AL-AZHAR ASSIUT MEDICAL JOURNAL COMPARATIVE STUDY BETWEEN THE EFFICACY OF REBAMIPIDE, SUCRALFATE AND PANTOPRAZOLE IN TREATMENT OF POST BANDING VARICEAL ULCERS Gamal Mohammad Mohammad Soliman 1,Yasser Amer 2 and Sadek Mostafa 3 Departments of Tropical Medicine 1, General Surgery 2 and Internal Medicine 3 faculty of Medicine - Al- Azhar University ABSTRACT Background: Endoscopic variceal band ligation (EVL) is an effective procedure to control and prevent variceal bleeding in patients with liver cirrhosis. Although EVL has some complications, yet these complications are related to post-evl ulcers. Few data exist regarding therapy of post-ligation ulcer and treatment been mostly empirical with drugs used for peptic ulcer diseases. Aim of the work: is to compare between the efficacy of rebamipide, sucralfate and pantoprazole in treatment of post banding variceal ulcers. Methods: seventy five patients with oesophageal varices eligible for elective band ligation represented the population of the study. The patients were allocated into three groups; rebamipide group, they received rebamipide 100 mg 3 times daily; pantoprazole group, they received pantoprazole 40 mg/day orally at morning; sucralfate group, they received sucralfate 1gm every 6 hours, for 14 days beginning at the next day of band ligation. Subjects underwent EGD 14 days after banding. Primary outcomes included the size and number of ulcers and the subjects' reports of bleeding, dysphagia, chest pain and vomiting. Results: At follow-up endoscopy, the number of patients with post-band ulcers and size of ulcers were similar in the three groups. However, the number of ulcers for each patient is statistically significant less in rebamipide group when compared to pantoprazole and sucralfate (P <.001). Chest pain, dysphagia and vomiting scores were not significantly different. Dysphagia was by far the most common symptom with no case of bleeding was reported in all patients of the studied groups. Conclusion: Rebamipide is effective in decreasing the post banding complication and reducing size of ulcer as well as the number of ulcers with no significant effect on post banding ulcer formation. Rebamipide can be used routinely in settings of post-evl as a good alternative to pantoprazole and sucralfate. Key words: Rebamipide, Pantoprazole, Sucralfate, Endoscopic variceal ligation (EVL), Post banding variceal ulcers. INTRODUCTION Esophageal varices are the major complication of portal hypertension. It is detected in about 50% of cirrhosis patients, and approximately 5 15% of cirrhosis patients show newly formed varices or worsening of varices each year (1). Endoscopic variceal ligation (EVL) is a standard endoscopic procedure in the management of acute variceal bleeding and is beneficial in the primary and secondary prophylaxis of esophageal variceal bleeding (2). EVL is associated with complications such as hemorrhage, chest pain, dysphagia, and odynophagia due to post-evl ulcers in the esophageal mucosa (3). The rubber band causes hemostasis, thrombosis and sloughing of variceal column; it slough off in the following 24-72 hours, leaving a shallow ulcer behind(4)that heals within 2 3 weeks, allowing the development of fibrosis in the sub mucosa. In case of premature detachment of the rubber band, before variceal thrombosis, marked alterations of the mucosa can be seen with dilated variceal vessels in necrotic areas (5). The behavior of post-ligation ulcer appears benign because of the instrument design which sucks up mucosa and submucosa leading only to the formation of superficial ulcers. They heal by fibrosis, entrapping only the mucosa, and submucosal venous channels, leaving the muscle layer unaffected(6). Few data exist regarding adjuvant therapy for EVL. The few groups who have attempted to determine if adjuvant therapy reduces complications have reported mixed results (7). Rebamipide is one of the gastroprotective drugs able to intervene effectively in the process of ulcer healing and effectively improve the quality of ulcer healing (8).Clinical and experimental data demonstrate that rebamipide accelerates gastric ulcer healing, prevents ulcer relapse, and protects gastric mucosa against acute injury caused by various noxious agents (9). Sucralfate has a significant role in decreasing the rate of occurrence of postbanding ulcers and as well their size (10). Several studies have reported that proton pump inhibitors (PPIs) decrease the size of post-evl ulcers (11, 12). 28 P a g e
Gamal Mohammad Mohammad Soliman et al THE AIM OF THIS STUDY is to compare between the efficacy of rebamipide, sucralfate and pantoprazole in treatment of post banding variceal ulcers. PATIENTS AND METHODS Study Design This study is a randomized controlled trial. Study Setting and time; This study was conducted in the endoscopy units of department of Tropical Medicine (Al-Hussein and Sayed Galal Uuniversity Hospitals) in the period from November 2013 to April 2014. Inclusion criteria: Patients above the age of 18 years and below age of 65 years presented for elective band ligation of esophageal varices. Exclusion criteria: Patients who had been subjected to injection sclerotherapy sessions or having endoscopically confirmed pre-existing oesophageal ulcers. Patient s ongoing therapy with sucralfate, rebamipide, H2 blockers or proton pump inhibitors. The presence of Barret's esophagus, isolated fundal varices or peptic ulcer disease and previous anti-reflux procedures.diabetic patients, pregnancy, patients with advanced systemic disease as heart failure renal failure or any depleting disease that might affect healing process and\or life expectancy and as well those with suspected malignancy. Allergy to rebamipide, sucralfate, pantoprazole and finally patients who refuse to participate in the trial. The Recruited Patients (75) were randomized into three groups: Group I (n=25) (Rebamipide group): They received rebamipide (Mucosta 100 mg 3 times daily for 14 days beginning at the next day of band ligation). Group II (n=25) (Pantoprazole group): They received pantoprazole, 40 mg/day orally at morning for 14 days beginning at the next day of band ligation). Group III (n=25) (Sucralfate group): This group included 25 patients. They received sucralfate (Gastrofait 1gm every 6 hours for 14 days beginning at the next day of band ligation). Ethical considerations: The objective of the study was explained to the patients who met the eligibility criteria and they were asked to sign a consent form. All the Studied Cases were subjected to the following Complete clinical evaluation;laboratory investigations [To detect the etiology of liver disease, to evaluate the liver function, and to detect the impact of liver disease and portal hypertension on kidney and blood elements]; evaluation of the patients according to Child classification (A, B, C); abdominal ultrasonography and esophagogastroduodenoscopy (EGD) Esophagogastroduodenoscopy: EGD was done to all patients to evaluate the following points and then to conduct the process of esophageal varices band ligation in eligible patients: A. Esophageal varices: to detect number and grade of esophageal varices according to Westby's grading system according to the size at the gastro-esophageal junction into four grades (13): Grade I: Varix is flush with the wall of the esophagus; Grade II: Protrusion of the varix, but not more than half way to the center of the lumen; Grade III: Protrusion of the varix more than half way to the center of the lumen; Grade IV: The varices are so large that they meet at the midline. Also, to detect presence of risky signs e.g.: cherry red spots and red color sign and number of placed bands. B.Portal hypertensive gastropathy (PHG): It's classified, according to consensus statement of Baveno IV meeting into; Mild PHG, mosaiclike pattern; Sever PHG, When mosaic-like pattern is superimposed by any red signs (red point lesions, cherry red spots, and black brown spots) (14).C.Other endoscopic finding. Endoscopic Band Ligation of Oesophageal Varices; the procedure of band ligation was conducted using Saeed multiband ligator shooter then the patients told to come in the predetermined dates for follow up; one week after the banding, two weeks after the first banding. Post-Procedure Follow up and Evaluation One week after the banding: Complete history using a special questionnaire about: 1- Post banding bleeding. 2- Chest pain (no, mild, moderate, sever) whereas. Mild: chest pain that could be tolerated Moderate: could be tolerated in between. Sever: awaken the patient from sleep and need medication 3- Dysphagia (no, mild, moderate, sever) whereas. 29 P a g e
AL-AZHAR ASSIUT MEDICAL JOURNAL Mild: dysphagia that could be tolerated Moderate: could be tolerated in between. Sever: couldn t be tolerated and need intervention. 4- Vomiting. 5- Compliance of patients in taking. Two weeks after the first banding: 1. History was taken about post banding complication and compliance as after one week. 2. EGD to assess for: number and grade of varices, number and size of ulcers (measured using an endoscopic measuring wire designed for ERCP to assess length (Wilson-Cook, Winston-Salem,NC) and an open 5-mm biopsy forceps to approximate width) (Shaheen et al., 2005), number of placed bands and other endoscopic finding. Statistical Analysis The data were processed and analyzed using the statistical package for social sciences (SPSS) program. A significant statistical finding is declared if p-value is less then or equal 0.05]. RESULTS This study was conducted on 75 patients eligible for elective band ligation. The studied groups were matched for age & gender. It is apparent that the majority of patients in both groups were males in the 5th decade, male (56%) were more than female (44%). (table 1). Both groups were also matched regarding the aetiology of liver disease and child-pugh classification (table 1), as well as the prebanding status of oesophageal varices (table 2). All patients of both groups were reevaluated clinically with good history taking 1 st week and 2 nd weeks following band ligation to clarify the possible, expected minor complications of band ligation with special stress on chest pain, dysphagia and rebleeding. Dysphagia was by far the most common symptom occurred in 27 patients (36%) being in; 10 patients (40%) of each pantoprazole and sucralfate groups, and less commonly in rebamipide group seven patients (28%). As regard bleeding, no case of bleeding was reported in all patients of the studied groups The difference between the studied groups regarding these complications (1st week and two weeks following band ligation) proved to be statistically insignificant (P-value >0.05). (Table 3) Also, we studied the number of postbanding ulcers in the studied groups as shown in table 4. In rebamipide group,12 patients (85.71%) had a single ulcer, two patients (14.29%) had two ulcers. However in in pantoprazole group the mean of number of all ulcers was 2.27±0.70. The number of single ulcer was two (13.33%), while number of two ulcers was seven (46.67%) and the number of three ulcers was six (40 %). In sucralfate group the number of single ulcer was one (7.14 %), while the number of two ulcers was eight (57.14%) and the number of three ulcers was five (35.71 %). The difference between the studied groups regarding the number of postbanding ulcers was statistically insignificant. During the follow up endoscopy after two weeks we compared the studied groups regarding the mean size of ulcers as shown in table 4. There is no statistically significant difference as regard size of post banding ulcers after the second week between the studied groups, as the mean size of ulcers in rebamipide group was 4.57 mm ±2.4, while in pantoprazole group was 4.85 mm ±1.972 and in sucralfate group was 4.44 mm ±2.132. 30 P a g e
Gamal Mohammad Mohammad Soliman et al Table 1 Demographic characteristics of the studied groups Parameter Rebamipide Pantoprazole Sucralfate (N=25) (N=25) (N=25) Age (year) (Mean± SD) 51.04±6.95 53.52±6.77 53.480±6.697 Gender Male 12(84.0%) 10 (40.0%) 11 (44.0%) Female 13(52.0%) 15 (60.0%) 14 (56.0%) Smoking 5 (20.0%) 6 (24.0%) 7 (28.0%) History of Hem / Mele 14 (56.0%) 17 (68.0%) 15 (60.0%) Encephalopathy 3 (12.0%) 5 (20.0%) 6(24.0%) Schistosomiasis 5 (20.0%) 8 (32.0%) 7 (28.0%) HBsAg +ve 1 (4.0%) 0 (0.0%) 1 (4.0%) HCV Ab+ve 24 (96.0%) 24 (96.0%) 24 (96.0%) Mixed HCV& HBV 0 (0.0%) 1 (4.0%) 0 (0.0%) Child score (Mean±SD) 8.40±2.646 8.20±2.398 8.12±2.261 A 9 (36.0%) 11 (44.0%) 9 (36.0%) Childs s class B 8 (32.0%) 8 (32.0%) 9 (36.0%) C 8 (32.0%) 6 (24.0%) 7 (28.0%) P Value t p=0.683 χ2 p =0.850 χ2 p =0.803 χ2 p =0.675 χ2 p =0.551 χ2 p =0.518 χ2 p =0.431 χ2 p =0.431 χ2 p =0.431 χ2 p =0.916 χ2 p =0.958 χ2 p =0.978 χ2 p =0.654 Table 2 Upper Endoscopy finding of the patients of the studied groups at the time of presentation EGD (at presentation) No. of columns Grade of OVs RCS No. of bands PHG Gastric Extension 2 3 4 II II-III III III-IV Rebamipide(N=25) Groups Pantoprazole Sucralfate (N=25) (N=25) Total (N=75) Chi- Square N % N % N % N % Pvalue 3 12 11 44 11 44 3 12 4 16 8 32 5 20 2 8 11 44 12 48 4 16 9 36 12 48 2 8 4 16 2 8 3 12 9 36 7 28 4 16 4 16 9 12 31 41.33 35 46.67 9 12 9 12 24 32 13 17.33 IV 5 20 8 32 7 28 20 26.67 No Yes 3 4 10 40 15 60 6 24 9 36 9 36 11 45.83 16 64 13 54.17 5 20 7 28 10 40 7 28 30 40.54 44 59.46 18 24 26 34.67 5 10 40 10 40 11 44 31 41.33 Mild Sever 12 48 13 52 11 44 13 52 14 56 12 48 No Yes 21 84 4 16 24 96 22 88 1 4 3 12 36 48 39 52 67 89.33 8 10.67 0.91 0.962 0.78 0.919 0.852 0.333 31 P a g e
AL-AZHAR ASSIUT MEDICAL JOURNAL Table 3 Follow up of the studied groups for post banding side effects after one & two weeks of band ligation. Post banding complication Rebamipide(N=25) Groups Pantoprazole Sucralfate Total (N=25) (N=25) (N=75) N % N % N % N % Chi- Square X 2 P- value Chest pain 1 st wk Dysphagia No Mild Moderate 23 92.00 2 8.00 0 0.00 16 64.00 17 68.00 56 74.67 7 28.00 7 28.00 16 21.33 2 8.00 1 4.00 3 4.00 No 18 72.00 15 60.00 15 60.00 48 64.00 Mild 7 28.00 10 40.00 10 40.00 27 36.00 Vomiting No 24 96.00 25 100.00 24 96.00 73 97.33 Chest pain 2nd wk Dysphagia Yes 1 4.00 No Mild Moderate 23 92.00 2 8.00 0 0.00 0 0.00 1 4.00 2 2.67 16 64.00 17 68.00 56 74.67 7 28.00 7 28.00 16 21.33 2 8.00 1 4.00 3 4.00 No 18 72.00 15 60.00 15 60.00 48 64.00 Mild 7 28.00 10 40.00 10 40.00 27 36.00 Vomiting No 24 96.00 25 100.00 24 96.00 73 97.33 Yes 1 4.00 0 0.00 1 4.00 2 2.67 7.953 0.093 1.042 0.594 1.649 0.438 7.953 0.093 1.042 0.594 1.649 0.438 Table 4 The number of patients with post-banding ulcers & number of ulcers per patient as well as mean size of the post banding ulcers in both groups Parameter Rebamipide Pantoprazole Sucralfate P Value Number of patients with post-band ulcers 14 (56.0%) 15 (60.0%) 14 (56.0%) 0.947 Number of ulcers / patients 1 2 12 (85.7%) 2 (14.3%) 2(13.3%) 7(46.7%) 1 (7.1%) 3 0 (0.0%) 6(40.0%) 5 (35.7%) 8 (57.2%) 0.001* Mean size of ulcers mm (Mean± SD) 4.57±2.40 4.85±1972 4.44±2.132 0.872 32 P a g e
Gamal Mohammad Mohammad Soliman et al DISCUSSION EVL is an effective procedure to control and prevent variceal bleeding, but can be complicated by bleeding from post-evl ulcers (15). It is associated with side effects, including pain from ulceration, dysphagia, odynophagia and post ligation bleeding (7). Shallow ulcerations at the site of each ligation are the rule and rarely bleed. The most worrisome complication was bleeding due to ultimately sloughing of bands caused by inadvertent contact with the endoscope during follow-up endoscopy, for this reason, two week intervals between ligation sessions have been adapted(16). Postligation ulcers are necessary accompaniment of EVL, similar to postsclerotherapy ulcers, they heal by time as follows; by the end of the third day, nearly one half of the varices will have overlying ulcers, after one week, all ligated varices will be replaced by superficial ulcers of the same size; more than one half of them will have been healed within two weeks, and all of them will have been completely healed by the end of the third week (10). These ulcers carry a potential risk of upper gastrointestinal bleeding (in very deep ulcers). In view of their rapid spontaneous healing, it is unclear whether the presence of post-band ulceration requires specific therapy to accelerate the healing process or not (7). Vanbiervliet et al studied bleeding related to post banding ulcers following EVL in 605 cirrhotic patients and they reported that bleeding occurred from 2-29 days with a mean of 13.5 following ligation in 21 patients and they concluded that bleeding related to post banding ulcer is a rare but a severe complication (5). Treatment of post-band ulcers has been mostly empirical with drugs used for peptic ulcer diseases with very few data existing regarding their beneficial effect (7). Nijhawan and Rai randomized 30 subjects undergoing elective EVL to treatment with either sucralfate or placebo. No difference in healing was found between the two groups (17). Conversely, treatment of sclerotherapy ulcers with sucralfate was shown to speed healing in a randomized controlled trial of 45 patients (18). However Lo et al found that the combination of ligation, nadolol and sucralfate (triple therapy) proved more effective than band ligation alone in term of prevention of variceal recurrence and upper gastrointestinal re-bleeding as well as variceal re-bleeding (19). Also, Sakr et al found that sucralfate has a significant role in decreasing the rate of occurrence of variceal post-banding ulcers and as well their size (10). Shaheen et al found that, pantoprazole reduces the size of post-banding ulcers after variceal band-ligation in a randomized controlled trial (7).The double-blind RCT by Shaheen et al (7) was quoted in guidelines to support PPI use post-evl (20, 21). Also, Wahib et al in a study comparing pantoprazole versus placebo inreducing post banding ulcers after variceal band ligation in secondary prophylaxis found that PPI has no significant effect on post banding ulcer formation, but it reduces the ulcer size at follow-up endoscopy (22). However Elsayed in randomized controlled trial (for assessing of PPI after EVL) conducted on 46 patients, showed no statistically significant difference in post banding ulcer s size between both groups (placebo &pantoprazol) (23). Rebamipide a novel mucosal-protective and ulcer-healing drug, is widely prescribed in East Asia (24). Two weeks after band ligation we observed that there was no statistically significant difference in the number of patients with post- band ulcers between the studied groups. In rebamipide and sucralfate groups the number of patients with post- band ulcers14 patients (56%) and in pantoprazole groups 15 patients (56%). These data were in agreement with Wahib et al who reported that 13 patients (52%) in pantoprazole group developed post band ulcers (22). Elsayed also demonstrated that the number of patients who developed post banding ulcers 13 patients (68.4%) of pantoprazole group (23). In contrast, Sakr et al (2011) reported in their study that the number of patients with post-band ulcerswho received sucralfate were 12 (38.7%) and 23(74.2%) in placebo group (10). It was evident in this study that the number of post banding ulcers for each patient was significance in rebamipide group compared to sucralfate and pantoprazole groups (P value <0.001) (table 4). After two weeks of banding the rebamipide group, the number of single ulcer was 12 (85.71%) and the number of two ulcers was two (14.29%).While, the mean was 2.27±0.7 ulcers in the sucralfate group; the number of single ulcer was one (7%), the 33 P a g e
AL-AZHAR ASSIUT MEDICAL JOURNAL number of two ulcers was eight (57.14%) and the number of three ulcers was five (35.71%) compared to pantoprazole group where, the number of single ulcer was two (13.33%), the number of two ulcer was seven (46.67%) and the number of three ulcer was six (40%) and this differences were statistically significant. Shaheen et al (7) and El Sayed (23) demonstrated that no significant difference in the number of post banding ulcers in the pantoprazole group and the placebo group. There was no statistically significant difference as regard size of post bandingulcers after the second week between the studied groups, as the mean size of ulcers in rebamipide group it was 4.57mm±2.4 compared to pantoprazole group where it was 4.85mm±1.972 and in sucralfate group was 4.44mm±2.132 (table 25 & figure 34). Our findings were in agreement with Wahib et al (2010) in a randomized controlled trial included 50 patients who were presented for variceal band ligation in secondary prophylaxis. Patients were randomized into two groups, one group received PPI and the other group received a placebo drug also for 14 days beginning at the next day of elective variceal band ligation. They demonstrated that the mean size of ulcers of PPI group was (4.5 mm) compared to (6.72 mm) in the placebo group. Similar findings were documented by other authors 3.7 mm compared to 8.2 mm as reported by Shaheen et al (7) Also, Sakr et al (10) revealed that the mean size of post-banding ulcers in sucralfate group was 2.7 mm ± 1.2. Where, El Sayed (23) found that the mean size of ulcers of drug group was 4.8 mm compared to 5.4 mm in the control group. In this study it seems that rebamipide is effective in decreasing the number of post banding ulcers for each patient after two weeks of post variceal band ligation. However, there were no statistically significant difference between rebamipide and other two drugs (pantoprazole and sucralfate) in reducing size of post-banding ulcers and in decreasing post banding complications as all of them are effective. CONCLUSION Endoscopic variceal band ligation (EVL) is a safe and effective therapeutic and prophylactic method in managing esophageal varices. Although EVL has some complications, yet these complications are minor and transient. Post-banding ulcers are expected; however, they are superficial and rarely bleed. Rebamipide, Pantoprazole and Sucralfate have no significant effect on post banding ulcer formation, but they reduce the ulcer size at follow-up endoscopy. The number of ulcers for each patient is statistically significant less in rebamipide group when compared to Pantoprazole and Sucralfate. REFERENCES 1. Maruyama H, Yokosuka O. Pathophysiology of portal hypertension and esophageal varices. International journal of hepatology. 2012;2012. 2. Tang S-j. Ligation of Esophageal Varices. Video Journal and Encyclopedia of GI Endoscopy. 2013;1(1):83-5. 3. Boo GB, Oh JC, Lee BJ, Lee DM, Kim YD, Park CG, et al. [The effect of proton pump inhibitor on healing of post-esophageal variceal ligation ulcers]. The Korean journal of gastroenterology= TaehanSohwagiHakhoe chi. 2008;51(4):232-40. 4. Bashir S, Roy P. Review Article Upper Gastrointestinal Bleeding A Review of the Literature (Part 4). Indian Journal for the Practising Doctor. 2008;5(2):6-8. 5. Vanbiervliet G, Giudicelli Bornard S, Piche T, Berthier F, Gelsi E, Filippi J, et al. Predictive factors of bleeding related to post banding ulcer following endoscopic variceal ligation in cirrhotic patients: a case control study. Alimentary pharmacology & therapeutics. 2010;32(2):225-32. 6. Young MF, Sanowski RA, Rasche R. Comparison and characterization of ulcerations induced by endoscopic ligation of esophageal varices versus endoscopic sclerotherapy. Gastrointestinal endoscopy. 1993;39(2):119-22. 7. Shaheen NJ, Stuart E, Schmitz SM, Mitchell KL, Fried MW, Zacks S, et al. Pantoprazole reduces the size of postbanding ulcers after variceal band ligation: a randomized, controlled trial. Hepatology. 2005;41(3):588-94. 8. Kangwan N, Park J-M, Kim E-H, Hahm KB. Quality of healing of gastric ulcers: natural products beyond acid suppression. 34 P a g e
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