Zhi Gan Cao) 3 g
                    Bletilla striata (Thunb.) Reichb. F.
                                (Baiji) 30 g

Sun 2013 [34]             Coptis chinensis Franch.
                             (Huang Lian) 10 g
                      Pinellia ternata (Thunb) Breit.
                              (Qing BanXia) 9g
                      Pinellia ternata (Thunb) Breit.
                              (Fa BanXia) 12g

Cao 2013 [35]             Coptis chinensis Franch.
                              (Huang Lian) 3 g
                                 Haematitum
                             (Dai Zhe Shi) 15 g

Zhu 2012 [36]             Coptis chinensis Franch.
                             (Huang Lian) 10 g
                          Zingiber officinale Rose
                             (Sheng Jiang) 10 g
                            Ziziphus jujuba Mill
                                (DaZao) 10 g

                      Pinellia ternata (Tliunb) Breit.
Shen 2012 [37]                (Fa BanXia) 9 g
                         Zingiber officinale Rose.
                              (Can Jiang) 6 g
                      Pinellia ternata (Tliunb) Breit.
                               (Ban Xia) 15 g

Lu 2010 [38]        Codonopsispilosula (Franch.) Nannf.
                              (Dang Shen) 15g
                            Cleistocactus sepium
                              (Wu Zei Gu) 12 g
                      Pinellia ternata (Tliunb) Breit.
                                (Fa BanXia)

Chen 2009 [39]            Panax ginseng C. A. Mey.
                                 (Ren Shen)
                      Evodia rutaecarpa (Juss.) Benth.
                                (Wu Zhu Yu)
                                 Haematitum
                               (Dai Zhe Shi)

Huang and Wu          Pinellia ternata (Tliunb) Breit.
2007 [40]                      (BanXia) 10 g
                    Codonopsis pilosula (Franch.) Nannf.
                              (Dang Shen) 12 g
                                 Haematitum
                             (Dai Zhe Shi) 15 g

Author                  Ingredients of each formula

He and Han 2016         Fritillaria thunbergii Miq.
[29]                         (Zhe Bei Mu) 15 g
                      Pinellia ternata (Thunb) Breit.
                                (BanXia) 9g

Shou 2015 [30]        Pinellia ternata (Thunb) Breit.
                             (Zhi Ban Xia) 10 g
                          Coptis chinensis Franch.
                              (Huang Lian) 5 g
                       Scutellaria baicalensis Georgi
                              (Huang Qin) 15 g

Yang 2015 [31]              Ziziphus jujuba Mill
                                (Da Zao) 9 g
                          Bambusa tuldoides Munro
                                (Zhu Ru) 9 g
                        Radix Glycyrrhizae preparata
                             (Zhi Gan Cao) 10 g

Wang 2013 [32]         Scutellaria baicalensis Georgi
                              (Huang Qin) 10 g
                         Zingiber officinale Rose.
                              (Gan Jiang) 10 g
                            Citrus aurantium L.
                              (Zhi Qiao) 20 g

Chen 2013 [33]                   Haematitum
                             (Dai Zhe Shi) 15 g
                       Scutellaria baicalensis Georgi
                              (Huang Qin) 9 g

                            Citrus aurantium L.
                              (Zhi Qiao) 12 g

Sun 2013 [34]          Scutellaria baicalensis Georgi
                              (Huang Qin) 10 g
                         Zingiber officinale Rose.
                              (Gan Jiang) 9 g
                       Scutellaria baicalensis Georgi
                            (Chao Huang Qin) 9 g

Cao 2013 [35]               Ziziphus jujuba Mill
                               (Da Zao) 20 g

Zhu 2012 [36]          Scutellaria baicalensis Georgi
                              (Huang Qin) 10 g
                           Inula japonica Tliunb.
                             (Xuan Fu Hua) 15 g
                        Radix Glycyrrhizae preparata
                               (Gan Cao) 8 g

                       Scutellaria baicalensis Georgi
Shen 2012 [37]               (Huang Qin) 6-9 g
                        Radix Glycyrrhizae preparata
                             (Zhi Gan Cao) 6 g
                       Scutellaria baicalensis Georgi
                              (Huang Qin) 12 g

Lu 2010 [38]               Inula japonica Tliunb.
                             (Xuan Fu Hua) 10 g
                          Salvia miltiorrhiza Bge.
                              (Dan Shen) 15 g
                       Scutellaria baicalensis Georgi
                                (Huang Qin)

Chen 2009 [39]              Ziziphus jujuba Mill
                                  (Da Zao)
                            Citrus aurantium L.
                                 (Zhi Qiao)
                            Cynanchum otophyllum
                                 (Bai Shao)

Huang and Wu           Scutellaria baicalensis Georgi
2007 [40]                     (Huang Qin) 10 g
                        Radix Glycyrrhizae preparata
                             (Zhi Gan Cao) 6 g

Author                  Ingredients of each formula

He and Han 2016       Taraxacum mongolicum Hand.-Mazz.
[29]                        (Pu Gong Ying) 15 g
                          Coptis chinensis Franch.
                              (Huang Lian) 6 g

Shou 2015 [30]              Ziziphus jujuba Mill
                               (Da Zao) 10 g
                        Radix Glycyrrhizae preparata
                             (Zhi Gan Cao) 5 g
                         Zingiber officinale Rose.
                              (Gan Jiang) 3 g

Yang 2015 [31]            Bupleurum chinensis DC.
                               (Chai Hu) 10 g
                    Bletilla striata (Thunb.) Reichb. F.
                                 (Baiji) 6g

Wang 2013 [32]      Codonopsis pilosula (Franch.) Nannf.
                              (DangShen) 10 g
                       Perilla frutescens (L.) Britt.
                             (Zi Su Geng) 10 g

Chen 2013 [33]      Codonopsis pilosula (Franch.) Nannf.
                              (Dang Shen) 15 g
                            Ziziphus jujuba Mill
                                (Da Zao) 6 g

                    Codonopsis pilosula (Franch.) Nannf.
                              (Dang Shen) 15 g

Sun 2013 [34]               Ziziphus jujuba Mill
                               (Da Zao) 10 g
                        Radix Glycyrrhizae preparata
                             (Zhi Gan Cao) 6 g
                         Zingiber officinale Rose.
                              (Gan Jiang) 9 g

Cao 2013 [35]           Radix Glycyrrhizae preparata
                             (Zhi Gan Cao) 9 g

Zhu 2012 [36]         Pinellia ternata (Tliunb) Breit.
                            (Jiang Ban Xia) 10 g
                                 Haematitum
                             (Dai Zhe Shi) 30 g

                          Coptis chinensis Franch.
Shen 2012 [37]               (Huang Lian) 3-6 g
                            Ziziphus jujuba Mill
                               (Da Zao) 20 g
                          Coptis chinensis Franch.
                              (Huang Lian) 5 g

Lu 2010 [38]                     Haematitum
                             (Dai Zhe Shi) 10 g
                     Magnolia officinalis Rehd.et Wils.
                               (Hou Po) 10 g
                          Coptis chinensis Franch.
                                (Huang Lian)

Chen 2009 [39]          Radix Glycyrrhizae preparata
                                 (Gan Cao)
                          Bambusa tuldoides Munro
                                  (Zhu Ru)
                   Bletilla striata (Tliunb.) Reichb. F.
                                  (Baiji)

Huang and Wu              Coptis chinensis Franch.
2007 [40]                     (Huang Lian) 3 g
                          Arca subcrenata Lischke
                              (WaLeng Zi) 12 g

Author                  Ingredients of each formula

He and Han 2016          Zingiber officinale Rose.
[29]                          (Gan Jiang) 10 g
                        Radix Glycyrrhizae preparata
                             (Zhi Gan Cao) 6 g

Shou 2015 [30]      Pseudostellaria heterophylla (Miq.)
                            Pax ex pax et Hoffm.
                             (Tai Zi Shen) 15 g

                    Codonopsis pilosula (Franch.) Nannf.
                              (Dang Shen) 15 g

Yang 2015 [31]              Cynanchum otophyllum
                               (BaiShao) 15 g
                            Rubus parvifolius L.
                             (Mao Mei Gen) 12 g

Wang 2013 [32]        Pinellia ternata (Thunb) Breit.
                              (Fa BanXia) 10g
                   Ophiopogon japonicus (Thunb.)Ker-Gawl.
                              (Mai Dong) 10 g

Chen 2013 [33]        Sepiella maindroni de Rochebrune
                             (Hai PiaoXia) 15 g
                          Coptis chinensis Franch.
                              (Huang Lian) 6 g

                   Curcuma wenyujin Y. H. Chen et C. Ling
                               (Yu Jin) 18 g

Sun 2013 [34]             Bambusa tuldoides Munro
                                (Zhu Ru) 9 g
                      Evodia rutaecarpa (Juss.) Benth.
                              (Wu Zhu Yu) 2 g
                    Codonopsis pilosula (Franch.) Nannf.
                              (Dang Shen) 9 g

Cao 2013 [35]              Inula japonica Thunb.
                             (Xuan Fu Hua) 12 g

Zhu 2012 [36]       Pseudostellaria heterophylla (Miq.)
                            Pax ex pax et Hoffm.
                             (Tai Zi Shen) 10 g
                      Evodia rutaecarpa (Juss.) Benth.
                              (Wu Zhu Yu) 3 g

Shen 2012 [37]      Pseudostellaria heterophylla (Miq.)
                            Pax ex pax et Hoffm.
                            (Tai Zi Shen) 9-15 g

                         Zingiber officinale Rose.
                              (Gan Jiang) 3 g

Lu 2010 [38]              Arca subcrenata Lischke
                           (Duan WaLeng Zi) 12 g
                        Radix Glycyrrhizae preparata
                               (Gan Cao) 5 g
                         Zingiber officinale Rose.
                                (Gan Jiang)

Chen 2009 [39]            Bupleurum chinensis DC.
                                 (Chai Hu)
                           Inula japonica Tliunb.
                               (Xuan Fu Hua)
                      Sepiella maindroni de Rochebrune
                              (Hai Piao Xiao)

Huang and Wu             Zingiber officinale Rose.
2007 [40]                     (Gan Jiang) 7 g
                           Inula japonica Tliunb.
                             (Xuan Fu Hua) 9 g

Table 3: Evaluation of methodological quality of the included studies.

Study ID                Baseline          Randomization

He et al. 2016       Comparability     Random number table

Shou 2015            Comparability    Mention not described
Yang et al. 2015     Comparability     Random number table

Wang et al. 2013     Comparability     Random number table
Chen 2013            Comparability    Mention not described
Sun et al. 2013      Comparability     Random number table
Cao 2013             Comparability    Mention not described
Zhu et al. 2012      Comparability    Mention not described

Shen 2012            Comparability     Random number table
Lu et al. 2010       Comparability    Mention not described
                                      Mention not described
Chen et al. 2009     Comparability

Huang et al. 2007    Comparability    Mention not described

Study ID              Double     Withdrawal     Allocation
                     blinding     or dropout    concealment

He et al. 2016          NR       E: 2 cases          NR
                                  C: 4 cases

Shou 2015               NR            NR             NR
Yang et al. 2015        NR            NR             NR

Wang et al. 2013        NR            NR             NR
Chen 2013               NR            NR             NR
Sun et al. 2013         NR            NR             NR
Cao 2013                NR            NR             NR
Zhu et al. 2012       Single-     C: 2 cases         NR
                       blind

Shen 2012               NR            NR             NR
Lu et al. 2010          NR            NR             NR

Chen et al. 2009        NR            NR             NR

Huang et al. 2007       NR            NR             NR

Study ID                     Follow-up           Side effects   Jadad
                                                                scores

He et al. 2016                  NR                    NR           3

Shou 2015                       NR                    NR           1
Yang et al. 2015        6-month recurrence            NR           2
                      (E: 5 cases C: 8 cases)
Wang et al. 2013              1 week                  NR           2
Chen 2013                       NR                    NR           1
Sun et al. 2013                 NR                    NR           2
Cao 2013                        NR                    NR           1
Zhu et al. 2012                 NR                 8 cases         2

Shen 2012                       NR                    NR           2
Lu et al. 2010                  NR                    no           1
                        12-week recurrence
Chen et al. 2009         (E: 3 cases C: 11       C: 14 cases       1
                              cases)
Huang et al. 2007            3 months                 NR           1

NR: not reported; E: experiment group; C: control group.

Figure 3: Forest plot of overall clinical efficacy (fixed effect model).

Study or subgroup                    Experimental        Control

                              Events     Total    Events     Total

2.4.1 GERD
  Chen 2013                     54        58        42        58
  Shou 2015                     40        43        32        44
  Sun et al. 2013               29        30        25        30
  Wang et al. 2013              51        55        43        56
  Subtotal (95% CI)                       186                 188
  Total events                  174                 142
  Heterogeneity: [chi square] = 0.17, df = 3 (P = 0.98); [I.sup.2] = 0%
  Test for overall effect: Z = 4.51 (P < 0.00001)

2.4.2 NERD
  He and Han 2016               41        43        32        41
  Subtotal (95% CI)                       43                  41
  Total events                  41                  32
  Heterogeneity: not applicable
  Test for overall effect: Z = 2.15 (P = 0.03)

2.4.3 RE
  Cao 2013                      28        32        23        32
  Chen et al. 2009              88        90        58        60
  Huang and Wu 2007             54        60        49        60
  Lu et al. 2010                36        39        35        39
  Shen 2012                     40        43        32        40
  Zhu et al. 2012               58        60        54        58
  Subtotal (95% CI)                       324                 289
  Total events                  304                 251
  Heterogeneity: [chi square] = 0.95, df = 5 (P = 0.97); [I.sup.2] = 0%
  Test for overall effect: Z = 2.67 (P = 0.008)
  Total (95% CI)                          553                 518
  Total events                  519                 425

  Heterogeneity: [chi square] = 4.60, df =10 (P = 0.92); [I.sup.2] = 0%
  Test for overall effect: Z = 5.55 (P < 0.00001)

  Test for subgroup
  differences: [chi square] = 3.45, df = 2 (P = 0.18),
  [I.sup.2] = 42.0%

Study or subgroup               Weight           Odds ratio

                                             M-H, fixed, 95% CI

2.4.1 GERD
  Chen 2013                     10.8%        5.14 [1.60, 16.53]
  Shou 2015                      8.3%        5.00 [1.30, 19.25]
  Sun et al. 2013                3.1%        5.80 [0.63, 53.01]
  Wang et al. 2013              11.6%        3.85 [1.17, 12.69]
  Subtotal (95% CI)             33.8%         4.73 [2.41, 9.28]
  Total events
  Heterogeneity: [chi square] = 0.17, df = 3 (P = 0.98); [I.sup.2] = 0%
  Test for overall effect: Z = 4.51 (P < 0.00001)

2.4.2 NERD
  He and Han 2016                5.7%        5.77 [1.16, 28.57]
  Subtotal (95% CI)              5.7%        5.77 [1.16, 28.57]
  Total events
  Heterogeneity: not applicable
  Test for overall effect: Z = 2.15 (P = 0.03)

2.4.3 RE
  Cao 2013                      10.8%        2.74 [0.75, 10.06]
  Chen et al. 2009               5.8%        1.52 [0.21, 11.08]
  Huang and Wu 2007             18.3%         2.02 [0.69, 5.87]
  Lu et al. 2010                10.1%         1.37 [0.29, 6.58]
  Shen 2012                      8.7%        3.33 [0.82, 13.60]
  Zhu et al. 2012                6.9%        2.15 [0.38, 12.21]
  Subtotal (95% CI)             60.5%         2.19 [1.23, 3.90]
  Total events
  Heterogeneity: [chi square] = 0.95, df = 5 (P = 0.97); [I.sup.2] = 0%
  Test for overall effect: Z = 2.67 (P = 0.008)
  Total (95% CI)                100.0%        3.25 [2.15, 4.94]
  Total events

  Heterogeneity: [chi square] = 4.60, df =10 (P = 0.92); [I.sup.2] = 0%
  Test for overall effect: Z = 5.55 (P < 0.00001)

  Test for subgroup differences: [chi square] = 3.45, df = 2
  (P = 0.18), [I.sup.2] = 42.0%

Figure 5: Forest plot of subgroup analysis (fixed effect model).

Study or subgroup                    Experimental        Control

                              Events     Total    Events     Total

2.6.1 PPIs
  Chen et al. 2009              88        90        58        60
  He and Han 2016               41        43        32        41
  Zhu et al. 2012               58        60        54        58
  Subtotal (95% CI)                       193                 159
  Total events                  187                 144
  Heterogeneity: [chi square] = 1.24, df = 2 (P = 0.54); [I.sup.2] = 0%
  Test for overall effect: Z = 2.25 (P = 0.02)

2.6.2 PPIs + 5-HT4RA
  Chen 2013                     54        58        42        58
  Huang and Wu 2007             54        60        49        60
  Lu et al. 2010                36        39        35        39
  Shou 2015                     40        43        32        44
  Subtotal (95% CI)                       200                 201
  Total events                  184                 158
  Heterogeneity: [chi square] = 2.87, df = 3 (P = 0.41); [I.sup.2] = 0%
  Test for overall effect: Z = 3.65 (P = 0.0003)

2.6.3 PPIs + [D.sub.2]RA
  Shen 2012                     40        43        32        40
  Sun et al. 2013               29        30        25        30
  Wang et al. 2013              51        55        43        56
  Subtotal (95% CI)                       128                 126
  Total events                  120                 100
  Heterogeneity: [chi square] = 0.17, df = 2 (P = 0.92); [I.sup.2] = 0%
  Test for overall effect: Z = 3.19 (P = 0.001)

2.6.4 [D.sub.2]RA + [H.sub.2]RA
  Cao 2013                      28        32        23        32
  Subtotal (95% CI)                       32                  32
  Total events                  28                  23
  Heterogeneity: [chi square] not applicable
  Test for overall effect: Z = 1.52 (P = 0.13)

Total (95% CI)                            553                 518
Total events                    519                 425

Study or subgroup              Weight         Odds ratio

                                          M-H, fixed, 95% CI

2.6.1 PPIs
  Chen et al. 2009              5.8%      1.52 [0.21, 11.08]
  He and Han 2016               5.7%      5.77 [1.16, 28.57]
  Zhu et al. 2012               6.9%      2.15 [0.38, 12.21]
  Subtotal (95% CI)            18.3%       3.07 [1.15, 8.19]
  Total events
  Heterogeneity: [chi square] = 1.24, df = 2 (P = 0.54); [I.sup.2] = 0%
  Test for overall effect: Z = 2.25 (P = 0.02)

2.6.2 PPIs + 5-HT4RA
  Chen 2013                    10.8%      5.14 [1.60, 16.53]
  Huang and Wu 2007            18.3%       2.02 [0.69, 5.87]
  Lu et al. 2010               10.1%       1.37 [0.29, 6.58]
  Shou 2015                     8.3%      5.00 [1.30, 19.25]
  Subtotal (95% CI)            47.5%       3.11 [1.69, 5.73]
  Total events
  Heterogeneity: [chi square] = 2.87, df = 3 (P = 0.41); [I.sup.2] = 0%
  Test for overall effect: Z = 3.65 (P = 0.0003)

2.6.3 PPIs + [D.sub.2]RA
  Shen 2012                   % .7 8.     3.33 [0.82, 13.60]
  Sun et al. 2013               3.1%      5.80 [0.63, 53.01]
  Wang et al. 2013             11.6%      3.85 [1.17, 12.69]
  Subtotal (95% CI)            23.4%       3.92 [1.70, 9.07]
  Total events
  Heterogeneity: [chi square] = 0.17, df = 2 (P = 0.92); [I.sup.2] = 0%
  Test for overall effect: Z = 3.19 (P = 0.001)

2.6.4 [D.sub.2]RA + [H.sub.2]RA
  Cao 2013                     10.8%      2.74 [0.75, 10.06]
  Subtotal (95% CI)            10.8%      2.74 [0.75, 10.06]
  Total events
  Heterogeneity: [chi square] not applicable
  Test for overall effect: Z = 1.52 (P = 0.13)

Total (95% CI)                 100.0%      3.25 [2.15, 4.94]
Total events

Heterogeneity: [chi square] = 4.60, df = 10 (P = 0.92); [I.sup.2] = 0%

Test for overall effect: Z = 5.55 (P < 0.00001)

Test for subgroup differences: = 0.29, df = 3 (P = 0.96),
[I.sup.2] = 0%

Figure 7: Forest plot of efficacy under gastroscope (fixed
effect model).

Study or subgroup             Experimental        Control

                       Events     Total    Events     Total

Cao 2013                 28        32        29        32
Chen et al. 2009         82        90        56        60
Sun et al. 2013          27        30        22        30
Wang et al. 2013         49        56        46        56
Yang et al. 2015         60        70        42        69
Total (95% CI)                     278                 247
Total events             246                 195

Study or subgroup        Weight          Odds ratio

                                     M-H, fixed, 95% CI

Cao 2013                 15.4%        0.72 [0.15, 3.53]
Chen et al. 2009         25.3%        0.73 [0.21, 2.55]
Sun et al. 2013           9.3%        3.27 [0.77, 13.83]
Wang et al. 2013         24.4%        1.52 [0.53, 4.33]
Yang et al. 2015         25.6%        3.86 [1.69, 8.81]
Total (95% CI)           100.0%       1.96 [1.21, 3.18]
Total events

Heterogeneity: [chi square] = 7.20, df = 4 (P = 0.13); [I.sup.2] = 44%
Test for overall effect: Z = 2.73 (P = 0.006)

Figure 9: Forest plot of acid regurgitation (random effect model).

Study or subgroup                Experimental            Control

                         Mean     SD     Total   Mean     SD     Total

1.1.1 0~3'
  Cao 2013                1.2     0.1     32      1.5     0.4     32
  Chen et al. 2009       0.51     0.7     90      0.5    0.63     60
  Zhu et al. 2012        0.08    0.01     60     0.03    0.01     60
  Subtotal (95% CI)                       182                     152
  Heterogeneity: [[tau].sup.2] = 5.99; [chi square] = 182.95,
  df = 2 (P < 0.00001); [I.sup.2] = 99%
  Test for overall effect: Z = 0.92 (P = 0.36)
1.1.2 0~6'
  Lu et al. 2010          0.6    0.21     39     0.92    0.54     39
  Subtotal (95% CI)                       39                      39
  Heterogeneity: not applicable
  Test for overall effect: Z = 3.29 (P = 0.001)
1.1.3 0~9'
  Yang et al. 2015       1.23    1.04     70     2.01    2.03     69
  Subtotal (95% CI)                       70                      69
  Heterogeneity: not applicable
  Test for overall effect: Z = 2.80 (P = 0.005)
  Total (95% CI)                          291                     260

Study or subgroup          Weight     Std. mean difference

                                       IV, random, 95% CI

1.1.1 0~3'
  Cao 2013                 19.9%      -1.02 [-1.54, -0.49]
  Chen et al. 2009         20.3%       0.01 [-0.31, 0.34]
  Zhu et al. 2012          19.4%        4.97 [4.24, 5.70]
  Subtotal (95% CI)        59.7%       1.31 [-1.48, 4.09]
  Heterogeneity: [[tau].sup.2] = 5.99; [chi square] = 182.95,
  df = 2 (P < 0.00001); [I.sup.2] = 99%
  Test for overall effect: Z = 0.92 (P = 0.36)
1.1.2 0~6'
  Lu et al. 2010           20.1%      -0.77 [-1.23, -0.31]
  Subtotal (95% CI)        20.1%       -0.77[-1.23, -0.31]
  Heterogeneity: not applicable
  Test for overall effect: Z = 3.29 (P = 0.001)
1.1.3 0~9'
  Yang et al. 2015         20.3%      -0.48 [-0.82, -0.14]
  Subtotal (95% CI)        20.3%      -0.48 [-0.82, -0.14]
  Heterogeneity: not applicable
  Test for overall effect: Z = 2.80 (P = 0.005)
  Total (95% CI)           100.0%      0.51 [-0.90, 1.92]

Heterogeneity: [[tau].sup.2] = 2.52, [chi square] = 209.26, df = 4
(P < 0.00001); [I.sup.2] = 98%

Test for overall effect: Z = 0.71 (P = 0.48)

Test for subgroup differences: [chi square] = 2.75, df = 2 (P =
0.25), [I.sup.2] = 27.2%

Figure 10: Forest plot of heartburn (random effect model).

Study or subgroup              Experimental            Control

                       Mean     SD     Total   Mean     SD     Total

1.2.1 0~3'
  Cao 2013              1.6     0.2     32      2.1     0.2     32
  Chen et al. 2009     0.39    0.66     90     0.49     0.7     60
  Zhu et al. 2012      0.14    0.08     60     0.17    0.09     60
  Subtotal (95% CI)                     182                     152
  Heterogeneity: [[tau].sup.2] = 0.85; [chi square] = 39.38,
  df = 2 (P < 0.00001); [I.sup.2] = 95%
  Test for overall effect: Z = 1.72 (P = 0.09)

1.2.2 0~6'
  Lu et al. 2010       0.71    0.53     39     0.95    0.87     39
  Subtotal (95% CI)                     39                      39
  Heterogeneity: not applicable
  Test for overall effect: Z = 1.45 (P = 0.15)

1.2.3 0~9'
  Yang et al. 2015     1.08    1.01     70     1.59    1.42     69
  Subtotal (95% CI)                     70                      69
  Heterogeneity: not applicable
  Test for overall effect: Z = 2.40 (P = 0.02)
  Total (95% CI)                        291                     260

Study or subgroup       Weight     Std. mean difference

                                    IV, random, 95% CI

1.2.1 0~3'
  Cao 2013              17.3%      -2.47 [-3.13, -1.81]
  Chen et al. 2009      21.1%      -0.15 [-0.47, 0.18]
  Zhu et al. 2012       20.8%      -0.35 [-0.71, 0.01]
  Subtotal (95% CI)     59.2%      -0.95 [-2.02, 0.13]
  Heterogeneity: [[tau].sup.2] = 0.85; [chi square] = 39.38,
  df = 2 (P < 0.00001); [I.sup.2] = 95%
  Test for overall effect: Z = 1.72 (P = 0.09)

1.2.2 0~6'
  Lu et al. 2010        19.9%      -0.33 [-0.78, 0.12]
  Subtotal (95% CI)     19.9%      -0.33 [-0.78, 0.12]
  Heterogeneity: not applicable
  Test for overall effect: Z = 1.45 (P = 0.15)

1.2.3 0~9'
  Yang et al. 2015      21.0%      -0.41 [-0.75, -0.08]
  Subtotal (95% CI)     21.0%      -0.41 [-0.75, -0.08]
  Heterogeneity: not applicable
  Test for overall effect: Z = 2.40 (P = 0.02)
  Total (95% CI)        100.0%     -0.68 [-1.25, -0.12]

Heterogeneity: [[tau].sup.2] = 0.37; [chi square] = 39.92,
df = 4 (P < 0.00001); [I.sup.2] = 90%

Test for overall effect: Z = 2.37 (P = 0.02)

Test for subgroup differences: = 1.07, df = 2 (P = 0.59),
[I.sup.2] = 0%

Figure 11: Forest plot of sternalgia (random effect model).

Study or subgroup                Experimental            Control

                         Mean     SD     Total   Mean     SD     Total

1.3.1 0~6'
  Lu et al. 2010         0.67    0.55     39     0.79    0.48     39
  Subtotal (95% CI)                       39                      39
  Heterogeneity: not applicable
  Test for overall effect: Z = 1.01 (P = 0.31)

1.3.2 0~9'
  Yang et al. 2015       1.12    1.07     70     2.17    1.85     69
  Subtotal (95% CI)                       70                      69
  Heterogeneity: not applicable
  Test for overall effect: Z = 3.96 (P < 0.0001)
  Total (95% CI)                          109                     108

Study or subgroup         Weight     Std. mean difference

                                      IV, random, 95% CI

1.3.1 0~6'
  Lu et al. 2010          45.1%      -0.23 [-0.68, 0.22]
  Subtotal (95% CI)       45.1%      -0.23 [-0.68, 0.22]
  Heterogeneity: not applicable
  Test for overall effect: Z = 1.01 (P = 0.31)

1.3.2 0~9'
  Yang et al. 2015        54.9%      -0.69 [-1.03, -0.35]
  Subtotal (95% CI)       54.9%      -0.69 [-1.03, -0.35]
  Heterogeneity: not applicable
  Test for overall effect: Z = 3.96 (P < 0.0001)
  Total (95% CI)          100.0%     -0.48 [-0.93, -0.03]

Heterogeneity: [[tau].sup.2] = 0.07; [chi square] = 2.60, df = 1
(P = 0.11); [I.sup.2] = 62%

Test for overall effect: Z = 2.11 (P = 0.04)

Test for subgroup differences: [chi square] = 2.60, df = 1
(P = 0.11), [I.sup.2] = 61.5%

Figure 12: Forest plot of recurrence rate (random effect model).

Study or subgroup           Experimental       Control

                     Events    Total    Events    Total

Chen et al. 2009        3        90       11        60
Yang et al. 2015        5        70        8        69
Total (95% CI)                  160                129
Total events            8                 19

Study or subgroup     Weight         Risk ratio

                                 M-H, random, 95% CI

Chen et al. 2009      46.7%       0.18 [0.05, 0.62]
Yang et al. 2015      53.3%       0.62 [0.21, 1.79]
Total (95% CI)        100.0%      0.35 [0.11, 1.16]
Total events

Heterogeneity: [[tau].sup.2] = 0.40; [chi square] = 2.17,
df = 1 (P = 0.14); [I.sup.2] = 54%
Test for overall effect: Z = 1.72 (P = 0.08)
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Article Details
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Author:Dai, Yunkai; Zhang, Yunzhan; Li, Danyan; Ye, Jintong; Chen, Weijing; Hu, Ling
Publication:Evidence - Based Complementary and Alternative Medicine
Article Type:Report
Geographic Code:9CHIN
Date:Jan 1, 2017
Words:10272
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