ORIGINAL INVESTIGATION

ORIGINAL INVESTIGATION A Prospective Randomized Comparative Trial Showing That Prevents Rebleeding in Patients With Bleeding Peptic Ulcer After Successful Endoscopic Therapy Hwai-Jeng Lin, MD, FACG; Wen-Ching Lo, MD; Fa-Yauh Lee, MD; Chin-Lin Perng, MD; Guan-Ying Tseng, MD Background: A blood clot in a peptic ulcer is unstable in a low ph environment. The use of omeprazole may prevent rebleeding by elevating intragastric ph in patients with bleeding peptic ulcer after hemostasis has been achieved. Objectives: To assess the influence of using omeprazole and cimetidine on 24-hour intragastric ph and to determine their ability to prevent rebleeding after having achieved initial hemostasis in patients with active bleeding or nonbleeding visible vessels. Methods: One hundred patients with bleeding peptic ulcers who had obtained initial hemostasis were enrolled in this randomized comparative trial. In the cimetidine group, a 300-mg intravenous bolus of cimetidine was given, followed by a 1200-mg continuous infusion daily for 3 days. Thereafter, 400 mg of cimetidine was given orally twice daily for 2 months. In the omeprazole group, a 40-mg intravenous bolus of omeprazole was given, followed by 160 mg of continuous infusion daily for 3 days. Thereafter, 20 mg of omeprazole was given orally once daily for 2 months. A ph meter was inserted in each patient s fundus under fluoroscopic guidance after the intravenous bolus of cimetidine or omeprazole had been administered. Results: The stigmata of recent hemorrhage before endoscopic therapy in the omeprazole and cimetidine groups were, respectively, spurting (9 vs 12), oozing (4 vs 9), and nonbleeding visible vessel (37 vs 29) (P.05). The duration of intragastric ph higher than 6.0 was longer in the omeprazole group (mean[±sd], 84.4%±22.9%) than that of the cimetidine group (mean[±sd], 53.5%±32.3%) (P.001). Rebleeding occurred in 2 patients (4%) in the omeprazole group and in 12 patients (24%) in the cimetidine group by day 14 after enrollment (P=.004). There was a tendency for patients in the omeprazole group to require less blood transfusion (median, 0 ml; range, 0-2500 ml) than those in the cimetidine group (median, 0 ml; range, 0-5000 ml) (P=.08). The hospital stay and number of operations and mortality rate were similar between both groups. Conclusions: The use of omeprazole is more effective than cimetidine in increasing intragastric ph and reducing rebleeding episodes in patients with bleeding peptic ulcers after successful endoscopic therapy. This suggests that omeprazole should be used routinely after successful endoscopic therapy. Arch Intern Med. 1998;158:54-58 From the Division of Gastroenterology, Department of Medicine, Veterans General Hospital, and National Yang-Ming University, School of Medicine, Taipei, Taiwan. PATIENTS WITH major bleeding and endoscopic evidence of an ulcer with active bleeding or a nonbleeding visible vessel (NBVV) are at high risk for persistent or recurrent bleeding and should receive endoscopic therapy. 1 In the various endoscopic treatments for peptic ulcer hemorrhage, heater probe thermocoagulation (HPT) and multipolar electrocoagulation (MPEC) are the 2 most promising techniques. 1 Although a high initial hemostatic rate can be obtained with endoscopic therapy, rebleeding occurs in 10% to 30% of these patients. 2-5 Rebleeding has been consistently described as the most important prognostic factor. 6,7 If it can be prevented, the mortality rate is reduced accordingly. A stable blood clot in a peptic ulcer is crucial to hemostasis. However, in a low ph environment, platelet dysfunction has been observed. 8,9 In addition, pepsin can lyse the blood clots that plug vessels in the ulcer base and induce rebleeding thereafter. 9-11 Thus, the hypothesis that by suppressing the intragastric acid, use of omeprazole might benefit patients at risk for further hemorrhage was proposed. inhibits H + -K + adenosine triphosphatase, dose-dependently suppressing basal and stimulated gastric acid secretion. 12 administered intravenously appears effective in maintaining an intragastric ph higher than 4 for a 54

PATIENTS, MATERIALS, AND METHODS CRITERIA FOR INCLUSION AND EXCLUSION Patients were accepted for endoscopic therapy if a peptic ulcer with active bleeding or an NBVV was observed within 12 hours of hospital admission. The possibility of endoscopic therapy was discussed with patients and/or their relatives and a written informed consent was obtained before the trial. After initial hemostasis was achieved with either HPT or MPEC, the patients were enrolled in this study. The study was approved by the Clinical Research Committee of the Veterans General Hospital, Taipei, Taiwan. Patients were excluded from the study if they were pregnant, did not give written informed consent, had bleeding tendency (platelet count 50 10 9 /L, serum prothrombin 30% of normal, or were taking anticoagulants), uremia, or bleeding gastric cancer. ENDOSCOPIC THERAPY Endoscopic hemostasis was performed by one of us (H.-J. L.) who had experience with at least 1000 patients in endoscopic hemostatic therapy. Two therapeutic modalities (HPT or MPEC) were used according to the availability of the hemostatic machine (we used HPT in the emergency department, and MPEC after admission). The methods of performing HPT or MPEC are described in our previous study. 4 RANDOMIZATION AND MEDICINE Patients enrolled in the study were randomly allocated into 2 groups using sealed envelopes containing a therapeutic option (cimetidine or omeprazole) derived from a randomized table. In the cimetidine group, a 300-mg intravenous bolus of cimetidine was given followed by a 1200-mg continuous infusion daily for 3 days. Thereafter, 400 mg of cimetidine was given orally twice daily for 2 months. In the omeprazole group, a 40-mg intravenous bolus of omeprazole was given followed by a 160-mg continuous infusion daily for 3 days. Thereafter, 20 mg of omeprazole was given orally once daily for 2 months. A nasogastric tube and a ph meter (Gastrograph Mark III, Medical Instruments Corporation, Solothurn, Switzerland) were inserted in each patient s fundus under fluoroscopic guidance after the intravenous bolus of cimetidine or omeprazole had been administered. The intragastric ph was recorded and stored at 6-second intervals for 24 hours. MONITORING Patients vital signs were checked every hour for the first 12 hours, every 2 hours for the second 12 hours, and every 4 hours for the following 24 hours until they became stable, then 4 times daily. The hemoglobin level and hematocrit were checked at least once daily, and a blood transfusion was given if the hemoglobin level decreased to lower than 90 g/l or if the patient s vital signs deteriorated. The attending physicians or surgeons were made aware of the exact endoscopic findings and treatment given in each case. Endoscopy was undertaken 72 hours later. If no blood clot or hemorrhage was observed at the ulcer base, the patient was discharged and followed up in the outpatient department. Active bleeding was defined as a continuous blood flow spurting or oozing from the ulcer base. An NBVV at endoscopy was defined as a discrete protuberance at the ulcer base that was resistant to washing and was often associated with the freshest clot in the ulcer base. Shock was defined as systolic blood pressure lower than 100 mm Hg and a pulse rate of more than 100/min accompanied by cold sweats, pallor, and oliguria. Initial hemostasis was defined as no visible hemorrhage lasting for 5 minutes after endoscopic therapy. Ultimate hemostasis was defined as no rebleeding during the 14 days after endoscopic therapy. Rebleeding was suspected if unstable vital signs, continued tarry, bloody stools, or a drop in the hemoglobin level of more than 20 g/l within 24 hours was observed during hospitalization. For these patients, an emergency endoscopy was performed immediately. Rebleeding was concluded if either blood in the stomach 24 hours after therapy or a fresh blood clot or bleeding in the ulcer base was found. All patients with rebleeding were treated a second time by endoscopic hemostasis unless they refused. An emergency operation was performed if bleeding could not be controlled with HPT or MPEC or if rebleeding occurred after 2 attempts with HPT or MPEC therapy. At entry to the study, the following data were recorded: age, sex, signs of bleeding (hematemesis or melena), the location of the ulcer (esophagus, stomach, duodenum, or stoma), ulcer size, presence of overlying clot, the appearance of gastric contents (clear, coffee grounds, and blood), stigmata of bleeding (spurting, oozing, and NBVV), volume of blood transfusion at entry, presence of shock, hemoglobin level, nonsteroidal anti-inflammatory drug ingestion, cigarette smoking, alcohol drinking, and comorbid illness. END POINTS The outcome of measure was the rebleeding rate at day 3 and day 14 after entry to the study. At day 14, volume of blood transfused, number of procedures performed, and the mortality rates of the 2 groups were compared as well. STATISTICS The sample size estimation was based on an expected rebleeding rate of 30% in the cimetidine group. The trial was designed to detect a 25% difference in favor of the omeprazole group with a type I error of 0.05 and type II error of 0.2. At least 43 patients were essential for each group. We used the Student t test (paired, 2-tailed) to compare the basic data of age, ulcer size, volume of blood transfused after entry, initial hemoglobin level, intragastric ph, and hospital stay between both groups. The 2 test, with or without Yates correction, and Fisher exact test were used when appropriate to compare sex, number of rebleeding episodes, emergency operations, mortality rate, the location of the bleeding, presence of overlying clot, gastric contents, stigmata of bleeding, presence of shock, nonsteroidal anti-inflammatory drug ingestion, cigarette smoking, alcohol drinking, comorbid illness, and the hemostatic effect between the 2 groups. A probability value of less than.05 was considered significant. 55

Table 1. Clinical Parameters of the and the Groups Parameters Median age, y (range) 65 (17-84) 66.5 (33-86)* Sex, M/F 46/4 43/7 Sign of bleeding Hematemesis 18 17 Melena 32 33 Location of bleeding Esophagus 0 1 Stomach 21 27 Duodenum 28 19 Stoma 1 3 Median ulcer size, cm (range) 0.6 (0.3-4.0) 0.9 (0.3-3.0) No. with overlying clot 24 23 Gastric content Clear 21 22 Coffee grounds 19 11 Blood 10 17 Stigmata of bleeding Spurting 9 12 Oozing 4 9 Nonbleeding visible vessel 37 29 Median volume of blood transfusion at entry, ml (range) 500 (0-2500) 0 (0-5000) No. with shock 14 9 Median hemoglobin, g/l (range) 99 (58-150) 105 (37-152) Median serum urea nitrogen, mmol/l [mg/dl] (range) 10.1 [28.5] (1.7-7.7 [5-216]) 12.1 [34] (2.1-26.0 [6-73]) Nonsteroidal anti-inflammatory drug ingestion 18 14 Cigarette smoking 17 14 Alcohol drinking 6 6 Comorbid illness 35 38 *No statistical significance of clinical parameters between the 2 groups. 24-hour period. 13-15 The role of omeprazole in preventing rebleeding in patients with peptic ulcer bleeding has been controversial. 16-23 The aims of this study were to assess the influence of omeprazole and cimetidine on 24- hour intragastric ph and to determine their ability to prevent rebleeding after having achieved initial hemostasis in patients with active bleeding or NBVV. RESULTS Between November 1995 and June 1996, 617 patients received emergency endoscopy in our hospital because of hematemesis and/or tarry stool. We found obscure bleeding in 15 patients, a clear ulcer in 184 patients, pigmented spots in 127 patients, adherent blood clots in 96 patients, an NBVV in 61 patients, active bleeding in 47 patients, and esophageal or fundic varices in 87 patients. Of the patients with active bleeding or an NBVV (n=108), we obtained initial hemostasis in 107 patients. Seven patients were excluded from the study because of inability to give informed consent (n=4), bleeding tendency (n=1), and the presence of a bleeding gastric malignant neoplasm (n=2). Hence, a total of 100 patients were enrolled in the trial. Fifty patients received omeprazole and the same number received cimetidine intravenously. There was no statistical difference in the clinical parameters of the 2 groups (Table 1). We performed HPT for 30 and 39 patients and MPEC for 20 and 11 patients Intragastric ph 7 6 5 4 3 2 1 Bolus 0 2 4 6 8 10 12 14 16 18 20 22 24 Time, h Mean intragastric ph profile in the omeprazole group and the cimetidine group during the 24 hours following initial bolus injection and sustained infusion. in the omeprazole and cimetidine groups, respectively (P.05). Eleven patients rebled after receiving HPT and 3 patients rebled after receiving MPEC (P.10). The mean intragastric ph rose to 6.0 one hour after the initial bolus of omeprazole in the omeprazole group; it persisted around this value for the rest of the 24 hours (Figure). In the cimetidine group, the mean intragastric ph rose to 4.0 one hour after the initial bolus of cimetidine and persisted around 4.5 to 5.5 for the rest of the 24 hours. The duration in time of the raised intra- 56

Table 2. Major Clinical Outcomes of Both Groups Clinical Outcomes gastric ph ( 6.0) was 84.4%±22.9% (mean±sd) in the omeprazole group, compared with 53.5%±32.3% in the cimetidine group (P.001). By day 3 after entry, no patient rebled in the omeprazole group, whereas 8 patients rebled in the cimetidine group (P=.003). By 2 weeks after entry, 2 patients rebled in the omeprazole group and 12 patients rebled in the cimetidine group (P=.004) (Table 2). Rebleeding episodes occurred in 2 patients in the omeprazole group 8 days after endoscopic therapy. One had uneventful recovery after conservative treatment, while another received HPT twice plus omeprazole and recovered smoothly. In the rebleeding patients in the cimetidine group, rebleeding occurred at 1 day (3 patients), 2 days (2 patients), 3 days (2 patients), 5 days (1 patient), 6 days (2 patients), 8 days (1 patient), and 10 days (1 patient) after endoscopic therapy. Six received MPEC plus omeprazole therapy, 2 received MPEC plus cimetidine therapy, 1 received HPT plus omeprazole therapy, and 1 received HPT plus cimetidine therapy. These 10 patients recovered uneventfully. The remaining 2 patients died despite further endoscopic therapy (one had cholangiocarcinoma with metastasis and died of bleeding after a second administration with MPEC plus omeprazole, while the other had renal cell carcinoma with metastasis and died of sepsis after endoscopic therapy was provided 3 times). Patients with ulcers located at the lesser curvature of the gastric high body (n=2, cimetidine group) and posterior wall of the duodenal bulb (n=5, 4 in the omeprazole group and 1 in the cimetidine group) did not have a higher rebleeding rate than patients with ulcers in other locations (2/7 vs 12/93, respectively; P=.25). There was a tendency for the patients in omeprazole group to have a lower volume of blood transfused (median, 0 ml; range, 0-2500 ml) compared with those in the cimetidine group (median, 0 ml; range, 0-5000 ml). The length of hospital stay, number of procedures performed, and mortality rates of the 2 groups were not statistically different. COMMENT Rebleeding Day 3 0 8.01 Day 14 2 12.01 Median volume of blood transfused 0 (0-2500) 0 (0-5000).05 after entry, ml (range) No. of operations 0 0.05 Mortality 0 2.05 Days in hospital 7 (3-27) 6 (3-31).05 A bleeding peptic ulcer remains a serious medical problem with significant morbidity and mortality. Endoscopic therapy significantly reduces further bleeding, surgery, and mortality in patients with bleeding peptic ulcers 24 P and is now recommended as the first hemostatic modality for these patients. 1,24 After obtaining initial hemostasis, rebleeding is another important impact to the prognosis. An ideal therapy includes a successful endoscopic therapy plus a low rebleeding rate. Rebleeding episodes occur within 3 days in most instances. 25-27 In addition, an intragastric ph higher than 6.0 is a prerequisite for preventing rebleeding in patients with bleeding peptic ulcers. 8 Therefore, a drug that rapidly increases intragastric ph and lasts for 3 to 4 days is necessary to prevent rebleeding. With conventional recommended doses of histamine 2 blockers, intragastric ph cannot be maintained higher than 4.0 for a long period in patients with a bleeding peptic ulcer. 15,28-30 Continuous intravenous histamine 2 - blocker infusion does not influence the natural history of bleeding peptic ulcers. 16 In this study, we achieved a similar intragastric recording and rebleeding rate. Pharmacologically, omeprazole can quickly achieve an optimal intragastric ph condition for support of the physiological cascade of hemostasis. 14 The optimal dose was found to be continuous infusion of 8 mg/h or 160 mg/24 h of omeprazole. 14,19,31 In this study, we used a similar dose of omeprazole and obtained intragastric ph of 6.0 or more in 84.4%±22.9% (mean±sd) time period in the omeprazole group. The use of omeprazole is reported to be ineffective in patients with peptic ulcer bleeding either with 17 or without endoscopic therapy. 16 In these 2 studies, the authors used an 80-mg intravenous bolus of omeprazole followed by 40 mg every 8 hours. There are at least 3 pitfalls in their studies. First, the dose of omeprazole was suboptimal. Second, the interval of omeprazole injection administered intravenously (8 hours) was too long. Because proton pumps are continuously being generated, 32 and the half-life of omeprazole in the circulation is short (50 minutes), it needs to be given more frequently (eg, every 3 hours) or continuously. 14 According to the published data, it will fail to raise intragastric ph higher than 4.0 continuously in the studied period with the above-mentioned methods. 14-16,33 Third, Daneshmend et al 16 did not restrict their patients to those from high-risk groups. Hence, a type II error may occur under these conditions. In this study, we obtained remarkable acid suppression in the omeprazole group; no rebleeding episodes occurred during continuous infusion of omeprazole. The 2 rebleeding episodes occurred after patients received 20 mg of omeprazole once daily (8 days after enrollment). One had minor rebleeding, which subsided spontaneously, while the other had an uneventful recovery after HPT was given a third time as well as 20 mg of omeprazole twice daily. Whether an increased dosage of omeprazole (eg, 20 mg twice daily) after continuous infusion can prevent rebleeding awaits further study. Hospital stay, number of procedures, and mortality rate of the 2 groups were similar. This may be due to the early detection of rebleeding episodes and the aggressive endoscopic therapy given, thus minimizing the difference between the 2 groups. administered intravenously as a 40-mg bolus followed by a 160-mg continuous infu- 57

sion daily can elevate intragastric ph remarkably and prevent rebleeding in patients with peptic ulcer bleeding after initial hemostasis has been achieved. It should be used routinely in these patients after successful endoscopic therapy. Accepted for publication April 23, 1997. Reprints: Hwai-Jeng Lin, MD, FACG, Division of Gastroenterology, Department of Medicine, Veterans General Hospital, Taipei, Taiwan, Republic of China. REFERENCES 1. Consensus Development Panel. Consensus statement on therapeutic endoscopy and bleeding ulcers. Gastrointest Endosc. 1990;36:S62-S65. 2. Lin HJ, Lee FY, Kang WM, Tsai YT, Lee SD, Lee CH. Heat probe thermocoagulation and pure alcohol injection in massive peptic ulcer haemorrhage: a prospective, randomized controlled trial. Gut. 1990;31:753-757. 3. Llach J, Bordas JM, Salmerón JM, et al. A prospective randomized trial of heater probe thermocoagulation versus injection therapy in peptic ulcer hemorrhage. Gastrointest Endosc. 1996;43:117-120. 4. 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