Treatment of Helicobacter pylori in Patients With Duodenal Ulcer Hemorrhage A Long-Term Randomized, Controlled Study

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1 THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 95, No. 9, by Am. Coll. of Gastroenterology ISSN /00/$20.00 Published by Elsevier Science Inc. PII S (00) Treatment of Helicobacter pylori in Patients With Duodenal Ulcer Hemorrhage A Long-Term Randomized, Controlled Study Kam-Chuen Lai, M.R.C.P. (UK), Wai-Mo Hui, M.D., Wai-Man Wong, M.R.C.P. (UK), Benjamin Chun-Yu Wong, M.R.C.P. (UK), Wayne Hsing Cheng Hu, M.R.C.P. (UK), Chi-Kong Ching, M.D., and Shiu-Kum Lam, M.D. Department of Medicine, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China OBJECTIVE: Eradication of Helicobacter pylori (H. pylori)in patients with uncomplicated duodenal ulcers prevents longterm recurrence of ulcers. We aimed to study whether treatment of H. pylori prevents the long-term recurrence of duodenal ulcer hemorrhage. METHODS: Patients with duodenal ulcer bleeding and confirmed H. pylori infection were recruited. A total of 120 patients were randomly assigned to triple therapy (DeNoltab 120 mg, amoxycillin 500 mg, and metronidazole 300 mg four times daily) or DeNoltab 120 mg four times daily alone. No maintenance therapy was given during the follow-up period. The endpoints were the cumulative rates of symptomatic and bleeding duodenal ulcer recurrences. RESULTS: Of the patients receiving the triple regimen, 85.1% had H. pylori eradicated as compared to 2.0% of patients receiving DeNoltab (p 0.05). More patients in the DeNoltab group than those in the Triple group had recurrence of ulcer bleeding, but this did not reach statistical significance (12/60 vs 6/60, p 0.20). Logistic regression analysis on clinical, personal, and endoscopic characteristics identified persistent H. pylori infection as the only independent predictor of recurrence of duodenal ulcer bleeding. CONCLUSIONS: Treatment of H. pylori alone with the present bismuth-based triple therapy in patients with duodenal ulcer hemorrhage did not result in significant reduction in further bleeding episodes, although a trend was seen for the group that was given triple therapy. On the other hand, posttreatment H. pylori status was found to be an independent predictor of bleeding recurrence. (Am J Gastroenterol 2000;95: by Am. Coll. of Gastroenterology) INTRODUCTION Helicobacter pylori (H. pylori) infection has been detected in 90% of patients with duodenal ulcer and in approximately 75% of those with gastric ulcer (1). The prevalence of H. pylori is slightly lower in patients presenting with complicated ulcers such as bleeding duodenal ulcers, and also varies with the diagnostic tests used (2, 3). Studies have shown that eradication of the H. pylori increased the rate of healing (4, 5) and prevented recurrences of the ulcers (6 9). Although some recent studies also demonstrated that eradication of the bacteria reduced the recurrence of peptic ulcer rebleeding, these studies had short follow-up (usually 1.5 yr) (10 13). The long-term natural history of peptic ulcer bleeding after eradication of H. pylori is largely unknown. The aim of our prospective randomized, controlled study was to investigate the role of anti-helicobacter treatment in the long-term management of patients with duodenal ulcer hemorrhage. We postulated that persistent H. pylori infection would predispose patients to recurrent gastrointestinal hemorrhage and that, therefore, eradication of the bacteria would prevent the long-term recurrence of gastrointestinal hemorrhage in those patients who remained free of H. pylori reinfection. MATERIALS AND METHODS This study took place at Queen Mary Hospital, Hong Kong, China, from 1992 to All patients gave informed consent to the study, which had been approved by the local institutional review board. Study Population Patients presenting with either hematemesis and/or melena received endoscopy within 24 h after admission. They were recruited into the study if: 1) duodenal ulcer, with or without stigmata of recent hemorrhage, was found on endoscopy, with no other lesion to account for the bleeding (an ulcer was defined as a break in the mucosa of 5 mm in diameter with unequivocal depth); 2) They were aged yr; and 3) Helicobacter pylori could be demonstrated by rapid urease test and histology on antral biopsy. Patients would be excluded if they had: 1) esophagitis on endoscopy; 2) gastric resective or acid reduction surgery; 3) allergy to the study drugs; 4) concomitant uncompensated or unstable medical conditions; 5) no H. pylori detected by

2 2226 Lai et al. AJG Vol. 95, No. 9, 2000 rapid urease test or histology examination on antral biopsies; or 6) concomitant nonsteroidal anti-inflammatory drugs use (NSAIDs). We excluded this group of patient because NSAIDs alone can cause peptic ulcers in patients without H. pylori infection, thus masking the benefit of treating the H. pylori. Endoscopy Endoscopy was performed with a forward viewing videoscope (Olympus, Tokyo, or Pentax, Tokyo, Japan). Duodenal ulcers with no stigmata of recent hemorrhage or with flat black spots were treated conservatively. Duodenal ulcers that were bleeding actively or that had visible blood vessels or adherent clots were treated by endoscopic injection of adrenaline (1:10,000 dilution) and coagulation with heater probe (3.2 mm, Olympus) at 25 J/pulse. Two antral biopsy specimens were taken from the incisura and the greater curve within 5 cm of the pylorus. One specimen was subjected to a standard rapid urease test, the CLO test (Delta West, Bently, Australia) (14). A negative CLO test was defined as the absence of color change after 24 h. The rapid urease test had a sensitivity and specificity of 90% for the detection of H. pylori infection in general. Another biopsy specimen was subjected to histological examination of H. pylori using hematoxylin and eosin stain and Warthin-Starry stain. Protocol Consecutive patients, if they met the inclusion criteria, were randomized to receive one of the following two treatment regimens: 1) DeNoltab group: Tripotassium dicitrato bismuthate (DeNoltab), 120 mg four times daily until ulcer was healed, or 2) Triple group: Triple therapy (including tripotassium dicitrato bismuthate 120 mg, amoxycillin 500 mg, and metronidazole 300 mg, all four times daily) for 2 wk, then tripotassium dicitrato bismuthate 120 mg four times daily until ulcer was healed. This therapy aimed to heal the ulcer and to eradicate H. pylori. The treatment regimen was determined previously by a list of random numbers generated by computer. Both the physicians and the research nurses were blinded to the randomization sequence, and the endoscopists were blinded to the patients treatments. Patients were allowed to take the bismuth compound only for a maximum of 8 wk. Patients would be taken out of the trial if the ulcer failed to heal at the end of 8 wk, as documented by endoscopic examination that was performed 4 wk and 8 wk after the start of treatment. Those patients who had their ulcers healed would have another endoscopy 4 wk after the end of all therapy to detect the presence of H. pylori by histology and rapid urease test. Eradication was defined as successful if both histology and rapid urease test failed to demonstrate H. pylori infection 4 wk after discontinuation of the study medication. Eradication was defined as unsuccessful if H. pylori could be detected by either rapid urease test or histology. Patients who were excluded from randomization (because of the exclusion criteria) would be given ulcer-healing drugs for 6 wk. For patients who had recurrent peptic ulcer hemorrhage, concomitant esophagitis, or uncompensated serious medical conditions, long-term maintenance with H2-antagonists would be given. No long-term maintenance treatment would be given to those patients presenting with the first episode of gastrointestinal hemorrhage. Patients with NSAIDs-related duodenal ulcers were asked to avoid further NSAIDs. If this was not possible, cotherapy with misoprostol was given to these patients. Follow-Up Patients recruited were followed-up every 6 months with no maintenance antiulcer therapy. Only antacids (Gelusil, Parke-Davis, Santurce, PR) were allowed for mild symptom control. Patients were advised to avoid taking NSAIDs if possible. They were asked to report to the outpatient clinics if they had persistent ulcer symptoms that were not relieved by antacids or to the emergency room if they had evidence of gastrointestinal bleeding. Endoscopy was then repeated to document the recurrence of duodenal ulcer. H. pylori was detected by rapid urease test and histology. If the patients did not return for follow-up, they would be contacted by telephone. If they refused to come back, they were questioned over the phone about recurrence of gastrointestinal bleeding and ulcer symptoms. Endpoints Endpoints of the study included, during the follow-up period, recurrence of: 1) bleeding duodenal ulcer (bleeding duodenal ulcer was defined as the presence of duodenal ulcer with or without stigmata of recent hemorrhage on endoscopy in patients with recurrent hematemesis and/or melena); and 2) painful duodenal ulcer (painful duodenal ulcer was defined as presence of duodenal ulcer on endoscopy in patients with persistent epigastric pain that was not relieved by antacids treatment). Patients with recurrence of peptic ulcers were given standard antiulcer treatment, including H2-antagonists, proton pump inhibitors, or sucralfate for ulcer healing. Sample Size The sample size was estimated on the assumption that 5% of patients in the Triple therapy group had recurrence of duodenal ulcer hemorrhage, whereas 30% of patients in the DeNoltab group had recurrence in the long-term follow-up. It was estimated that each treatment group should consist of 53 patients to show a difference of 25% with a type I error of 0.02 and type II error of 0.2 (two-sided test). Assuming a 10% dropout rate, a total of 120 patients would be needed for the study. Statistical Analysis The baseline characteristics of each group were compared using the 2 test for categorical variables or t test for continuous variables. Fisher s exact test was used when necessary.

3 AJG September, 2000 H. pylori in Patients With Duodenal Ulcer Hemorrhage 2227 Table 1. Reasons for Exclusion Reason Positive (n) Negative (n) Esophagitis 2 1 Gastric surgery 0 1 Allergy to study drugs 1 0 Unstable comorbid disease 13 9 negative 0 39 Recent NSAID use 7 5 Total NSAID nonsteroidal anti-inflammatory drug. The endpoints were analyzed according to the treatment groups using intention-to-treat analysis (ITT) and per-protocol analysis (PP). Intention-to-treat analysis included those patients who were randomized and had consumed at least one dose of the study medication. Per-protocol analysis included those patients who had consumed all of the study medication, had undergone the last endoscopy examination, and had completed follow-up. A secondary analysis of the endpoints was also performed according to posttreatment H. pylori status. The 2 test was used for comparison of presence or absence of recurrent bleeding and ulcers. The probability of patients in remission during follow-up was analyzed by Kaplan-Meier survival estimates. The log rank test was performed to test the differences in time to recurrent bleeding between defined groups. We also performed a subgroup analysis in patients who presented with severe upper gastrointestinal bleeding. Severe episodes of upper gastrointestinal bleeding were defined as bleeding episodes that required endoscopic hemostatic treatment, or those that were associated with hypotension on presentation (systolic blood pressure 100 mm Hg). Patients who completed the study were subjected to logistic regression analysis with bleeding recurrence as the outcome variable and the baseline characteristics listed in Table 1, as well as the posttreatment H. pylori status and initial drug treatment, as the independent variables. The Statistical Package for the Social Sciences (SPSS/ PC; SPSS, Chicago, IL) program was used for all statistical calculations (15). A p value (two-sided) of 0.05 was considered statistically significant. RESULTS A total of 198 patients presented with duodenal ulcer hemorrhage during the recruitment period; 78 patients were excluded from randomization because of the reasons listed in Table 1. H. pylori infection could not be detected in 53 patients (26.8%) by rapid urease test and histological examination on antral biopsies. Of these 53 patients, 39 patients (19.7%) who were negative for H. pylori did not have any concomitant medical illnesses or NSAIDs use. The high prevalence of negative duodenal ulcers may be related to the lower sensitivity of biopsy-based diagnostic tests in bleeding peptic ulcers (2, 3). Twelve patients (6.1%) were excluded because of recent NSAIDs use. Slightly more than half (7/12, 58.3%) of these NSAIDs users were also infected with H. pylori. Baseline Characteristics A total of 120 patients met the recruitment criteria; 60 patients were allocated to the Triple group, and the other 60 patients to the DeNoltab group. All patients had H. pylori infection detected by positive rapid urease test and/or histological examination of the antral biopsies. The patients demographic data, which are shown in Table 2, were com- Table 2. Baseline Characteristics of Patients With Duodenal Ulcer Bleeding Characteristics DeNoltab Group (n 60) Triple Group (n 60) Continuous variables* Age (yr), range , , Mean follow-up duration (months) Mean hemoglobin (g/dl) Categorical variables, n (%) Male gender 49 (81.7) 49 (81.7) Age 65 yr (%) 2 (3.3) 4 (6.7) Ulcer-related pain (%) 30 (50) 36 (60) Hematemesis (%) 3 (5) 6 (10) Melena (%) 58 (96.7) 60 (100) Smoking (%) 15 (25) 15 (25) Alcohol (%) 6 (10) 3 (5) Stable comorbid disease (%) 9 (15.0) 12 (20.0) Past history of bleeding (%) 44 (73.3) 37 (61.7) Systolic blood pressure 100 mm Hg (%) 12 (20) 14 (23.3) Pulse 100 beats/min (%) 17 (39.5) 10 (16.7) Hemoglobin 10 g/dl (%) 16 (26.7) 22 (36.7) Initial ulcer size 10 mm (%) 19 (31.7) 10 (16.7) Endoscopic treatment (%) 24 (40.0) 24 (40.0) * Continuous variables are expressed as mean SD.

4 2228 Lai et al. AJG Vol. 95, No. 9, 2000 Table 3. Reasons for Drop-Outs From the Study Subjects DeNoltab Group Triple Group Randomised subjects Drop-outs Rebleeding after hemostasis 0 2 Trial drugs not finished 2 2 Follow-up endoscopy refused 3 4 Unhealed ulcers posttreatment 4 1 Lost to follow-up 2 4 Completed study parable. Only a small proportion of patients (6.7% in the Triple group and 3.3% in the DeNoltab group) were aged 65 yr. In all, 20% (12/60) and 15.0% (9/60) of patients had stable comorbid diseases in the Triple group and DeNoltab group, respectively. There was no significant difference between the two treatment groups for all variables. In all, 33 patients (55.0%) in the Triple group and 32 patients (53.3%) in the DeNoltab group presented with severe gastrointestinal bleeding as defined earlier. Of the 120 patients originally allocated, 81 (67.5%) had at least one episode of duodenal ulcer hemorrhage before. The interval from the last bleeding to present index bleeding ranged from 12 months to 96 months, and 48 (59.3%) patients had their last episode of bleeding 18 months before. Follow-up Eleven patients in the DeNoltab group and 13 patients in the Triple group did not complete the study; Table 3 lists the reasons. There was no significant differences between ulcer healing rates in the DeNoltab and Triple groups (ITT: 51/60, 85% vs 51/60, 85%, p 1.20). The mean duration of follow-up at the time of analysis was 52.8 months (range, months). Eradication of Helicobacter pylori H. pylori was successfully eradicated in 40 of 47 patients (85.1%, 95% CI 72 94) in the Triple group. All patients finished the prescribed treatment, although some of them reported moderate side effects including dizziness, taste disturbance, upper gastrointestinal discomfort, and headache. One patient out of the 49 patients receiving DeNoltab monotherapy had successful eradication of H. pylori infection (2.0% eradication rate, 95% CI 0 11; p as Table 4. Ulcer and Bleeding Recurrences According to Treatment Group Recurrence DeNoltab Group (n 60) Triple Group (n 60) Recurrence of bleeding ulcer 12 (20.0) 6 (10.0)* Symptomatic ulcer recurrence 16 (26.7) 1 (1.7) without bleeding Total ulcer recurrence 28 (46.7) 7 (11.7) Data are given as number of patients, with percentage given in parentheses * p 0.20 for comparison with the DeNoltab group. p for comparison with the DeNoltab group. Table 5. Characteristics of Patients According to Posttreatment H. pylori Status Characteristics Positive (n 55) Negative (n 41) Continuous variables* Age (yr) Mean follow-up duration (months) Mean hemoglobin (g/ dl) Categorical variables, n (%) Male gender 44 (80) 33 (80.5) Age 65 yr 2 (3.6) 2 (4.9) Ulcer-related pain (%) 26 (47.3) 23 (56.1) Hematemesis (%) 3 (5.5) 5 (12.2) Melena (%) 52 (94.5) 41 (100) Smoking (%) 13 (23.6) 9 (22.0) Alcohol (%) 4 (7.3) 3 (7.3) Comorbid diseases 10 (18.2) 7 (17.1) Past history of 38 (70.4) 22 (53.7) bleeding (%) Systolic blood pressure 12 (21.8) 10 (24.4) 100 mm Hg (%) Pulse 100 beats/min 13 (23.6) 8 (19.5) (%) Hemoglobin 10 g/dl 16 (29.1) 18 (43.9) (%) Initial ulcer size (21.8) 9 (22.0) mm (%) Endoscopic treatment (%) 20 (36.4) 21 (51.2) * Continuous variables are expressed as the mean SD. compared with the Triple group). No major side effects were reported in those patients receiving DeNoltab monotherapy. Ulcer and Bleeding Recurrences The outcomes in each treatment groups are shown in Table 4. In the intention-to-treat analysis, more ulcers (bleeding and painful) recurred in patients in the DeNoltab group as compared to patients in the Triple group (28/60, 46.7%, 95% CI vs 7/60, 11.7%, 95% CI 5 23, p 0.001). Out of these ulcer recurrences, more ulcers rebled in the DeNoltab group as compared with the Triple group (12/60, 20.0%, 95% CI vs 6/60, 10.0%, 95% CI 4 20, p 0.20). There was a trend in favor of the Triple group in Table 6. Ulcer and Bleeding Recurrences According to Posttreatment H. pylori Status Recurrence Positive (n 55) Negative (n 41) Recurrence of bleeding ulcer 16 (29.1) 2 (4.9)* Symptomatic ulcer recurrence 17 (30.9) 0 (0) without bleeding Total ulcer recurrence 33 (60.0) 2 (4.9) Data are given as number of patients, with percentage given in parentheses. * p for the comparison with the H. pylori negative group. p for the comparison with the H. pylori negative group.

5 AJG September, 2000 H. pylori in Patients With Duodenal Ulcer Hemorrhage 2229 Figure 1. A Kaplan-Meier plot showing the actuarial probability of being free of rebleeding according to treatment groups during a mean follow-up of 52.8 months. preventing ulcer rebleeding, although statistical significance could not be obtained. A high proportion of the bleeding ulcer recurrences were not associated with any epigastric pain (8/18, 44.4%). The per-protocol analysis included 49 patients in the DeNoltab group and 47 patients in the Triple group. More ulcers in the DeNoltab group than the Triple group rebled (12/49, 24.5%, 95% CI vs 6/47, 12.8%, 95% CI 5 26, p 0.19), but this did not reach statistical significance. Time to Recurrent Bleeding: Intention-to-Treat Analysis Figure 1 shows the probability of bleeding ulcers remaining in remission over a mean follow-up period of 52.8 months. According to survival analysis by the log rank test, the proportion of patients without ulcer rebleeding in the Triple group was not significantly different from that in the De- Noltab group (p 0.15). Of the 18 patients with rebleeding, seven (38.9%) had recurrence 18 months after the index bleed. Helicobacter pylori Status and the Relationship to Recurrent Ulcer Bleeding Of the 96 patients who finished the whole course of treatment, 41 patients had eradication of H. pylori infection. The baseline characteristics of the patients with H. pylori eradicated and with persistent H. pylori infection are shown in Figure 2. A Kaplan-Meier plot showing the probability of being free of rebleeding according to posttreatment H. pylori status during a mean follow-up of 52.8 months.

6 2230 Lai et al. AJG Vol. 95, No. 9, 2000 Table 5. The two groups were comparable. The outcomes in ulcer bleeding and painful ulcer recurrence with respect to the H. pylori status 4 wk after treatment are shown in Table 6. During the follow-up period, two of 41 patients (4.9%, 95% CI 1 17) with eradication had ulcer recurrences, whereas 33 of 55 patients (60%, 95% CI 46 73) without eradication had ulcer recurrences (p 0.001). Two out of 41 patients (4.9%, 95% CI 1 17) with eradication had bleeding relapse, as compared to 16 of 55 patients (29.1%, 95% CI 4 22) without eradication (p 0.003). In the two patients in the eradication group who had recurrence of ulcer bleeding, one had H. pylori detected by both rapid urease test and histology, and the other had recent history of NSAID use. Figure 2 shows the probability of bleeding ulcers remaining in remission according to the status of H. pylori over a mean follow-up 52.8 months. In the survival analysis, the proportion of patients without ulcer rebleeding was significantly greater in the group with eradication than in the group without eradication (p 0.014). Ulcer and Bleeding Recurrences in Severe Duodenal Ulcer Hemorrhage Of the 65 patients with severe duodenal ulcer bleeding (as defined above), 52 were available for subgroup analysis. In all, 14 of 29 patients (48.3%, 95% CI 29 67) with persistent H. pylori infection had ulcer recurrences, whereas none of the 23 patients with eradication had ulcer recurrence (p 0.001). In addition, seven of the 29 patients (24.1%, 95% CI 10 44) without eradication had rebleeding as compared to none of the 23 patients with eradication (p 0.01). Predictors of Rebleeding Logistic regression analysis identified posttreatment H. pylori status as the only predictor for long-term recurrence of duodenal ulcer bleeding (odds ratio 27.64, 95% CI , p 0.014). DISCUSSION It is now well accepted that Helicobacter pylori is the cause of type B gastritis and a large proportion of peptic ulcers. Eradication of the organism reduces the recurrences of peptic ulcers (6 10). Before the discovery of H. pylori, acid suppression was the mainstay of treatment for peptic ulcer diseases. Despite the high efficacy of acid-reducing agents, duodenal ulcer recurs in 50 90% of patients at the end of 1 yr after treatment (16, 17). Treatment with bismuth-containing compounds decreased the 1-yr relapse rate as compared to that of H2-antagonists (18, 19). This may be related to the suppressing effect of bismuth compounds on H. pylori (20). Bleeding is the most frequent complication of duodenal ulcer disease, occurring in 20% of patients with ulcers (21, 22). Despite the introduction of endoscopic hemostatic methods, mortality from duodenal ulcer bleeding has remained significantly high (23 27). About one third of them will experience rebleeding within the next 1 3 yr (28). In 1994, the National Institutes of Health Consensus Development Conference recommended that all patients with gastric or duodenal ulcers who were infected with H. pylori should be treated with antimicrobial agents. The Conference panel also recommended that well designed studies on the role of H. pylori eradication in peptic ulcer disease with complications be conducted before these patients could be managed alone with H. pylori eradication in view of the high risks associated with rebleeding (6). It has recently been shown, in a placebo-controlled, randomized study, that maintenance treatment with ranitidine significantly reduces the risk of rebleeding (28). However, the problems associated with long-term maintenance therapy include high cost and long-term compliance. Eradication of the organism with a regimen that has a high efficacy is therefore a more attractive option. Some studies had also assessed the effect of H. pylori eradication in those patients with duodenal ulcer bleeding. However, these studies generally had a mean follow-up of 18 months (12, 13). Our study was a prospective, randomized, controlled study involving about 100 patients with duodenal ulcer bleeding. The mean follow up was 52.8 months, and the longest was 60 months. A long-term randomized study is essential, as a high proportion of patients with bleeding ulcers can rebleed several years later. In the present study, 59.3% of patients had had their last episodes of bleeding 18 months ago. Follow-up of our patients without eradication showed that more than one third of them had further ulcer bleeding 18 months after the index bleeding. Moreover, recurrence of peptic ulcers was associated with H. pylori reinfection. This is of importance to areas with a high prevalence of H. pylori, such as Hong Kong (55% of subjects are reported to be infected; unpublished data). High reinfection rate offsets the expected beneficial effects of H. pylori eradication. Long-term follow-up is therefore necessary to determine the effect of reinfection on the occurrence of ulcer. One of the major drawbacks of the study is that, during the long-term follow-up, medications (such as low-dose aspirin, over-the-counter NSAIDs, and herbal medications with salicylates) that might influence the outcomes could not easily be identified. Certainly these factors are important risk factors for rebleeding, especially if we follow the patients for longer period of time. In our study, in contrast to other studies, bleeding recurrence was not significantly reduced in the Triple group, and rebleeding could still occur in those patients who had been given anti-helicobacter therapy. This suggested that simply giving anti-helicobacter therapy does not guarantee that patients will not rebleed. Although a trend was seen for the Triple group that was given anti-helicobacter therapy, considerably more patients (220 in each treatment group) would have to be included in the study to find a significant differ-

7 AJG September, 2000 H. pylori in Patients With Duodenal Ulcer Hemorrhage 2231 ence, based on the results of this study (10% and 20% rebleeding rates in the Triple group and DeNoltab group, respectively). The similar rates of rebleeding in both treatment groups could possibly be explained by the high dropout rate, the low eradication rate, and the reinfection rate. The primary aim of our study was to test the treatment with bismuth-based triple therapy and not the results of the treatment, including eradication. Our policy was therefore to withhold further eradication treatment in patients who failed eradication of the H. pylori infection. This policy, together with the low efficacy (85.1% eradication rate) of the present bismuth-based triple therapy, contributed to the similar rebleeding rates in the two treatment groups. Our secondary analysis showed that eradication of H. pylori infection was associated with a statistically significant reduction in further episodes of ulcer bleeding and that, among the various clinical, personal, and endoscopic characteristics, H. pylori was the only independent predictor of recurrent duodenal ulcer bleeding. It is likely that confirming eradication and retreating those patients with persistent H. pylori infection will prevent further rebleeds. The high rate of reinfection of H. pylori can be a problem in the long-term management of patients with bleeding peptic ulcers, as mentioned earlier, and this can also contribute to the similar rebleeding rates in the two treatment groups in our study. This was well illustrated in our study by the patient who had rebleeding with reappearance of the H. pylori 48 months after the triple therapy. We do not know whether the reappearance of the H. pylori infection in this patient was due to recrudescence of the original organism or to reinfection from the other H. pylori, because typing of the H. pylori strains was not performed before the eradication therapy. On the other hand, it is generally believed that the earlier the reappearance of the H. pylori infection, the more likely that it is a recrudescence of the original infection. True reinfection of H. pylori is more likely if it happens after the first year of eradication therapy. A recent study by our group showed a reinfection rate of 4.8%, 0.6%, and 0.6% over yr 1, 2, and 3, respectively, in patients with bleeding peptic ulcers who were treated with omeprazole, clarithromycin, and amoxycillin (unpublished data). The reinfection rate is as low as that reported in Western populations. In conclusion, treatment of H. pylori did not result in a significant reduction in further bleeding episodes in patients with bleeding duodenal ulcers, although a trend was seen for the group that was given anti-helicobacter therapy. The most likely reason for the similar rates is the low eradication rate of the bismuth-based triple therapy. It is likely that documenting eradication after treatment of H. pylori can decrease the risk for further rebleedings. Treatment with anti-helicobacter therapy alone, without documenting eradication, may not be sufficient to decrease the risk of rebleedings. It must be emphasized that most of our patients belong to the low-risk group. For patients who are high risk for complications, such as those aged 65 yr and with concomitant serious medical diseases, further studies are needed to examine whether this policy alone is adequate to prevent rebleedings. It has been suggested that maintenance antisecretory therapy be continued after H. pylori eradication in frail elderly patients with serious concurrent illness, in whom another bleeding episode might be catastrophic (29). ACKNOWLEDGMENTS We are grateful to Nurse Specialist M. Chong, Registered Nurses L. Y. C. Fan, H. S. Lee, K. W. Wong, S. Y. Tang, and M. Y. Lee for nursing assistance; to Ms. E. Kwok for technical support; to Ms. April Wong for data management; and to Mr. Stanley Yeung for statistical calculations. This work was supported by Peptic Ulcer Research Fund (311/ 041/0372) of the University of Hong Kong. Reprint requests and correspondence: Kam-Chuen Lai, M.R.C.P. (UK), Division of Gastroenterology, Department of Medicine, Room 304, New Clinical Building, Queen Mary Hospital, Pokfulam, Hong Kong, China. Received Oct. 21, 1999; accepted Apr. 12, REFERENCES 1. Marshall BJ. Helicobacter pylori. Am J Gastroenterol 1994; 89(suppl):S Lai KC, Hui WM, Lam SK. Bleeding ulcers have high false positive rates for antral Helicobacter pylori when tested with urease test. Gastroenterology 1996;110:A Tu TC, Lee CL, Wu CH, et al. Comparison of invasive and noninvasive tests for detecting Helicobacter pylori infection in bleeding peptic ulcers. Gastrointest Endosc 1999;49: Labenz J, Borsch G. Evidence for the essential role of Helicobacter pylori in gastric ulcer disease. Gut 1994;35: Marshall BJ, Goodwin CS, Warren JR, et al. Prospective double-blind trial of duodenal ulcer relapse after eradication of Campylobacter pylori. Lancet 1988;ii: NIH Consensus Conference. Helicobacter pylori in peptic ulcer disease. JAMA 1994;272: Graham DY, Lew GM, Klein PD, et al. Effect of treatment of Helicobacter pylori infection on the long-term recurrence of gastric and duodenal ulcer: A randomized, controlled study. Ann Intern Med 1992;116: Hentschel E, Brandatatter G, Dragosics B, et al. Effect of ranitidine and amoxycillin plus metronidazole on the eradication of Helicobacter pylori and the recurrence of duodenal ulcer. N Engl J Med 1993;328: Rauws EAJ, Tytgat GNJ. Cure of duodenal ulcer associated with eradication Helicobacter pylori. Lancet 1990;335: Graham DY, Hepps KS, Ramirez FC, et al. Treatment of Helicobacter pylori reduces the rate of re-bleeding in peptic ulcer disease. Scand J Gastroenterol 1993;28: Labenz J, Borsch G. Role of Helicobacter pylori eradication in the prevention of peptic ulcer bleeding relapse. Digestion 1994;55: Rokkas T, Karameris A, Mavrogeorgis A, et al. Eradication of Helicobacter pylori reduces the possibility of re-bleeding in peptic ulcer disease. Gastrointest Endosc 1995;41: Jaspersen D, Koerner T, Schorr W, et al. Helicobacter pylori

8 2232 Lai et al. AJG Vol. 95, No. 9, 2000 eradication reduces the rate of re-bleeding in ulcer haemorrhage. Gastrointest Endosc 1995;41: Marshall BJ, Warren JR, Francis GJ, et al. Rapid urease test in the management of Campylobacter pyloridis-associated gastritis. Am J Gastroenterol 1987;92: Norusis MJ. SPSS/PC Professional statistics, Version 5.0. Chicago, IL: SPSS: Thomas JM, Misiewicz G. Histamine H2 receptor antagonists in the short and long term treatment of duodenal ulcer. Clin Gastroenterol 1984;13: Van Deventer GM, Elashoff JD, Reedy TJ, et al. A randomized study of maintenance therapy with ranitidine to prevent the recurrence of duodenal ulcer. N Engl J Med 1989;320: Miller JP, Faragher EB. Relapse of duodenal ulcer: Does it matter which drug is used in initial treatment? Br Med J 1986;293: Martin DF, Hollanders D, May SJ, et al. Difference in relapse rates of duodenal ulcer after healing with cimetidine or tripotassium dicitrato bismuthate. Lancet 1981;ii: McNulty CA, Dent J, Wise R. Susceptibility of clinical isolates of Campylobacter pyloridis to 11 antimicrobial agents. Antimicrob Agents Chemother 1985;28: Schiller KFR, Truelove SC, Williams DG. Haematemesis and melaena, with special reference to factors influencing the outcome. Br Med J 1970;2: Fry J. Peptic ulcer disease: A profile. Br Med J 1964;2: Rockall TA, Logan RF, Devlin HB, et al. Incidence and mortality of acute upper gastrointestinal haemorrhage in the United Kingdom. Br Med J 1995;311: Laine L. Multipolar electrocoagulation in the treatment of active upper gastrointestinal haemorrhage: A prospective controlled trial. N Engl J Med 1987;316: Panes J, Viver J, Forne M, et al. Controlled trial of endoscopic sclerosis in bleeding peptic ulcers. Lancet 1987;ii: Jensen DM. Heat probe for haemostasis of bleeding peptic ulcers: Techniques and results of a randomised controlled trial. Gastrointest Endosc 1990;36:S Matthewson K, Swain CP, Bland M, et al. Randomised comparison of Nd:YAG laser, heater probe, and no endoscopic therapy for bleeding peptic ulcers. Gastroenterology 1990;98: Jensen DM, Cheng S, Kovacs TOG, et al. A controlled study of ranitidine for the prevention of recurrent haemorrhage from duodenal ulcer. N Engl J Med 1994;330: Laine L, Peterson WL. Bleeding peptic ulcer. N Engl J Med 1994;331: