Pantoprazole infusion as adjuvant therapy to endoscopic treatment in patients with peptic ulcer bleeding: Prospective randomized controlled trial

Blackwell Publishing AsiaMelbourne, AustraliaJGHJournal of Gastroenterology and Hepatology0815 93192006 Blackwell Publishing Asia Pty Ltd200621716721Original Article Pantoprazole in bleeding peptic ulcerssa Zargar et al. doi:10.1111/j.1440-1746.2006.04292.x GASTROENTEROLOGY Pantoprazole infusion as adjuvant therapy to endoscopic treatment in patients with peptic ulcer bleeding: Prospective randomized controlled trial Showkat Ali Zargar, Gul Javid, Bashir Ahmad Khan, Ghulam Nabi Yattoo, Altaf Hussain Shah, Ghulam Mohammad Gulzar, Jaswinder Singh Sodhi, Sheikh Abdul Mujeeb, Mushtaq Ahmad Khan, Nisar Ahmad Shah and Hakim Mohamad Shafi Department of Gastroenterology, Sher-i-Kashmir Institute of Medical Sciences, Srinagar, Kashmir, India Key words endoscopic hemostasis, pantoprazole, peptic ulcer bleeding, peptic ulcer rebleeding, proton pump inhibitors, randomized trials. Accepted for publication 30 November 2004. Correspondence Dr Showkat Ali Zargar, Professor and Head, Department of Gastroenterology, Sher-i- Kashmir Institute of Medical Sciences., PO Box 27; Soura Srinagar, Kashmir, India. Email: showkatzargar@yahoo.com Abstract Background and Aim: Following successful endoscopic therapy in patients with peptic ulcer bleeding, rebleeding occurs in 20% of patients. Rebleeding remains the most important determinant of poor prognosis. We investigated whether or not administration of pantoprazole infusion would improve the outcome in ulcer bleeding following successful endoscopic therapy. Methods: In this double-blind, placebo-controlled, prospective trial, patients who had gastric or duodenal ulcers with active bleeding or non-bleeding visible vessel received combined endoscopy therapy with injection of epinephrine and heater probe application. Patients who achieved hemostasis were randomly assigned to receive pantoprazole (80 mg intravenous bolus followed by an infusion at a rate of 8 mg per hour) or placebo for 72 h. The primary end-point was the rate of rebleeding. Results: Rebleeding was lower in the pantoprazole group (8 of 102 patients, 7.8%) than in the placebo group (20 of 101 patients, 19.8%; P = 0.01). Patients in the pantoprazole group required significantly fewer transfusions (1 ± 2.5 vs 2 ± 3.3; P = 0.003) and days of hospitalization (5.6 ± 5.3 vs 7.7 ± 7.3; P = 0.0003). Rescue therapies were needed more frequently in the placebo group (7.8% vs 19.8%; P = 0.01). Three (2.9%) patients in the pantoprazole group and eight (7.9%) in the placebo group required surgery to control their bleeding (P = 0.12). Two patients in the pantoprazole group and four in the placebo group died (P = 0.45). Conclusion: In patients with bleeding peptic ulcers, the use of high dose pantoprazole infusion following successful endoscopic therapy is effective in reducing rebleeding, transfusion requirements and hospital stay. 2006 Blackwell Publishing Asia Pty Ltd Introduction Despite remarkable progress in the treatment of chronic peptic ulcer disease, acute gastroduodenal ulcer bleeding remains a therapeutic challenge with significant morbidity and mortality. Endoscopic therapy using injection or thermal methods significantly reduces rebleeding, the need for surgery and mortality in patients with peptic ulcer bleeding (PUB), and is now recommended as the first hemostatic modality of choice for these patients. 1 Although this therapy achieves successful hemostasis in more than 90% of patients, unfortunately rebleeding occurs in 10 30% of patients, 2 5 with an average of 21%. 6 Because rebleeding has been recognized as the single most important adverse prognostic factor contributing to morbidity and mortality, 7,8 it is likely that further improvements in the outcome will be aimed at preventing rebleeding. Gastric acidity may play an important role in the pathogenesis of rebleeding. Both acid and pepsin may produce adverse effects on coagulation by interfering with the intrinsic and extrinsic coagulation system, fibrinogen polymerization, and platelet aggregation. 8,9 Numerous trials of H 2 receptor antagonists have not consistently shown a significant benefit in such patients. 10,11 However, two recent reviews of the use of a high-dose of omeprazole in patients with PUB concluded that it improves the outcome. 12,13 716 Journal of Gastroenterology and Hepatology 21 (2006) 716 721

SA Zargar et al. Pantoprazole in bleeding peptic ulcers Until now, oral proton pump inhibitors have not been available as parenteral therapy in the acute care setting in many countries, including the USA and India. Pantoprazole is the first parenteral proton pump inhibitor to become available in India and has provided opportunities to evaluate if its use would be beneficial in PUB. Intravenous pantoprazole is especially distinguished by its lack of clinically relevant drug interactions, and it requires no dosage adjustment for patients with renal insufficiency or with mild to moderate hepatic dysfunction. Therefore, we designed a double-blind, placebo-controlled, clinical trial to investigate whether or not administration of high dose pantoprazole infusion would reduce rebleeding after having achieved endoscopic hemostasis in patients with peptic ulcers with active bleeding or nonbleeding visible vessel. Method Study population The present study was conducted in our department (Department of Gastroenterology) between January 2001 and August 2003 and was approved by the Postgraduate Clinical Research and Ethics Committee of Medicine. At our hospital (Sher-i-Kashmir Institute of Medical Sciences, Kashmir, India), a trained faculty member is on duty around the clock because of the heavy demand for emergency endoscopies. All patients admitted to this hospital with a history of hematemesis and/or melena, or who bleed while in hospital, undergo emergency endoscopy as soon as possible, always within 12 h of bleeding or immediately after resuscitation in patients with massive bleeding or shock. The possibility of endoscopic therapy was discussed with the patient and/or their relatives and written informed consent was obtained before the endoscopy. Endoscopic therapy was given if endoscopy showed a peptic ulcer in the stomach or duodenum with active bleeding (spurting hemorrhage, oozing hemorrhage) or stigmata of recent hemorrhage (a non-bleeding visible vessel). Assessment of the presence of those stigmata was made after adherent clots and debris of the ulcer base had been vigorously washed away. Patients who achieved hemostasis with endoscopic therapy were eligible for entry into the study. Patients were excluded if they were under 18 years of age; unable or unwilling to give written informed consent; pregnant or lactating; taking anticoagulants; had more than one possible source of bleeding; had severe coagulopathy (prothrombin time 30% or less than normal, or platelet count less than 50 000/mm 3 ); had previous acid reducing surgeries (vagotomy, gastric resection); were moribund because of terminal cancer or severe comorbid illness; or had bleeding gastric cancer. Endoscopic treatment Endoscopic hemostasis was achieved using a combination of heat probe preceded by epinephrine injection. Epinephrine (1:10 000 diluted in normal saline) was injected in aliquots of 0.5 1 ml into and around the bleeding area. After injection therapy, heater probe thermocoagulation was given to the ulcer using the Olympus heat probe unit with 2.8 mm probe (Olympus USE-2; Olympus, Tokyo, Japan). The energy output of the heat probe was set at 25 J and coaptive pulses (minimum of three) were applied until cavitation and adequate coagulation were obtained. Randomization and pharmacological treatment Immediately after endoscopic control of bleeding, eligible patients were randomly assigned to receive pantoprazole (Sun Pharmaceutical Industries, Ahamadabad, India) given as an intravenous bolus of 80 mg followed by a continuous infusion of 8 mg per hour for 72 h, or identical placebo prepared and dispensed by a pharmacist in a double-blind manner. Pantoprazole or placebo injection was administered through a dedicated line. Patients were not given intravenous bolus H2-antagonist/proton pump inhibitors before endoscopic therapy. Randomization was carried out in the endoscopy laboratory by opening an opaque sealed numbered envelope by the senior endoscopy technologist. Randomization was stratified according to the location of the ulcer (stomach or duodenum). Treatment assignments were made based on random numbers derived from a table of random numbers in blocks of four. Patients and the attending physicians taking care of the patient were blinded to the nature of treatment. The treatment code was known only to the senior endoscopy technologist and pharmacist. After completion of the study, 15 patients with peptic ulcer and active hemorrhage (n = 3) or non-bleeding visible vessel (n = 12) underwent 72-h intragastric ph-metry using a ph electrode connected to a data recorder (Proxima, Light 2, Mantova, Italy). These patients were enrolled after written informed consent was obtained and received pantoprazole as described previously. This was performed to evaluate the effect of pantoprazole on gastric ph. The electrode was positioned in the gastric body under fluoroscopic guidance and continuously recorded ph at 6-s intervals. Clinical monitoring Patients were observed for rebleeding in a high-care facility of the gastroenterology ward. Rebleeding was defined by fresh hematemsis, melena or both, with either shock (systolic blood pressure of 100 mmhg or less, or a pulse rate of 100 per minute or more, accompanied by cold sweats, pallor, oliguria); or a fall in hemoglobin of 2 g/dl or more over a 24-h period after initial stabilization of vital signs. Patients meeting these criteria underwent emergency endoscopy within 4 h to confirm the diagnosis of rebleeding. Rebleeding was managed in both groups with repeat endoscopic therapy as before. Failure of endoscopic retreatment or occurrence of a second rebleed constituted indications for surgery. Patients were given standard medical treatment for peptic ulcer bleeding. Patients vital signs were checked every hour during the first 12 h, every 2 h for the second 12 h and 4 h thereafter until they were discharged. The hemoglobin level and hematocrit were checked at least once daily, and a blood transfusion was given if the hemoglobin level fell to 9 g/dl or less, or vital signs deteriorated. Adverse effects were monitored throughout the study in both groups. After 3 days, all patients received pantoprazole 40 mg orally once daily for 6 weeks; those positive for Helicobacter pylori were treated with triple therapy. Patients underwent clinical examinations on weeks 1, 2, 4 and 6 and repeat endoscopy at 8 weeks. The primary end-point was the rate of rebleeding. Secondary end-points were the need for rescue therapy, need for surgery, Journal of Gastroenterology and Hepatology 21 (2006) 716 721 717

Pantoprazole in bleeding peptic ulcers SA Zargar et al. mortality, duration of hospital stay; and blood transfusion requirements. Statistical analysis The sample size estimation was based on an expected rate of rebleeding of 20% after emergency endoscopic therapy. The trial was designed to detect a 33% difference in favor of the pantoprazole infusion with a type I error of 0.05 and a type II error of 0.8. At least 98 patients were required for each group. 14 Analyses were performed on an intention-to-treat basis and included all patients who underwent randomization. All data were expressed as the mean ± standard deviation. Quantitative data between two treatment groups were compared using the Student s t-test for parametric data and the Mann Whitney U-test for non-parametric data (blood transfusions and hospitalization). Categorical data were compared with Pearson s χ 2 test and Fisher s exact test. The relative risks and 95% confidence intervals associated with proportions were calculated. A two-tailed P-value of less than 0.05 was considered significant. Statistical analysis was carried out with SPSS for Windows (version 7.5.1; SPSS, Chicago, IL, USA). Results During the study period, 537 patients with PUB were seen. The prevalence of various types of stigmata of recent hemorrhage were as follows: 91 (16.9%) active bleeders (spurter and oozing); 126 (23.5%) non-bleeding visible vessel; 103 (19.2%) adherent clot or flat red spot; and 217 (40.4%) clean base. Of these, 217 patients who revealed active bleeding (91 patients) or non-bleeding visible vessel (126 patients) underwent emergency endoscopic therapy. Initial endoscopic hemostasis was obtained in 209 (96.3%) patients. Endoscopic treatment was unsuccessful in eight patients due to torrential bleeding that obscured the bleeding area and prevented adequate endoscopic treatment; these patients were treated by emergency surgery. Six other patients were excluded because they had advanced malignant disease (two patients); severe coagulopathy (one patient); severe comorbid illness (one patient); or were less than 14 years of age (two patients). The remaining 203 patients underwent randomization; 102 received pantoprazole and 101 received placebo. The groups were well matched with respect to patient and endoscopic features (Table 1), however, the mean age of patients was higher in the pantoprazole group than in the placebo group. Although the median number of heater probe pulses used was higher in the pantoprazole group compared to the placebo group, the mean number of pulses used was not significantly different in the two groups (6.6 ± 2 vs 6.7 ± 1.8; P = 0.72) (Table 1). Moreover, the mean number of heater probe pulses required in relation to different stigmata of hemorrhage was not different in the two groups (Table 2). (relative risk 0.35; 95% confidence interval 0.09 1.37; P = 0.12). Two (2%) patients in the pantoprazole group died compared with four (4%) patients in the placebo group (P = 0.45); none of the deaths in either group was caused by rebleeding. Among the patients who died, three (two in the placebo group and one in the pantoprazole group) were inpatients at the onset of bleeding. A total of 23 rescue therapies (15 endoscopic retreatment, three endoscopic retreatment and surgery, and five surgery alone) were given to 20 patients in the placebo group compared with nine (six endoscopic retreatment, one endoscopic retreatment and surgery, two surgery alone) in the pantoprazole group (P = 0.007). The subgroup analysis of the rate of rebleeding according to stigmata of ulcer related hemorrhage at the time of randomization also showed that pantoprazole therapy was associated with significant reductions in rates of rebleeding among patients with spurting, oozing and non-bleeding visible vessel (Table 4). Hospital stay and transfusion requirements Although the number of transfusions before randomization was similar in both groups (P = 0.9), after randomization it was significantly higher in the placebo group than in the pantoprazole group (1.6 ± 2.6 vs 0.7 ± 1.9 units, P = 0.0005, Mann Whitney U-test). Twenty-three (22.5%) patients in the pantoprazole group and 41 (40.6%) patients in the placebo group received transfusions (P = 0.006). The total duration of the hospital stay was significantly more in the placebo group than in the pantoprazole group (7.7 ± 7.3 vs 5.6 ± 5.3 days, P = 0.0003). Among patients who were inpatients at the onset of bleeding, the duration of hospitalization was not significantly different in the two groups. All sideeffects in both groups were minor and their frequencies were similar. None of the patients required termination of the drug infusion. The median time to reach a gastric ph of 6 was 45 min (range 29 118 min) after initial bolus of pantoprazole infusion and persisted around 5.6 7.1 for the remaining 72 h (Fig. 1). The median ph on days 1, 2 and 3 was 6.1, 6.3 and 6.1, respectively. The 25th and 75th percentiles of ph were 6.0 and 6.48, respectively. Duration in time of intragastric ph of 6 or more was 86.5% ± 19.8%. Rebleeding, surgery and mortality Rebleeding occurred in eight (7.8%) patients in the pantoprazole group compared with 20 patients (19.8%) in the placebo group (relative risk 0.35; 95% confidence interval 0.14 0.82; P = 0.01) (Table 3). Emergency surgery was required in three (2.9%) patients in the pantoprazole group compared with eight (7.9%) patients in the placebo group; this difference was insignificant Figure 1 The 72-h median intragastric ph after pantoprazole infusion. 718 Journal of Gastroenterology and Hepatology 21 (2006) 716 721

SA Zargar et al. Pantoprazole in bleeding peptic ulcers Table 1 Clinical and endoscopic data of patients Placebo group Pantoprazol group P-value No. patients 101 102 Mean age (years) 52.4 ± 8.8 55.3 ± 9.2 0.02 Age range (years) 23 85 24 82 No. patients >60 years of age 37 34 0.62 Sex (male/female) 63/38 70/32 0.35 Presentation Hemetemesis 23 20 0.58 Melena 52 55 0.73 Both 26 27 0.91 Shock at presentation 24 28 0.55 Previous ulcer disease 19 16 0.56 Previous upper gastrointestinal bleeding 18 21 0.62 No. who were inpatients at onset of bleeding 14 12 0.66 Smokers 47 52 0.52 NSAIDs users 15 18 0.59 Mean hemoglobin (g/dl) (range) 9.1 ± 2.1 9.4 ± 1.8 0.28 (5 13) (6.1 13.3) Helicobacter pylori positive 58 62 0.63 Associated diseases 22 25 0.64 Cardiac 6 5 0.74 Respiratory 7 7 0.99 Renal 3 2 0.68 Neurological 2 4 0.68 Combination 4 7 0.36 Location of the ulcer Duodenum 85 84 0.73 Stomach 16 18 0.73 High risk ulcers (site) Posterior duodenal wall 21 24 0.64 High lesser curvature 3 2 0.68 Incisura 4 4 1.0 Stigmata of bleeding Spurting bleeding 14 12 0.66 Oozing bleeding 31 25 0.32 Non-bleeding visible vessel 56 65 0.23 Mean ulcer size (cm) (range) 1.3 ± 0.8 1.2 ± 0.8 0.37 (0.7 2.5) (0.8 2.2) Size of ulcer >1.5 cm 14 16 0.71 Mean dose of epinephrine (ml) (range) 11.4 ± 2.2 12.4 ± 2.3 0.002 (5 17) (6 15) No. heater probe pulses used Mean (range) 6.7 ± 1.8 6.6 ± 2 0.72 Median 7 (5 11) 5 (4 11) Discussion Endoscopic therapy is considered the most effective way to stop PUB but the risk of rebleeding is significantly associated with morbidity and mortality. At a low ph, platelet aggregation is severely impaired and pepsin is activated from pepsinogen; both of these mechanisms may promote bleeding by digesting blood clots overlying ulcer craters. This has led investigators to evaluate the efficacy of adjunctive therapy with H 2 receptor antagonists and proton pump inhibitors. A meta-analysis of 27 trials on the use of H 2 receptor antagonists has demonstrated a marginal benefit only among those with bleeding gastric ulcers. 10 The largest trial, enrolling 1005 patients, on the use of famotidine infusion failed to show any benefit. 11 This is due to the inability of H 2 receptor antagonists to maintain ph higher than 4.0 for a long period in patients with PUB because of tachyphylaxis. 15 Conversely, intravenous proton pump inhibitors can achieve faster, greater and longer-lasting acid suppression optimal for stability of clot and hemostasis; they have been shown to increase intragastric ph to greater than 6.0 for 84% to 99% of the day. 15 An 80 mg bolus of pantoprazole followed by 8 mg/h achieved and maintained a ph >6 for 84% of the day; 16 we achieved almost similar results. Journal of Gastroenterology and Hepatology 21 (2006) 716 721 719

Pantoprazole in bleeding peptic ulcers SA Zargar et al. Table 2 Number of heater probe pulses applied to achieve hemostasis according to the stigmata of recent hemorrhage Spurting hemorrhage Non-bleeding visible vessel Oozing hemorrhage Placebo Panto. Placebo Panto. Placebo Panto No. cases 14 12 56 65 31 25 No. heater probe pulses applied 4 0 0 0 2 0 1 5 0 0 26 35 17 14 6 1 0 4 6 2 1 7 or more 13 12 26 22 12 9 Heater probe pulses Mean 9.2 ± 1.9 9.6 ± 1.4 6.3 ± 1.4 6.2 ± 1.7 6.2 ± 1.5 6.2 ± 1.9 Range 6 11 7 11 5 10 4 11 5 10 4 11 P-value 0.58 0.6 0.91 Panto, pantoprazole. Table 3 Results of treatment Placebo group (n = 101) Pantoprazole group (n = 102) Relative risk; 95% confidence interval P-value No. with rebleeding at 2 weeks 20 8 0.35; 0.14 0.82 0.01 At day 3 18 7 0.34; 0.14 0.85 0.02 At day 7 19 8 0.37; 0.15 0.88 0.02 No. requiring urgent surgery 8 3 0.35; 0.09 1.37 0.12 No. requiring rescue therapy 20 8 0.35; 0.14 0.82 0.01 Total no. of rescue therapies 23 9 0.007 Mortality 4 2 0.49; 0.09 2.71 0.45 Mean units of blood transfused (range) Total blood transfused 2 ± 3.3 (0 16) 1 ± 2.5 (0 14) 0.003 Before randomization 0.4 ± 0.9 (0 5) 0.4 ± 0.8 (0 4) 0.9 After randomization 1.6 ± 2.6 (0 12) 0.7 ± 1.9 (0 8) 0.0005 Mean hospital stay (days; range) 7.7 ± 7.3 (3 46) 5.6 ± 5.3 (3 42) 0.0003 Table 4 Outcome of patients with bleeding peptic ulcer according to the stigmata of recent hemorrhage and treatment received Active bleeding Non-bleeding visible vessel Oozing hemorrhage Placebo Panto. Placebo Panto. Placebo Panto No. cases 14 12 56 65 31 25 Rebleeding 6 (42.8) 3 (25) 11 (19.6) 4 (6.1) 3 (9.7) 1 (4) Surgery 2 (14.3) 1 (8.3) 4 (7.1) 1 (1.5) 2 (6.5) 1 (4) Death 1 (6.3) 1 (8.3) 2 (3.6) 1 (1.5) 1 (3.2) 0 Panto, pantoprazole. Our results demonstrated that pantoprazole infusion after initial successful endoscopic control of bleeding from peptic ulcers produced a statistically significant beneficial effect in terms of rebleeding, need for rescue therapy, shorter hospital stay, and a lower need for blood transfusions. The need for salvage surgery and mortality showed a trend towards better results in the pantoprazole group, although this difference was statistically insignificant. However, no published randomized trial is available examining the use of intravenous pantoprazole for PUB. A number of randomized controlled trials published in the English literature have evaluated the role of a high dose of omeprazole administered orally 17 19 and intravenously as intermittent infusion 20 22 or continuous infusion 14,23 25 in patients with PUB; all these trials enrolled 25 or more patients in each of the omeprazole and control groups. All randomized trials on oral and continuous infusion of omeprazole reported improved outcome in terms of reduction in rebleeding, 24,25 the need for surgery, 14 or both. 17 19,23 Three trials using intermittent bolus injection of omeprazole showed mixed results, 20 22 however, omeprazole was used in suboptimal doses and at 8-h intervals which is too long to maintain an intragastric ph of more than 4.0 continuously. Seven randomized controlled trials examined the effect of omeprazole on the rate of rebleeding in patients with peptic ulcer bleeding after achieving initial hemostasis with endoscopic therapy; 14,18,19,21,23 25 all these trials except one 21 reported clinical benefits with omeprazole. From these trials, 14,17 25 two conclusions can safely be made. First, 720 Journal of Gastroenterology and Hepatology 21 (2006) 716 721

SA Zargar et al. Pantoprazole in bleeding peptic ulcers omeprazole is superior to H 2 receptor antagonists or placebo in improving the clinical outcome by decreasing both rebleeding and the need for surgery in patients with PUB with high-risk lesions. Second, although oral omeprazole also reduces rebleeding following endoscopic therapy, continuous intravenous infusion of omeprazole seems to be superior to intermittent bolus administration. Besides pharmacotherapy, routine follow-up ( second-look ) endoscopy combined with endoscopic treatment has been used prophylactically to prevent rebleeding. Published controlled trials on the use of prophylactic endoscopic treatment have reported mixed results. 26 29 The main reason for the divergent results most probably arises from the use of different inclusion criteria and inadequate patient numbers. Furthermore, prophylactic endoscopic retreatment has several disadvantages: it is uncomfortable for the patient, expensive and increases workload. Although the present evidence that prophylactic endoscopic retreatment is of value is not good, it remains possible that such an approach will be of value in selected high-risk patients. In summary, our findings indicate that after endoscopic hemostasis of PUB, a high-dose pantoprazole infusion reduces the rate of rebleeding, the length of hospital stay, the need for rescue therapies and blood transfusions. Acknowledgments The authors thank Nazir Ahmad Pottoo, Chief Pharmacist, Drug and Pharmacy and his staff, Ghulam Nabi Dar, Technical Officer, Endoscopy Unit, Ghulam Mustafa, Technical Officer, Motility Laboratory, and their staff for their assistance in this study. We greatly acknowledge the director of our institute who supported the study. References 1 Consensus Development Panel. Consensus statement on therapeutic endoscopy and bleeding ulcers. JAMA 1989; 262: 1369 72. 2Kubba AK, Murphy W, Palmer KR. Endoscopic injection for bleeding peptic ulcer: a comparison of adrenaline alone with adrenaline plus human thrombin. Gastroenterology 1996; 111: 623 8. 3 Lin HJ, Wang K, Perng CL, Lee CH, Lee SD. Heat probe thermocoagulation and multipolar electrocoagulation for arrest of peptic ulcer bleeding: a prospective randomized comparative trial. J. Clin. Gastroenterol. 1995; 21: 99 102. 4 Laine L. Multipolar electrocoagulation versus injection therapy in the treatment of bleeding peptic ulcers: a prospective randomized trial. Gastroenterology 1990; 99: 1303 6. 5 Lin HJ, Lee FY, Kang WM, Tsai YT, Lee SD, Lee CH. Heat probe thermocoagulation and pure alcohol injection in massive peptic ulcer hemorrhage. Gut 1990; 31: 753 7. 6 Laine L, Peterson WL. Bleeding peptic ulcer. N. Engl. J. Med. 1994; 331: 717 27. 7 Clason AE, Macleod DAD, Elton RA. Clinical factors in the prediction of further hemorrhage or mortality in acute upper gastrointestinal hemorrhage. Br. J. Surg. 1986; 73: 985 7. 8 Rockall TA, Logan RFA, Devlin HB, Northfield TC. Risk assessment after acute upper gastrointestinal hemorrhage. Gut 1996; 38: 316 21. 9 Green FW Jr, Kaplan MM, Curtis LE, Levine PH. Effect of acid and pepsin on blood coagulation and platelet aggregation: a possible contributor to prolonged gastroduodenal mucosal hemorrhage. Gastroenterology 1978; 74: 38 43. 10 Collins R, Langman M. Treatment with histamine H2 antagonists in acute gastrointestinal hemorrhage. N. Engl. J. Med. 1985; 313: 660 6. 11 Walt RP, Cottrell J, Mann SG, Freemantle NP, Langman MI. Continuous intravenous famotidine for hemorrhage from peptic ulcer. Lancet 1992; 340: 1058 62. 12 Zed PJ, Loewen PS, Slavik RS, Marra CA. Meta-analysis of proton pump inhibitors in treatment of bleeding peptic ulcers. Ann. Pharmacother. 2001; 35: 1528 34. 13 Morgan D. Intravenous proton pump inhibitors in the critical care setting. Crit. Care Med. 2002; 30 (6 Suppl.): S369 72. 14 Hasselgren G, Lind T, Lundell L et al. Continuous intravenous infusion of omeprazole in elderly patients with peptic ulcer bleeding. Results of a placebo-controlled multicenter study. Scand. J. Gastroenterol. 1997; 32: 328 33. 15 Netzer P, Gaia C, Sandoz M et al. Effect of repeated injection and continuous infusion of omeprazole and ranitidine on intragastric ph over 72 hours. Am. J. Gastroenterol. 1999; 94: 351 7. 16 Brunner G, Luna P, Hartmann M, Wurst W. Optimizing the intragastric ph as a supportive therapy in upper GI bleeding. Yale J. Biol. Med. 1996; 69: 225 31. 17 Khuroo MS, Yattoo GN, Javid G et al. A comparison of omeprazole and placebo for bleeding peptic ulcer. N. Engl. J. Med. 1997; 336: 1054 8. 18 Javid G, Masoodi I, Zargar SA et al. Omeprazole as adjuvant therapy to endoscopic combination injection sclerotherapy for treating bleeding peptic ulcer. Am. J. Med. 2001; 111: 280 4. 19 Kaviani MJ, Hashemi MR, Kazemifar AR et al. Effect of oral omeprazole in reducing re-bleeding in bleeding peptic ulcers: a prospective, double-blind, randomized, clinical trial. Aliment. Pharmacol. Ther. 2003; 17: 211 16. 20 Daneshmend TK, Hawkey CJ, Langman MJ, Logan RF, Long RG, Walt RP. Omeprazole versus placebo for acute upper gastrointestinal bleeding: randomised double blind controlled trial. BMJ 1992; 304: 143 7. 21 Villanueva C, Balanzo J, Torras X et al. Omeprazole versus ranitidine as adjunct therapy to endoscopic injection in actively bleeding ulcers. A prospective and randomized study. Endoscopy 1995; 27: 308 12. 22 Lanas A, Artal A, Blas JM, Arroyo MT, Lopez-Zaborras J, Sainz R. Effect of parenteral omeprazole and ranitidine on gastric ph and the outcome of bleeding peptic ulcer. J. Clin. Gastroenterol. 1995; 21: 103 6. 23 Schaffalitzky de Muckadell OB, Havelund T, Harling H et al. Effect of omeprazole on the outcome of endoscopically treated bleeding peptic ulcers. Randomized double-blind placebo-controlled multicentre study. Scand. J. Gastroenterol. 1997; 32: 320 7. 24 Lau JYW, Sung JJY, Lee KKC et al. Effect of intravenous omeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers. N. Engl. J. Med. 2000; 343: 310 16. 25 Lin HJ, Lo WC, Lee FY, Perng CL, Tseng GY. A prospective randomized comparative trial showing omeprazole prevents rebleeding in patients with bleeding peptic ulcer after successful endoscopic therapy. Arch. Intern. Med. 1998; 158: 54 8. 26 Villanueva C, Balanzo J, Torras X, Soriano G, Sainz S, Vilardell F. Value of second-look endoscopy after injection therapy for bleeding peptic ulcer: a prospective and randomized trial. Gastrointest. Endosc. 1994; 40: 34 9. 27 Saeed ZA, Cole RA, Ramirez FC, Schneider FE, Hepps KS, Graham DY. Endoscopic retreatment after successful initial hemostasis prevents ulcer rebleeding: a prospective randomized trial. Endoscopy 1996; 28: 288 94. 28 Rutgeerts P, Rauws E, Wara P et al. Randomized trial of single and repeated fibrin glue compared with injection of polidocanol in treatment of bleeding peptic ulcer. Lancet 1997; 350: 692 6. 29 Messmann H, Schaller P, Andus T et al. Effect of programmed followup examinations on the rebleeding rates of gastric or duodenal peptic ulcers treated by injection therapy: a prospective randomized controlled trial. Endoscopy 1998; 30: 583 9. Journal of Gastroenterology and Hepatology 21 (2006) 716 721 721