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COMPARATIVE STUDY BETWEEN THE EFFICACY OF , SUCRALFATE AND IN TREATMENT OF POST BANDING VARICEAL ULCERS Gamal Mohammad Mohammad Soliman1,Yasser Amer2 and Sadek Mostafa3 Departments of Tropical Medicine1, General Surgery2 and Internal Medicine3 faculty of Medicine - Al- Azhar University ـــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ ABSTRACT Background: Endoscopic variceal band ligation (EVL) is an effective procedure to control and prevent variceal bleeding in patients with cirrhosis. Although EVL has some complications, yet these complications are related to post-EVL ulcers. Few data exist regarding 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 The behavior of post-ligation ulcer Esophageal varices are the major appears benign because of the instrument design complication of portal hypertension. It is which sucks up mucosa and submucosa leading detected in about 50% of cirrhosis patients, and only to the formation of superficial ulcers. They approximately 5–15% of cirrhosis patients show heal by fibrosis, entrapping only the mucosa, newly formed varices or worsening of varices and submucosal venous channels, leaving the each year (1). muscle layer unaffected(6). Endoscopic variceal ligation (EVL) is a Few data exist regarding adjuvant therapy standard endoscopic procedure in the for EVL. The few groups who have attempted to management of acute variceal bleeding and is determine if adjuvant therapy reduces beneficial in the primary and secondary complications have reported mixed results (7). prophylaxis of esophageal variceal bleeding (2). Rebamipide is one of the gastroprotective drugs EVL is associated with complications such as able to intervene effectively in the process of hemorrhage, chest pain, dysphagia, and ulcer healing and effectively improve the odynophagia due to post-EVL ulcers in the quality of ulcer healing (8).Clinical and esophageal mucosa (3). experimental data demonstrate that rebamipide The rubber band causes hemostasis, accelerates gastric ulcer healing, prevents ulcer thrombosis and sloughing of variceal column; it relapse, and protects gastric mucosa against slough off in the following 24-72 hours, leaving acute injury caused by various noxious agents a shallow ulcer behind(4)that heals within 2–3 (9). Sucralfate has a significant role in weeks, allowing the development of fibrosis in decreasing the rate of occurrence of post- the sub mucosa. In case of premature banding ulcers and as well their size (10). detachment of the rubber band, before variceal Several studies have reported that proton pump thrombosis, marked alterations of the mucosa inhibitors (PPIs) decrease the size of post-EVL can be seen with dilated variceal vessels in ulcers (11, 12). necrotic areas (5). 28 | P a g e

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THE AIM OF THIS STUDY disease, to evaluate the liver function, and to is to compare between the efficacy of detect the impact of liver disease and portal rebamipide, sucralfate and pantoprazole in hypertension on kidney and blood elements]; treatment of post banding variceal ulcers. evaluation of the patients according to Child PATIENTS AND METHODS classification (A, B, C); abdominal ultrasonography and Study Design esophagogastroduodenoscopy (EGD) This study is a randomized controlled trial. Esophagogastroduodenoscopy: Study Setting and time; This study was EGD was done to all patients to evaluate the conducted in the endoscopy units of department following points and then to conduct the process of Tropical Medicine (Al-Hussein and Sayed of esophageal varices band ligation in eligible Galal Uuniversity Hospitals) in the period from patients: A. Esophageal varices: to detect November 2013 to April 2014. number and grade of esophageal varices Inclusion criteria: Patients above the age of 18 according to Westby's grading system according years and below age of 65 years presented for to the size at the gastro-esophageal junction into elective band ligation of esophageal varices. four grades (13): Grade I: Varix is flush with Exclusion criteria: Patients who had been the wall of the ; Grade II: Protrusion subjected to injection sclerotherapy sessions or of the varix, but not more than half way to the having endoscopically confirmed pre-existing center of the lumen; Grade III: Protrusion of oesophageal ulcers. Patient’s ongoing therapy the varix more than half way to the center of the with sucralfate, rebamipide, H2 blockers or lumen; Grade IV: The varices are so large that proton pump inhibitors. The presence of Barret's they meet at the midline. Also, to detect esophagus, isolated fundal varices or peptic presence of risky signs e.g.: cherry red spots and ulcer disease and previous anti-reflux red color sign and number of placed bands. procedures.Diabetic patients, , B.Portal hypertensive gastropathy (PHG): It's patients with advanced systemic disease as heart classified, according to consensus statement of failure renal failure or any depleting disease that Baveno IV meeting into; Mild PHG, mosaic- might affect healing process and\or life like pattern; Sever PHG, When mosaic-like expectancy and as well those with suspected pattern is superimposed by any red signs (red malignancy. Allergy to rebamipide, sucralfate, point lesions, cherry red spots, and black brown pantoprazole and finally patients who refuse to spots) (14).C.Other endoscopic finding. participate in the trial. Endoscopic Band Ligation of Oesophageal The Recruited Patients (75) were randomized Varices; the procedure of band ligation was into three groups: conducted using Saeed multiband ligator Group I (n=25) (Rebamipide group): shooter then the patients told to come in the They received rebamipide (Mucosta 100 mg 3 predetermined dates for follow up; one week times daily for 14 days beginning at the next after the banding, two weeks after the first day of band ligation). banding. Group II (n=25) (Pantoprazole group): Post-Procedure Follow up and Evaluation  One week after the banding: They received pantoprazole, 40 mg/day orally at Complete history using a special questionnaire morning for 14 days beginning at the next day about: of band ligation). Group III (n=25) (Sucralfate group): 1- Post banding bleeding. This group included 25 patients. They received 2- Chest pain (no, mild, moderate, sever) sucralfate (Gastrofait 1gm every 6 hours for 14 whereas. days beginning at the next day of band ligation).  Mild: chest pain that could be Ethical considerations: The objective of the tolerated study was explained to the patients who met the  Moderate: could be tolerated in eligibility criteria and they were asked to sign a between. consent form. All the Studied Cases were subjected to the  Sever: awaken the patient from following sleep and need 3- Dysphagia (no, mild, moderate, sever) • Complete clinical evaluation;laboratory whereas. investigations [To detect the etiology of liver 29 | P a g e

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 Mild: dysphagia that could be clarify the possible, expected minor tolerated complications of band ligation with special  Moderate: could be tolerated in stress on chest pain, dysphagia and rebleeding. between. Dysphagia was by far the most common symptom occurred in 27 patients (36%) being  Sever: couldn’t be tolerated and in; 10 patients (40%) of each pantoprazole and need intervention. sucralfate groups, and less commonly in 4- Vomiting. rebamipide group seven patients (28%). As 5- Compliance of patients in taking. regard bleeding, no case of bleeding was  Two weeks after the first banding: reported in all patients of the studied groups The difference between the studied groups regarding 1. History was taken about post banding these complications (1st week and two weeks complication and compliance as after one following band ligation) proved to be week. statistically insignificant (P-value >0.05). 2. EGD to assess for: number and grade of (Table 3) varices, number and size of ulcers (measured Also, we studied the number of post- using an endoscopic measuring wire designed banding ulcers in the studied groups as shown in for ERCP to assess length (Wilson-Cook, table 4. In rebamipide group,12 patients Winston-Salem,NC) and an open 5-mm (85.71%) had a single ulcer, two patients biopsy forceps to approximate width) (14.29%) had two ulcers . However in in (Shaheen et al., 2005), number of placed pantoprazole group the mean of number of all bands and other endoscopic finding. ulcers was 2.27±0.70. The number of single Statistical Analysis ulcer was two (13.33%), while number of two The data were processed and analyzed using the ulcers was seven (46.67%) and the number of statistical package for social sciences (SPSS) three ulcers was six (40 %). In sucralfate group program. A significant statistical finding is the number of single ulcer was one (7.14 %), declared if p-value is less then or equal 0.05]. while the number of two ulcers was eight RESULTS (57.14%) and the number of three ulcers was This study was conducted on 75 patients five (35.71 %). The difference between the eligible for elective band ligation. The studied studied groups regarding the number of groups were matched for age & gender. It is postbanding ulcers was statistically apparent that the majority of patients in both insignificant. During the follow up endoscopy groups were males in the 5th decade, male after two weeks we compared the studied (56%) were more than female (44%). (table 1). groups regarding the mean size of ulcers as Both groups were also matched regarding the shown in table 4. There is no statistically aetiology of liver disease and child-pugh significant difference as regard size of post classification (table 1), as well as the banding ulcers after the second week between prebanding status of oesophageal varices (table the studied groups, as the mean size of ulcers in 2). rebamipide group was 4.57 mm ±2.4, while in All patients of both groups were re- pantoprazole group was 4.85 mm ±1.972 and in st evaluated clinically with good history taking 1 sucralfate group was 4.44 mm ±2.132. week and 2nd weeks following band ligation to

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Table 1 Demographic characteristics of the studied groups Rebamipide Pantoprazole Sucralfate Parameter P Value (N=25) (N=25) (N=25) Age (year) (Mean± SD) 51.04±6.95 53.52±6.77 53.480±6.697 tp=0.683 Gender Male 12(84.0%) 10 (40.0%) 11 (44.0%) Female 13(52.0%) 15 (60.0%) 14 (56.0%) χ2p =0.850 Smoking 5 (20.0%) 6 (24.0%) 7 (28.0%) χ2p =0.803 History of Hem / Mele 14 (56.0%) 17 (68.0%) 15 (60.0%) χ2p =0.675 Encephalopathy 3 (12.0%) 5 (20.0%) 6(24.0%) χ2p =0.551 Schistosomiasis 5 (20.0%) 8 (32.0%) 7 (28.0%) χ2p =0.518 HBsAg +ve 1 (4.0%) 0 (0.0%) 1 (4.0%) χ2p =0.431 HCV Ab+ve 24 (96.0%) 24 (96.0%) 24 (96.0%) χ2p =0.431 Mixed HCV& HBV 0 (0.0%) 1 (4.0%) 0 (0.0%) χ2p =0.431 Child score (Mean±SD) 8.40±2.646 8.20±2.398 8.12±2.261 χ2p =0.916 A 9 (36.0%) 11 (44.0%) 9 (36.0%) χ2p =0.958

Childs’s class B 8 (32.0%) 8 (32.0%) 9 (36.0%) χ2p =0.978 C 8 (32.0%) 6 (24.0%) 7 (28.0%) χ2p =0.654

Table 2 Upper Endoscopy finding of the patients of the studied groups at the time of presentation Groups Total Chi- Rebamipide(N=25) Pantoprazole Sucralfate (N=75) Square EGD (at presentation) (N=25) (N=25) N % N % N % N % Pvalue 2 3 12 2 8 4 16 9 12 No. of columns 3 11 44 11 44 9 36 31 41.33 0.91 4 11 44 12 48 12 48 35 46.67 II 3 12 2 8 4 16 9 12 II-III 4 16 2 8 3 12 9 12 Grade of OVs 0.962 III 8 32 9 36 7 28 24 32 III-IV 5 20 4 16 4 16 13 17.33 IV 5 20 8 32 7 28 20 26.67 10 40 9 36 11 45.83 30 40.54 RCS No Yes 0.78 15 60 16 64 13 54.17 44 59.46 3 6 24 5 20 7 28 18 24 No. of bands 0.919 4 9 36 10 40 7 28 26 34.67 5 10 40 10 40 11 44 31 41.33 Mild 12 48 11 44 13 52 36 48 PHG 0.852 Sever 13 52 14 56 12 48 39 52 Gastric 67 89.33 8 No Yes 21 84 4 16 24 96 22 88 1 4 3 12 0.333 Extension 10.67

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Table 3 Follow up of the studied groups for post banding side effects after one & two weeks of band ligation. Groups Chi- Pantoprazole Sucralfate Total Rebamipide(N=25) Square Post banding (N=25) (N=25) (N=75) complication X P- N % N % N % N % 2 value

No 23 92.00 16 64.00 17 68.00 56 74.67 Chest 7.953 Mild 2 8.00 7 28.00 7 28.00 16 21.33 pain 0.093 Moderate 0 0.00 2 8.00 1 4.00 3 4.00 1st wk 1.042 No 18 72.00 15 60.00 15 60.00 48 64.00 Dysphagia 0.594 Mild 7 28.00 10 40.00 10 40.00 27 36.00 1.649 Vomiting No 24 96.00 25 100.00 24 96.00 73 97.33 0.438 Yes 1 4.00 0 0.00 1 4.00 2 2.67 16 64.00 17 68.00 56 74.67 No 23 92.00 Chest 7 28.00 7 28.00 16 21.33 7.953 pain Mild 2 8.00 2 8.00 1 4.00 3 4.00 0.093 Moderate 0 0.00 2nd wk 1.042 No 18 72.00 15 60.00 15 60.00 48 64.00 Dysphagia 0.594 Mild 7 28.00 10 40.00 10 40.00 27 36.00 1.649 Vomiting No 24 96.00 25 100.00 24 96.00 73 97.33 0.438 Yes 1 4.00 0 0.00 1 4.00 2 2.67

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 14 (56.0%) 15 (60.0%) 14 (56.0%) 0.947 post-band ulcers

Number of ulcers / 1 12 (85.7%) 2(13.3%) 1 (7.1%) patients 2 2 (14.3%) 7(46.7%) 8 (57.2%) 0.001* 3 0 (0.0%) 6(40.0%) 5 (35.7%)

Mean size of ulcers mm 4.57±2.40 4.85±1972 4.44±2.132 0.872 (Mean± SD)

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DISCUSSION rate of occurrence of variceal post-banding EVL is an effective procedure to control ulcers and as well their size (10). and prevent variceal bleeding, but can be Shaheen et al found that, pantoprazole complicated by bleeding from post-EVL ulcers reduces the size of post-banding ulcers after (15) . It is associated with side effects, including variceal band-ligation in a randomized pain from ulceration, dysphagia, odynophagia controlled trial (7).The double-blind RCT by and post ligation bleeding (7). Shallow Shaheen et al (7) was quoted in guidelines to ulcerations at the site of each ligation are the support PPI use post-EVL (20, 21). Also, rule and rarely bleed. The most worrisome Wahib et al in a study comparing pantoprazole complication was bleeding due to ultimately versus placebo inreducing post banding ulcers sloughing of bands caused by inadvertent after variceal band ligation in secondary contact with the endoscope during follow-up prophylaxis found that PPI has no significant endoscopy, for this reason, two week intervals effect on post banding ulcer formation, but it between ligation sessions have been reduces the ulcer size at follow-up endoscopy adapted(16). Postligation ulcers are necessary (22). However Elsayed in randomized accompaniment of EVL, similar to controlled trial (for assessing of PPI after EVL) postsclerotherapy ulcers, they heal by time as conducted on 46 patients, showed no follows; by the end of the third day, nearly one statistically significant difference in post half of the varices will have overlying ulcers, banding ulcer’s size between both groups after one week, all ligated varices will be (placebo &pantoprazol) (23). replaced by superficial ulcers of the same size; more than one half of them will have been Rebamipide a novel mucosal-protective and healed within two weeks, and all of them will ulcer-healing drug, is widely prescribed in East have been completely healed by the end of the Asia (24). third week (10). These ulcers carry a potential Two weeks after band ligation we risk of upper gastrointestinal bleeding (in very observed that there was no statistically deep ulcers). In view of their rapid spontaneous significant difference in the number of patients healing, it is unclear whether the presence of with post- band ulcers between the studied post-band ulceration requires specific therapy to groups. In rebamipide and sucralfate groups the accelerate the healing process or not (7). number of patients with post- band ulcers14 Vanbiervliet et al studied bleeding related to patients (56%) and in pantoprazole groups 15 post banding ulcers following EVL in 605 patients (56%). cirrhotic patients and they reported that bleeding occurred from 2-29 days with a mean of 13.5 These data were in agreement with following ligation in 21 patients and they Wahib et al who reported that 13 patients (52%) concluded that bleeding related to post banding in pantoprazole group developed post band ulcer is a rare but a severe complication (5). ulcers (22). Elsayed also demonstrated that the number of patients who developed post banding Treatment of post-band ulcers has been ulcers 13 patients (68.4%) of pantoprazole mostly empirical with drugs used for peptic group (23). In contrast, Sakr et al (2011) ulcer diseases with very few data existing reported in their study that the number of regarding their beneficial effect (7). Nijhawan patients with post-band ulcerswho received and Rai randomized 30 subjects undergoing sucralfate were 12 (38.7%) and 23(74.2%) in elective EVL to treatment with either sucralfate placebo group (10). or placebo. No difference in healing was found between the two groups (17). Conversely, It was evident in this study that the treatment of sclerotherapy ulcers with sucralfate number of post banding ulcers for each patient was shown to speed healing in a randomized was significance in rebamipide group compared controlled trial of 45 patients (18). However Lo to sucralfate and pantoprazole groups (P value et al found that the combination of ligation, <0.001) (table 4). After two weeks of banding nadolol and sucralfate (triple therapy) proved the rebamipide group, the number of single more effective than band ligation alone in term ulcer was 12 (85.71%) and the number of two of prevention of variceal recurrence and upper ulcers was two (14.29%).While, the mean was gastrointestinal re-bleeding as well as variceal 2.27±0.7 ulcers in the sucralfate group; the re-bleeding (19). Also, Sakr et al found that number of single ulcer was one (7%), the sucralfate has a significant role in decreasing the

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number of two ulcers was eight (57.14%) and Post-banding ulcers are expected; however, they the number of three ulcers was five (35.71%) are superficial and rarely bleed. Rebamipide, compared to pantoprazole group where, the Pantoprazole and Sucralfate have no significant number of single ulcer was two (13.33%), the effect on post banding ulcer formation, but they number of two ulcer was seven (46.67%) and reduce the ulcer size at follow-up endoscopy. the number of three ulcer was six (40%) and The number of ulcers for each patient is this differences were statistically significant. statistically significant less in rebamipide group when compared to Pantoprazole and Sucralfate. Shaheen et al (7) and El Sayed (23) demonstrated that no significant difference in REFERENCES the number of post banding ulcers in the 1. Maruyama H, Yokosuka O. pantoprazole group and the placebo group. Pathophysiology of portal hypertension and There was no statistically significant esophageal varices. International journal of difference as regard size of post bandingulcers hepatology. 2012;2012. after the second week between the studied groups, as the mean size of ulcers in rebamipide 2. Tang S-j. Ligation of Esophageal Varices. group it was 4.57mm±2.4 compared to Video Journal and Encyclopedia of GI pantoprazole group where it was Endoscopy. 2013;1(1):83-5. 4.85mm±1.972 and in sucralfate group was 4.44mm±2.132 (table 25 & figure 34). 3. Boo GB, Oh JC, Lee BJ, Lee DM, Kim YD, Park CG, et al. [The effect of proton pump Our findings were in agreement with inhibitor on healing of post-esophageal Wahib et al (2010) in a randomized controlled variceal ligation ulcers]. The Korean journal trial included 50 patients who were presented of gastroenterology= for variceal band ligation in secondary TaehanSohwagiHakhoe chi. prophylaxis. Patients were randomized into two 2008;51(4):232-40. groups, one group received PPI and the other group received a placebo drug also for 14 days 4. Bashir S, Roy P. Review Article Upper beginning at the next day of elective variceal Gastrointestinal Bleeding – A Review of the band ligation. They demonstrated that the mean Literature (Part 4). Indian Journal for the size of ulcers of PPI group was (4.5 mm) Practising Doctor. 2008;5(2):6-8. compared to (6.72 mm) in the placebo group. Similar findings were documented by other 5. Vanbiervliet G, Giudicelli Bornard S, Piche authors 3.7 mm compared to 8.2 mm as reported T, Berthier F, Gelsi E, Filippi J, et al. by Shaheen et al (7) Also, Sakr et al (10) Predictive factors of bleeding related to revealed that the mean size of post-banding post banding ulcer following endoscopic ulcers in sucralfate group was 2.7 mm ± 1.2. variceal ligation in cirrhotic patients: a Where, El Sayed (23) found that the mean size case control study. Alimentary of ulcers of drug group was 4.8 mm compared pharmacology & therapeutics. to 5.4 mm in the control group. 2010;32(2):225-32. In this study it seems that rebamipide is 6. Young MF, Sanowski RA, Rasche R. effective in decreasing the number of post Comparison and characterization of banding ulcers for each patient after two weeks ulcerations induced by endoscopic ligation of post variceal band ligation. However, there of esophageal varices versus endoscopic were no statistically significant difference sclerotherapy. Gastrointestinal endoscopy. between rebamipide and other two drugs 1993;39(2):119-22. (pantoprazole and sucralfate) in reducing size of post-banding ulcers and in decreasing post 7. Shaheen NJ, Stuart E, Schmitz SM, Mitchell banding complications as all of them are KL, Fried MW, Zacks S, et al. Pantoprazole effective. reduces the size of postbanding ulcers after variceal band ligation: a randomized, CONCLUSION controlled trial. Hepatology. Endoscopic variceal band ligation (EVL) 2005;41(3):588-94. is a safe and effective therapeutic and prophylactic method in managing esophageal 8. Kangwan N, Park J-M, Kim E-H, Hahm varices. Although EVL has some complications, KB. Quality of healing of gastric ulcers: yet these complications are minor and transient. natural products beyond suppression. 34 | P a g e

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2013;2013(1):27-8. 16. Waterman M, Gralnek IM. Preventing complications of endoscopic hemostasis in acute upper gastrointestinal hemorrhage. Gastrointestinal endoscopy clinics of North America. 2007;17(1):157-67. 35 | P a g e