Gastroprotective Therapy Does Not Improve Outcomes of Patients With Helicobacter pylori Negative Idiopathic Bleeding Ulcers

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012;10: Gastroprotective Therapy Does Not Improve Outcomes of Patients With Helicobacter pylori Negative Idiopathic Bleeding Ulcers GRACE LAI HUNG WONG, KIM WING LAM AU, ANGELINE OI SHAN LO, YEE KIT TSE, JESSICA YUET LING CHING, KA FAI TO, and FRANCIS KA LEUNG CHAN Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, SAR, China BACKGROUND & AIMS: We performed a prospective cohort study to investigate the effects of gastroprotective agents (such as proton pump inhibitors or histamine-2 receptor antagonists) on long-term clinical outcomes of patients with Helicobacter pylori negative idiopathic bleeding ulcers. METH- ODS: Patients with H pylori negative idiopathic bleeding ulcers were recruited from a single center from April 2002 to March 2009 (n 663). Age- and sex-matched patients with H pylori positive bleeding ulcers were used as controls (n 633). After ulcers had healed, 566 patients in the H pylori negative idiopathic ulcer cohort received gastroprotective agents at clinicians discretion, whereas controls received no gastroprotective agent after H pylori eradication therapy. Patients were followed until September 2011 for end points that included recurrent ulcer bleeding and all-cause mortality. RESULTS: During the exposed period of 534 person-years, the incidence rates of recurrent ulcer bleeding and death were 3.8 (95% confidence interval [CI], ) and 21.8 (95% CI, ) per 100 person-years among the patients given gastroprotective agents, compared with incidence rates of 2.4 (95% CI, ; P.08) and 13.8 (95% CI, ; P.001) per 100 person-years, respectively, during the unexposed period of 1588 person-years. Use of gastroprotective agents was not associated with mortality, after adjusting for confounders (hazard ratio, 1.1; 95% CI, ). Incident rates of recurrent ulcer bleeding and death were significantly higher in patients with H pylori negative idiopathic ulcers (2.9 and 17.0 per 100 person-years, respectively) than in controls (1.1 and 5.9 per 100 person-years, respectively; P.001). CONCLUSIONS: Gastroprotective agents do not reduce the risk of recurrent bleeding or mortality for patients with H pylori negative idiopathic bleeding ulcers. Keywords: Proton Pump Inhibitor (PPI); H2RA; Clinical Trial; Stomach. Helicobacter pylori negative idiopathic peptic ulcers have been recognized as a distinct group of peptic ulcers. 1 We previously reported that the absolute incidence of H pylori idiopathic bleeding peptic ulcers has increased by 5-fold during the past decade. 2,3 This increasing trend in Asia was echoed by a Korean study, which reported that more than 20% of the peptic ulcers were negative for H pylori infection and nonsteroidal anti-inflammatory drug (NSAID) use. 4 This trend probably happened a decade later in Asia than in the West, where more than one-fourth of the duodenal ulcers were not associated with NSAID use or H pylori infection, as demonstrated in a pooled analysis of 6 clinical trials involving 2900 patients at the end of the last century. 5 Their high prevalence was further supported in the findings of a meta-analysis of 7 US trials, which reported that 20% of patients with H pylori associated ulcers had recurrent ulcers within 6 months, despite successful cure of H pylori infection and no reported use of NSAIDs. 6 Preliminary data suggest that patients with H pylori negative idiopathic ulcers have a poor long-term outcome. In a prospective cohort study of 120 patients with H pylori negative idiopathic bleeding ulcers, we previously showed the incidence rate of recurrent ulcer bleeding was 3.8 per 100 person-years, compared with 0.4 per 100 person-years in patients with prior H pylori bleeding ulcers. 7 Patients with H pylori negative idiopathic bleeding ulcers also had significantly higher mortality (14.9 per 100 person-years) than patients with H pylori bleeding ulcers (5.4 per 100 person-years). 7 However, there has been no consensus or guideline on the long-term use of gastroprotective agents (GPAs) such as proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs) for this disease because prospective interventional data are not available. In clinical practice, use of GPAs in patients with H pylori negative idiopathic bleeding ulcers is still at the discretion of attending clinicians. In this prospective cohort study, we aimed to investigate the effect of GPAs on the long-term risk of recurrent bleeding and mortality. Methods Study Population This was a 9-year, single-center, prospective cohort study conducted at the Prince of Wales Hospital, which serves a local population of 1.2 million people in Hong Kong. We screened consecutive patients with a clinical diagnosis of upper gastrointestinal bleeding from April 2002 to March All patients who were diagnosed to have upper gastrointestinal bleeding underwent endoscopy within 24 hours of onset of bleeding. An ulcer was defined as a mucosal break with an apparent depth and a diameter of at least 5 mm. Biopsy specimens were taken from the antrum (2 biopsies), corpus (2 biopsies), and ulcer edge (4 quadrant biopsies) to exclude H pylori infection and other pathologic conditions such as neo- Abbreviations used in this paper: ASA, American Society of Anesthesiology; CI, confidence interval; GPA, gastroprotective agent; H2RA, histamine-2 receptor antagonist; IBD, inflammatory bowel disease; NSAID, nonsteriodal anti-inflammatory drug; PPI, proton pump inhibitor by the AGA Institute /$

2 October 2012 H PYLORI NEGATIVE IDIOPATHIC BLEEDING ULCERS 1125 plasms, Crohn s disease, cytomegalovirus, and herpes infection. H pylori infection was diagnosed by using a biopsy urease test (CLO test; Delta West, Bentley, Western Australia, Australia) and histology by using hematoxylin-eosin stain and Giemsa stain if necessary. H pylori infection was considered to be present if either the biopsy urease test or histology was positive for the bacterium. We repeated these diagnostic tests for H pylori in the absence of acid suppressive therapy on follow-up endoscopy. Patients underwent gastric acid secretion tests if suspected to have Zollinger Ellison syndrome as previously described. 3 Patients were excluded if they were in the intensive care unit, suffered from terminal diseases, were diagnosed to have malignancy, had previous gastrectomy, or failed to give written consent. We also excluded patients who used NSAIDs, aspirin, over-the-counter analgesics, or traditional Chinese medicine within 4 weeks before the index ulcer bleeding. The study was approved by the Joint Chinese University of Hong Kong New Territories East Cluster Clinical Research Ethics Committee. All patients provided informed written consent. Drug History Any recent use of aspirin, NSAIDs, or traditional Chinese medicine was meticulously screened from all patients. Patients who denied taking any analgesics were further screened for musculoskeletal pain or other pain disorders including headache, toothache, and dysmenorrhea. For patients with a painful condition who denied taking analgesics, a collateral drug history was obtained from family members and primary care physicians. A territory-wide electronic database was used to identify prescriptions of ulcerogenic drugs, acid suppressants, antibiotics, potassium supplements, calcium channel blockers, and antidepressants before the onset of gastrointestinal bleeding. We also retrieved over-the-counter drugs and prescriptions from patients, family members, and primary care physicians. Serum salicylate level was checked on admission to look for unreported use of NSAIDs. Exposure to NSAIDs or aspirin was defined as at least 1 dose of the drug taken within the 4 weeks before hospitalization. Patients who had used traditional Chinese herbal medicine were considered as possible NSAID users because previous reports indicated that these drugs may contain NSAIDs. 8 Study Cohorts Diagnosis of H pylori negative idiopathic ulcers was made on the basis of the following 3 prerequisites: (1) no exposure to aspirin, NSAIDs, or drugs of unknown nature including traditional Chinese medicine within the 4 weeks before hospitalization; (2) negative tests for both the biopsy urease test and histology for H pylori in the absence of gastroprotective therapy; and (3) no other identifiable causes of ulceration. Among the patients with H pylori negative idiopathic ulcers, we studied their gastric antrum and corpus biopsy specimens to detect any evidence of past H pylori infection, which was defined by the presence of intestinal metaplasia and/or gastric atrophy without H pylori. Age- and sex-matched cohort of patients with a history of H pylori positive bleeding peptic ulcers acted as control. H pylori positive ulcers were defined as having a positive test for H pylori in any of the biopsy specimens and no exposure to NSAIDs, aspirin, over-the-counter analgesics, or traditional Chinese medicine within 4 weeks before the bleeding episode. Grading of overall health and comorbidity was performed according to the American Society of Anesthesiology (ASA) classification as previously described. 3 Follow-up An 8-week course of a PPI was prescribed to patients with H pylori negative idiopathic ulcers. A 1-week PPI-based triple therapy was given to those with H pylori positive ulcers. We tested the H pylori status at least 4 weeks after completion of eradication therapy. In the H pylori negative idiopathic ulcer group, follow-up endoscopy to check ulcer healing reconfirmed negative H pylori status when patients had stopped PPI therapy for at least 1 week. Drug compliance was checked before follow-up endoscopy. Biopsies were taken from both the antrum and the corpus for histologic evidence of H pylori. IntheH pylori positive ulcer group, follow-up endoscopy was performed on all patients with gastric ulcers and those with duodenal ulcers who had poor drug compliance or who remained symptomatic 8 weeks after completion of eradication therapy to retest for H pylori status. After ulcer healing, the H pylori negative idiopathic ulcer cohort and the H pylori positive ulcer cohort were followed up at regular intervals until September Prophylactic GPAs such as PPIs and/or H2RAs were prescribed at the discretion of attending physicians. A reminder that clearly stated that patients should avoid taking NSAIDs and aspirin because of the risk of recurrent ulcer bleeding was inserted in patients electronic medical record, which was accessible to all doctors including non-gastroenterologists working under the local health authority, which provides health care to more than 90% of the Hong Kong population. During each follow-up visit, patients were advised to avoid taking NSAIDs and aspirin if possible. They were assessed for symptoms of recurrent bleeding (including hematemesis, coffeeground vomiting, melena, or fresh blood), dyspepsia, musculoskeletal pain, drug violation, and hemoglobin level. Antacids and simple analgesics including paracetamol, dextropropoxyphene, or tramadol were prescribed if clinically indicated. Endoscopy was repeated if patients experienced any symptoms of recurrent bleeding, a drop of hemoglobin level 2 g/dl, or dyspeptic symptoms not relieved by antacids. Biopsy urease test and histologic specimens from antrum, corpus, and ulcer margin were repeated. Because prescription of GPAs would vary during a long period of follow-up, we estimated the total duration of drug exposure from the cumulative period of prescriptions. Current use was defined as the period between the filling of the prescription and the end of the days of drug supply. Any prescription that was issued 30 days after the previous prescription was assumed to be continuous exposure. A territory-wide electronic database of the Hospital Authority, which provides health care to more than 90% of the Hong Kong population, was adopted to identify drug violations, comorbid medical conditions, dates of admission and discharge, and death as previously described. 3,7 End Points The primary end points were recurrent ulcer bleeding and all-cause mortality. Recurrent ulcer bleeding was defined as any of the bleeding symptoms (including hematemesis, coffeeground vomiting, melena, or fresh blood per rectum) together with ulcers confirmed by endoscopy or a decrease in the hemo-

3 1126 WONG ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 10 Table 1. Baseline Clinical Characteristics H pylori negative idiopathic ulcer cohort (n 663) H pylori ulcer cohort (n 633) P value Follow-up duration, median (range), mo 32.0 ( ) 53.0 ( ).001 Age at baseline, median (range), y 73 (18 100) 70 (20 96).08 Male (%) 377 (56.9) 370 (58.5).49 Hemoglobin, median (range), g/dl 8.6 ( ) 9.0 ( ).11 Ulcer location (%).08 Gastric 316 (47.7) 333 (52.6) Duodenal/gastroduodenal 347 (52.3) 300 (47.4) Ulcer diameter, median (range), mm 10 (2 60) 10 (2 50).85 ASA grade 3 (%) 315 (47.5) 193 (30.5).001 Patients who bled while in hospital (%) 204 (30.8) 50 (7.9).001 ASA classification: grade 1, normal healthy patients; grade 2, mild systemic illness; grade 3, severe but incapacitating systemic illness; grade 4, life-threatening illness. globin level 2 g/dl in the presence of endoscopically proven ulcers. A clinical event (rebleeding or mortality) was classified as within the period of GPA use if it occurred within 7 days from the last dose of prescription, whereas an event was classified as without exposure to GPAs if it occurred on 8 days or after the last dose of GPAs. Statistical Analysis The patients baseline characteristics were presented as descriptive data. We used Student t test to compare means, Mann Whitney U test to compare medians, and Pearson 2 test to compare categorical data. Incidence rates of recurrent ulcer bleeding or death were estimated by dividing the number of events by the number of person-years in year of diagnosis of index ulcer bleeding. The 95% confidence intervals (CIs) for the incidence rates were calculated by using Byar s formula. 9 A Cox proportional hazards model with backward stepwise regression was used to identify possible covariates as significant predictors of recurrent ulcer bleeding and mortality. All statistical tests were two-sided. Statistical significance was taken as P.05. Statistical analysis was performed by Statistical Package for Social Science (SPSS version 15.0; Chicago, IL). Results Baseline Characteristics From April 2002 to March 2009, 4827 patients had bleeding ulcers confirmed by endoscopy. Six hundred sixtythree patients (13.8%) of median age 72 years (range, ) had H pylori negative idiopathic bleeding ulcers (H pylori negative idiopathic ulcer cohort). We enrolled 633 age- and sexmatched patients with H pylori positive bleeding peptic ulcers as control (H pylori positive ulcer cohort). Compared with patients with H pylori positive ulcers, those with H pylori negative idiopathic ulcers had shorter follow-up duration, higher ASA grades, and a higher proportion of patients who bled while in hospital (Table 1). One hundred fifty-two patients (22.9%) had histologic evidence of past H pylori infection. None of the patients had cytomegalovirus inclusion bodies, herpes infection, or evidence of Crohn s disease. None of the patients fulfilled the screening criteria for Zollinger Ellison syndrome as previously described. 3 Follow-up There were 2122 person-years of observation in the H pylori negative idiopathic ulcer cohort and 2910 person-years in the H pylori positive ulcer cohort. The median follow-up was 32.0 months ( ) and 53.0 months ( ) in the H pylori negative idiopathic ulcer cohort and the H pylori positive ulcer cohort (P.001), respectively. The difference in follow-up duration between the 2 cohorts was due to the significantly higher mortality in the H pylori negative idiopathic ulcer cohort. Regular use of other prohibited drugs, including misoprostol, sucralfate, bismuth, NSAIDs, and aspirin, was not found in both cohorts. Pattern of Bleeding Peptic Ulcer Over the Years From April 2002 to March 2009, the annual incidence of all bleeding ulcers ranged from 613 to 819 cases. The annual incidence of H pylori negative idiopathic ulcers ranged from 72 to 118, whereas their annual proportions ranged from 12.1% to 16.4%. Both the annual incidence and proportions of H pylori negative idiopathic ulcers remained stable over these years. The annual incidence of H pylori positive ulcers ranged from 144 to 230, and the incidence was lowered in 2008 and The annual incidence of NSAID/aspirin-related ulcers ranged from 195 to 255, which remained stable over these years (Figure 1). Recurrent Ulcer Bleeding A total of 115 patients in the H pylori negative idiopathic ulcer cohort underwent endoscopy for suspected rebleeding; 57 were confirmed to have bleeding from recurrent ulcers. Fourteen patients with recurrent ulcer bleeding (24.6%) used concomitant NSAIDs or low-dose aspirin; none of the recurrent bleeding ulcers were positive for H pylori. Forty-three (41.9%) had no cause identified for their recurrent bleeding ulcers (ie, recurrent idiopathic bleeding ulcers). Thirty-nine patients in the H pylori positive ulcer cohort underwent endoscopy for suspected rebleeding; 31 were confirmed to have recurrent ulcer bleeding. Among them, 16 patients (51.6%) used concomitant NSAIDs or low-dose aspirin, 2 (6.5%) had relapse of H pylori infection, and 13 (41.9%) had idiopathic bleeding ulcers. In the H pylori negative cohort, the incidence rates of allcause recurrent ulcer bleeding (2.9 per 100 person-years; 95% CI, per 100 person-years) and idiopathic recurrent ulcer

4 October 2012 H PYLORI NEGATIVE IDIOPATHIC BLEEDING ULCERS 1127 Figure 1. Annual numbers of all bleeding ulcers, H pylori negative idiopathic ulcers, H pylori positive ulcers, and NSAID/aspirin-related ulcers in 2002 (April 2002 March 2003), 2003 (April 2003 March 2004), 2004 (April 2004 March 2005), 2005 (April 2005 March 2006), 2006 (April 2006 March 2007), 2007 (April 2007 March 2008), and 2008 (April 2008 March 2009). bleeding (2.1 per 100 person-years; 95% CI, per 100 person-years) were significantly higher than in the H pylori positive ulcer cohort (all-cause recurrent ulcer bleeding: 1.1 per 100 person-years, 95% CI, per 100 person-years, P.001; idiopathic recurrent ulcer bleeding: 0.5 per 100 personyears, 95% CI, per 100 person-years, P.001). In the Cox proportional hazards model, concomitant NSAID use was an independent factor predicting recurrent ulcer bleeding in the H pylori negative idiopathic ulcer cohort (Table 2). After adjusting for possible confounding covariates including age, ASA grade, location of ulcer, and concomitant NSAID and ulcer bleeding after hospitalization, H pylori negative idiopathic ulcer remained an independent risk factor associated with recurrent ulcer bleeding (hazard ratio, 2.7; 95% CI, ; P.001). Recurrent Ulcer Bleeding and Exposure to Gastroprotective Therapy Five hundred sixty-six patients in the H pylori negative idiopathic ulcer cohort (85.4%) were exposed to GPAs with overall exposure of 534 person-years; 470 (70.9%) and 340 (51.3%) patients in this cohort were exposed to PPIs and H2RAs, respectively. The incidence rate of recurrent ulcer bleeding during the period with GPA use (all-cause rebleeding: 3.8 per 100 person-years, 95% CI, per 100 person-years; idiopathic rebleeding: 2.8 per 100 person-years, 95% CI, per 100 Table 2. Analysis of Possible Factors Predicting Recurrent Ulcer Bleeding and Overall Mortality Using the Cox Proportional Hazard Model H pylori negative idiopathic ulcer cohort (N 663) Recurrent ulcer bleeding Overall mortality Hazard ratio 95% CI P value Hazard ratio 95% CI P value Age 70 y ASA grade Location of ulcer (duodenal vs nonduodenal) Past H pylori infection NSAID use Patients who bled while in hospital

5 1128 WONG ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 10 person-years) was not significantly different from that without GPA use (all-cause rebleeding: 2.4 per 100 person-years, 95% CI, per 100 person-years, P.08; idiopathic rebleeding: 2.7 per 100 person-years, 95% CI, per 100 person-years, P.16). After adjusting for age, ASA grade, location of ulcer, and ulcer bleeding after hospitalization, GPA use was not an independent risk or protective factor for recurrent ulcer bleeding (hazard ratio, 0.7; 95% CI, ; P.32). Mortality A total of 432 patients died, 360 (54.3%) in the H pylori negative idiopathic ulcer cohort and 172 (27.2%) in the H pylori positive ulcer cohort. In the Cox proportional hazards model, age older than 70 years, ASA grade 3, and ulcer bleeding after hospitalization were independent risk factors predicting all-cause mortality in the H pylori negative idiopathic ulcer cohort (Table 2). H pylori negative idiopathic ulcer remained an independent risk factor associated with all-cause mortality (hazard ratio, 2.0; 95% CI, ; P.001) after adjusting for age, ASA grade, location of ulcer, and ulcer bleeding after hospitalization. The overall incidence rates of death were significantly higher in the H pylori negative idiopathic ulcer cohort (17.0 per 100 person-years; 95% CI, per 100 person-years), compared with those in the H pylori positive ulcer cohort (5.9 per 100 person-years; 95% CI, per 100 person-years). The annual incidence rates varied from per 100 personyears in the H pylori negative idiopathic ulcer cohort, which were significantly higher than those in the H pylori positive ulcer cohort (range, per 100 person-years). Seventy-five patients in the H pylori negative idiopathic ulcer cohort (11.3%) died within 30 days of the index episode of bleeding, which was significantly higher than in the H pylori positive ulcer cohort (20 patients, 3.2%; P.001). Mortality and Exposure to Gastroprotective Agents The incidence rate of death was 21.8 per 100 personyears (95% CI, per 100 person-years) during the GPAexposed period, which was significantly higher than that during the nonexposed period (13.8 per 100 person-years; 95% CI, per 100 person-years; P.001). After adjusting for possible confounders including age, ASA grade, location of ulcer, and ulcer bleeding after hospitalization, GPA use was not an independent predictive factor of all-cause mortality (hazard ratio, 1.1; 95% CI, ; P.48). Discussion In this prospective cohort study, we found that H pylori negative idiopathic bleeding ulcer is not uncommon, accounting for about 12% 16% of all bleeding ulcers per year. Our study confirmed that patients with a history of H pylori negative idiopathic ulcer bleeding were at substantial risk of recurrent ulcer bleeding and death. Importantly, gastroprotective co-therapy did not protect patients from recurrent ulcer bleeding and death. The long-term management of H pylori negative idiopathic ulcers is poorly defined because its pathophysiology is largely unknown. Early studies suggested that some of these patients had increased gastrin and acid hypersecretion. 10 However, these abnormalities might be related to rebound acid secretion after withdrawal of PPIs. 10 The role of acid in the pathogenesis of H pylori negative idiopathic ulcers remains controversial. Unlike some Western series, our study cohort had more gastric ulcers than duodenal ulcers. 5,11,12 Our findings suggested that acid hypersecretion is unlikely to be a major pathogenetic factor. Similar observation was previously reported by Japanese and Korean case series, 4,13 which could be related to the high prevalence of gastric hypochlorhydria associated with past H pylori infection in many Asian countries. 14 Our findings question the efficacy of acid-suppressive therapy for prevention of recurrent bleeding in patients with a history of H pylori idiopathic ulcer bleeding. 15,16 The lack of protective effect of acid-suppressive drugs in this study suggests that either higher dose of acid-suppressive agents or other GPAs such as misoprostol would be the alternatives. Unfortunately, the side effects of misoprostol including diarrhea might limit its use in this group of patients who often have multiple comorbidities. An alternative explanation for the apparent failure of acid-suppressive therapy is that GPAs might be preferentially prescribed to older and sicker patients. After adjusting for comorbidity indicators such as age and ASA grade, the increase in mortality associated with GPA use disappeared. Our findings echoed the apparently increased risks of numerous adverse events, namely fracture risk, community-acquired pneumonia, enteric infections, and malignancy, which subsequently found the risk was not substantially increased for most of these events after controlling for potential confounders. 17 On the other hand, GPAs did not reduce the all-cause mortality either, which could be explained by the fact that most of the deaths were unrelated to the ulcer disease. We adopted a robust protocol to establish a diagnosis of H pylori negative idiopathic ulcer. Both urease test and histology were taken from multiple sites on repeated occasions to minimize false-negative tests for H pylori. To minimize underreporting of NSAID exposure, we used a systematic and scrupulous approach to identify drug use and measured serum salicylate level. We also excluded patients who had prior exposure to any unknown drugs including Chinese herbs because we believed these drugs might contain NSAIDs. The possible underlying etiologies of H pylori negative idiopathic ulcers include other medications such as potassium supplements, calcium channel blockers, and antidepressants, infections such as cytomegalovirus, inflammatory bowel disease (IBD), chronic mesenteric ischemia, and Zollinger Ellison syndrome. 14 We had meticulously screened for those drugs as we did for NSAIDs and aspirin. None of the patients had other infective pathogens or evidence of IBD identified on histology of gastric mucosa. Furthermore, no patient had clinical presentation suggestive of hypergastrinemia or Zollinger Ellison syndrome. Chronic mesenteric ischemia could not be totally excluded because some patients did have multiple cardiovascular risk factors such as atrial fibrillation and atherosclerosis. However, it was unlikely to be a major cause of the H pylori negative idiopathic ulcers in this cohort because our patients did not have any clinical evidence of ischemia in other parts of the gastrointestinal tract, in particular the colon, which might be more commonly affected by chronic mesenteric ischemia. Our study had limitations. First, this was not a randomized trial so that GPAs might be preferentially prescribed to older and sicker patients. Because of the relatively small number of

6 October 2012 H PYLORI NEGATIVE IDIOPATHIC BLEEDING ULCERS 1129 patients with H pylori negative idiopathic ulcer bleeding, a large-scale randomized trial to detect a difference in clinical outcomes is unlikely to be feasible. Our study findings reflect a more real-life situation. Second, the high recurrent bleeding and mortality of our study cohort could be related to old age and multiple comorbidities. However, these factors could not be the entire explanation because H pylori negative idiopathic bleeding ulcer per se was an independent risk factor predicting rebleeding and mortality. In conclusion, patients with a history of H pylori negative idiopathic ulcer bleeding have a considerable risk of recurrent bleeding and all-cause mortality. H pylori negative idiopathic ulcer bleeding is an independent risk factor predicting adverse clinical outcomes. The use of acid-suppressive drugs did not protect patients from recurrent ulcer bleeding. Optimal gastroprotective therapy for prevention of recurrent bleeding in patients with a history of H pylori negative idiopathic ulcers remains unclear and should be further investigated in prospective randomized controlled trials. References 1. McColl KE. Helicobacter pylori-negative nonsteroidal anti-inflammatory drug-negative ulcer. Gastroenterol Clin North Am 2009; 38: Chan HL, Wu JC, Chan FK, et al. Is non-helicobacter pylori, non-nsaid peptic ulcer a common cause of upper GI bleeding? A prospective study of 977 patients. Gastrointest Endosc 2001; 53: Hung LC, Ching JY, Sung JJ, et al. Long-term outcome of Helicobacter pylori-negative idiopathic bleeding ulcers: a prospective cohort study. Gastroenterology 2005;128: Jang HJ, Choi MH, Shin WG, et al. Has peptic ulcer disease changed during the past ten years in Korea? A prospective multicenter study. Dig Dis Sci 2008;53: Ciociola AA, McSorley DJ, Turner K, et al. Helicobacter pylori infection rates in duodenal ulcer patients in the United States may be lower than previously estimated. Am J Gastroenterol 1999;94: Laine L, Hopkins RJ, Girardi LS. Has the impact of Helicobacter pylori therapy on ulcer recurrence in the United States been overstated? A meta-analysis of rigorously designed trials. Am J Gastroenterol 1998;93: Wong GL, Wong VW, Chan Y, et al. High incidence of mortality and recurrent bleeding in patients with Helicobacter pylori-negative idiopathic bleeding ulcers. Gastroenterology 2009;137: Gertner E, Marshall PS, Filandrinos D, et al. Complications resulting from the use of Chinese herbal medications containing undeclared prescription drugs. Arthritis Rheum 1995;38: Rothman KJ. Epidemiology: an introduction. New York: Oxford University Press, Gillen D, Wirz AA, Ardill JE, et al. Rebound hypersecretion after omeprazole and its relation to on-treatment acid suppression and Helicobacter pylori status. Gastroenterology 1999;116: Bytzer P, Teglbjaerg PS. Helicobacter pylori-negative duodenal ulcers (prevalence, clinical characteristics, and prognosis): results from a randomised trial with 2-year follow-up. Am J Gastroenterol 2001;96: McColl KE, el-nujumi AM, Chittajallu RS, et al. A study of the pathogenesis of Helicobacter pylori negative chronic duodenal ulceration. Gut 1993;34: Nishikawa K, Sugiyama T, Kato M, et al. Non-Helicobacter pylori and non-nsaid peptic ulcer disease in the Japanese population. Eur J Gastroenterol Hepatol 2000;12: Chan FK. Proton-pump inhibitors in peptic ulcer disease. Lancet 2008;372: Quan C, Talley NJ. Management of peptic ulcer disease not related to Helicobacter pylori or NSAIDs. Am J Gastroenterol 2002;97: Chow DK, Sung JJ. Non-NSAID non-h. pylori ulcer disease. Best Pract Res Clin Gastroenterol 2009;23: Sheen E, Triadafilopoulos G. Adverse effects of long-term proton pump inhibitor therapy. Dig Dis Sci 2011;56: Reprint requests Address requests for reprints to: Francis K. L. Chan, MD, Department of Medicine and Therapeutics, 9/F Prince of Wales Hospital, Ngan Shing Street, Shatin, Hong Kong. fklchan@cuhk.edu.hk; fax: Conflicts of interest These authors disclose the following: Grace L. H. Wong has received a consulting fee from Otsuka and paid lecture fees by Echosens. Francis K. L. Chan received an independent research grant and a consulting fee from Pfizer and paid lecture fees by Pfizer, Takeda, and AstraZeneca. The remaining authors disclose no conflicts.