Efficacy of Sucralfate in Reflux Disease in comparison to H 2 – Receptor Antagonist : A Meta-Analysis of Randomized Trials

Background and Aim: Reflux esophagitis is characterized by the erosions of esophagus due to gastric acids. H2-Recptor antagonists are considered as effective therapy. We compared sucralfate with H2-receptor antagonist for treatment of reflux esophagitis. Methods: Seven studies are selected from different databases (PUBMED, MEDLINE, COCHRANE LIBRARY, CINAHL etc.) comparing the treatment of sucralfate with H2-receptor antagonists (cimetidine and ranitidine). All studies selected are randomized controlled clinical trials. We applied inclusion and exclusion criteria for selection of studies. We also checked for heterogeneity and publication bias. We calculated odds ratio and 95% confidence interval for each study. We searched for national library of medicine’s clinical trial registry for any unpublished data. Results: Seven studies consisting of 319 patients finally selected for meta-analysis. We evaluated confidence interval and odds ratio for each study. None of the study show statistical significant result (p>0.05). The overall effect obtained by combining studies shows no statistical significant result (OR= 1.357, 95% CI=0.834 to 2.206, P-value=0.219, I2=0) between sucralfate and H2-recptor antagonist. There is no heterogeneity among the studies (I2=0, χ2 =4.8). Conclusion: We can conclude that sucralfate is an effective alternate for treatment of reflux disease. Renesh Bedre1,Utkarsh Raj2, and Pritish Varadwaj2* Renesh Bedre1,Utkarsh Raj2, and Pritish Varadwaj2* 1Louisiana State University, Agricultural Center, Baton Rouge, LA. 2Department of Bioinformatics, Indian Institute of Information Technology, Allahabad, India. Correspondence Department of Bioinformatics, Indian Institute of Information Technology, #CC2-4203, Jhalwa Campus, Deoghat, Allahabad-211012, UttarPradesh, Allahabad, INDIA. Email: pritish@iiita.ac.in Phone: +91-532-2922219 (O), +91-941-5264599 (M) History • Submission Date: 03-09-15; • Review completed: 18-06-16; • Accepted Date: 22-06-16. DOI : 10.5530/BEMS.2016.1.4 Article Available online http://www.bemsreports.org Copyright © 2016 Phcog.Net. This is an openaccess article distributed under the terms of the Creative Commons Attribution 4.0 International license. Cite this article : Bedre RH, Raj U, Varadwaj P. Efficacy of Sucralfate in Reflux Disease in comparison to H2 –Receptor Antagonist: A Meta-Analysis of Randomized Trials. BEMS Reports. 2016; 2(1): 18-22. paper, we performed comparison of sucralfate and H2­receptor antagonist by quantitative estimation technique called meta­analysis with R programming.


INTRODUCTION
Gastrointestinal reflux disease is a common gastro intestinal disorder prevalent in western world. 1 Esophagitis occurs when the gastric acid move back to the esophagus.Regular backing of gastric acid causes the burning and erosion of esophagus.Reflux esophagitis causes severe heartburn and regurgitation.If not given proper treatment for healing of esopha gitis, it may result into chronic disorder.The other term to denote reflux esophagitis are gastroesophagal reflux disease (GERD), acid reflux disease etc. some of the common symptoms of reflux esophagitis includes heartburn, belching, upper abdominal pain, salivation,long term cough, vomiting etc. the failure of clearing the esophageal content is also responsible for reflux disease. 1,2 2 receptor antagonists (cimetidine and ranitidine) are considered as most effective treatment for reflux disease since 1976 and these acts by reducing gastric acid secretion. 3,4The other comparable drug sucralfate has the same symptomatic relief as that of H 2 receptor antagonist. 5 But certain studies give the inconsistent result.So, we obtained a combined effect of efficacy of sucralfate in gastrointestinal reflux disease by performing metaanalysis on eligible studies. 6In this for our studies as mentioned in Figure 1 (the flowchart for metaanalyis used in the study).

Inclusion and exclusion criteria
Selection criteria are applied to our selected studies, to include study of interest in metaanalysis.The inclusion criteria for study is 1.The study should be either double blind or single blind randomized control trial 2. The intervention treatment is with sucralfate.3. The study is compared with H 2 receptor antagonist (ranitidine or cimetidine).4. Patient involved in study should have manifestation of esophagitis before entering into the study.5.The healing of esophagitis occurs at four, eight and twelve weeks.Of 1760 identified trials, only eight trials met our inclusion criteria. 714he one study from eight studies is excluded due to patient may not had esophagitis manifestation before entering into the study. 13Finally, only seven trials included in our study (Table 1).The study selected for meta analysis is all having same protocol for treatment.Information on healing of the symptoms of esophagitis is extracted from the trials.We have not applied any exclusion criteria.All the selected studies reviewed and obtained full texts for further evaluation in statistical analysis.

Extraction of data
From the selected studies, all data needed for the metaanalysis is obtained and feed to the statistical analysis.The data abstracted is 1.Name of studies 2. Number of patient (Number of men and women participants in study) 3. Year of publication 4. Location of studies 5. Study design 6. Age of patient 7. Alcohol consumption within patients 8. Smokers patients 9. Randomization ratio of patients.This data used in the metaanalysis.We contacted to authors if data is seem to be insufficient.The data from different studies is compared to each other.

Outcome measures
We have designed the endoscopically healing of ulcers as our primary outcome.From different study, healing of ulcers is occurred at interval four, eight and twelve weeks.The complete healing measured by endo scopically is taken into consideration.We combined this data as our outcome measure for metaanalysis.There are also secondary outcomes such as epigastric pain, nausea, headache but these are not considered in this study.

Identification of heterogeneity and publication bias
All the studies selected for metaanalysis are subjected to the estimation of heterogeneity and publication bias measurement.Funnel plot is used for the assessment of the publication bias within the studies. 15Asymmetry of funnel plot leads to the publication bias. 15,16Heterogeneity measure ment is done by chisquare (χ 2 ) statistics and I 2 statistics.Pvalue less than 0.10 are indication of significant heterogeneity.Heterogeneity in study is estimated using Cochrane's Q and I 2 statistics. 17I 2 statistics is derived from the Cochrane Q.
Where, df = degree of freedom I 2 greater than 50% represent significant heterogeneity in the study.If I 2 is equal to 0% then there is no heterogeneity among the studies.

RESULTS
The data extracted from study is subjected to metaanalysis.Dichotomous data calculated as odd ratio for the representation of effect size.The confidence is measured at 95% level.Pvalue is also measured for calcu lation statistical significant result.We have calculated weight for each study.Random effect model is applied to metaanalysis using DerSimonian and Laird method.Overall, the patient's clinical characteristics distributed among study as 55.31% men, 44.68% women, 59.67% smokers, 22.88% alcohol consumers.The trials are varied from four weeks to twelve weeks.The dosages used in the intervention are 1 gm. of sucralfate four times daily with exception of 6 gm. per day in Bremner (1991).The dosages of ranitidine are 150 mg of tablet twice a daily and those of cimetidine are 400 mg twice or four times daily.As indicated in Table 2, the patients in sucralfate group are 176 (48.88%) and those in H 2 receptor antagonist group are 184 (51.11%) from overall 360 patients.When we analyzed the all studies there is no statistical signi ficant difference is found in all study.All studies are having pvalue greater than 0.05.Overall, we found that there is no clinical significant difference after combining all studies (odds ratio=1.283,95% CI= 0.817 2.017, pvalue=0.279).So, there is no statistical difference between the two treatments.We checked heterogeneity among studies.The test for heterogeneity shows that there is no significant difference among studies (I 2 =0% and χ 2 =5.17, pvalue=0.521).The chisquare statistics (χ 2 ) value obtained is 5.17 (less than degree of freedom) which indicate there is no significant heterogeneity among studies.Pvalue less than 0.10 suggest the hetero geneity.So heterogeneity is absent in the Meta analysis of these studies.The funnel plot for six studies shows that there is no publication bias as depicted in Figure 2. Studies are symmetrically distributed.The statistical calculations are performed using R packages.The packages used are "rmeta" and "meta" for forest plot as indicated in Figure 3.And funnel plot as shown in Figure 2.

DISCUSSION
Sucralfate and H 2 receptor antagonists are prescribed for the treatment of reflux esophagitis.The exaggerated movement of the gastric acid into the lower esophagus through lower sphincter causes the erosions to esophagus. 14The reflux disease may lead to complex condition such as Barrett's epithelium and esophageal adenocarcinoma. 1 It is more common between 20 to 50 year patients and equally distributed in male and female.The drugs used for the treatment for common ulcers are ineffective in treating the esophageal erosions.The most common symptoms of reflux esophagitis are heartburn and regurgitation. 2 The available treatment for the treatment of reflux esophagitis are H 2 receptor    antagonist (cimetidine, ranitidine etc.), proton pump inhibitors (lansoprazole, omeprazole etc.), prokinetics (cisapride, domperidone etc.), sucralfate are commonly used. 19Certain study didn't mention the use of sucralfate in treatment of reflux disease 1 .In contrast to these study, we evaluated two treatments sucralfate and H 2 receptor antagonist for the treatment of reflux esophagitis.We compared the efficacy of both drugs using the technique metaanalysis.Metaanalysis is most effective approach for combining individual study.The metaanalysis performed for seven relevant studies containing more than 300 patient's shows that there is no statistical significant difference between the two treatments.We compared the seven different studies Elsborg and Jorgenesen (1991)  Each study contains the different number of patients.We assess the effect of sucralfate on reflux disease in comparison to ranitidine and cimetidine.We compared the seven studies for metaanalysis involving more than 300 subjects.We considered the different baseline characteristic for each study.The numbers of male patients are more than the female patients.
The combined pvalue obtained is 0.279 which is more than 0.05.In this research, we included the publication bias and the heterogeneity to boost our result.We assessed the heterogeneity and publication bias for the study of interest.We obtained the positive result for the publica tion bias and the heterogeneity.The chisquare statistics (χ 2 =5.17) and I 2 =0% shows the absence of heterogeneity in the trials.Funnel plots are used for the assessing of publication bias.Funnel plot shows the scat tered distribution of studies.The symmetry of funnel plot represents the absence of publication bias.We used odd ratio in calculating effect sizes rather than relative risk and hazard ratios.We also calculated the weight of each study.The metaanalysis is performed by using random effect model (DerSimonian and Laird method).Thus analysis of seven clinical trials suggests that we can use sucralfate as potential drug for treatment in place of ranitidine or cimetidine for the gastrointestinal reflux disease.The H 2 receptor antagonists are con sidered the effective treatment for treating gastrointestinal reflux disease still now.Conclusively from the metaanalysis performed on trials com paring treatment of sucralfate and ranitidine or cimetidine, we found that there is no statistical significant between the two treatments for treating reflux disease.From our findings, we can conclude that sucralfate is an effective alternative treatment for treating gastrointestinal reflux disease.The clinical effectiveness of sucralfate and that of H 2 receptor antagonists are comparable.So, we can focus our research on sucralfate for healing of the reflux esophagitis and gastrointestinal disorders.We can also relate sucralfate for other gastrointestinal disorders.
18 A total of 375 patients are involved in analysis from seven different studies.The all studies are published during 1985 to October 2010.All patients are adults.A comparison of sucralfate is made with H 2 receptor antagonist in all studies.Elsborg and Jorgenesen (1991), Tytgat (1987), Hameeteman W. et al. (1987), Ros et al. (1991) compares sucralfate with cimetidine and Bremner (1991), Simon and Mueller (1987), B.K. chopra et al (1992) compares sucralfate with ranitidine.

Figure 1 :
Figure 1: Flow chart for meta-analysis (n= number of studies).

Figure 2 :
Figure 2: Funnel plot for publication bias (funnel plot is showing equal distribution of studies indicating no publication bias).