SUMMARY INTRODUCTION. Accepted for publication 25 May 2005

Aliment Pharmacol Ther 2005; 22: 243 249. doi: 10.1111/j.1365-2036.2005.02554.x Trends in the prevalence of peptic ulcer disease and Helicobacter pylori infection in family physician-referred uninvestigated dyspeptic patients in Hong Kong B.XIA*,H.H.X.XIA, C.W.MA*,K.W.WONG, F.M.Y.FUNG, C.K.HUI, C.K.CHAN, A. O. O. CHAN, K.C.LAI, M.F.YUEN &B.C.Y.WONG *Department of Internal Medicine, Research Center of Digestive Diseases of Zhongnan Hospital, Key Laboratory of Allergy and Immune-related Diseases, Wuhan University School of Medicine, China; Department of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China Accepted for publication 25 May 2005 SUMMARY Background: Peptic ulcer disease is mainly caused by Helicobacter pylori infection and the use of non-steroidal anti-inflammatory drugs. Aim: To investigate the trends in the prevalence of peptic ulcer disease, H. pylori infection and non-steroidal anti-inflammatory drug use in uninvestigated dyspeptic patients over recent years in Hong Kong. Methods: Data from consecutive patients with uninvestigated dyspeptic symptoms referred by family physicians for open access upper endoscopy during 1997 and 2003 were analysed in relation to peptic ulcer disease, H. pylori infection and non-steroidal anti-inflammatory drug use. Results: Among 2700 patients included, 405 (15%) had peptic ulcer disease and 14 (0.5%) had gastric cancer. There was a reduced trend from 1997 to 2003 in the prevalence of peptic ulcer disease (17, 20, 14, 16, 13, 14 and 14%, respectively, v 2 ¼ 5.80, P ¼ 0.016) (mainly because of decrease in duodenal ulcers), H. pylori infection (44, 50, 49, 44, 40, 40, 36 and 43%, respectively, v 2 ¼ 13.55, P < 0.001) and non-steroidal anti-inflammatory drug use (13, 5, 5, 6, 3, 4, 4 and 5% respectively, v 2 ¼ 13.61, P < 0.001). The prevalence of peptic ulcer disease, H. pylori infection and non-steroidal anti-inflammatory drug use between 2001 and 2003 were significantly lower than that between 1997 and 2000 (17% vs. 13%, OR ¼ 0.78, 95% CI: 0.63 0.96, P ¼ 0.020 for peptic ulcer disease; 47% vs. 39%, OR ¼ 0.72, 95% CI: 0.60 0.86, P < 0.001 for H. pylori infection; and 6% vs. 4%, OR ¼ 0.56, 95% CI: 0.39 0.82, P ¼ 0.002 for non-steroidal anti-inflammatory drug use). H. pylori infection was associated with both duodenal ulcer (OR ¼ 15.87, 95% CI: 10.60 23.76, P < 0.001) and gastric ulcer (OR ¼ 3.12, 95% CI: 2.15 4.53, P < 0.001) whereas non-steroidal antiinflammatory drug use was only associated with gastric ulcer (OR ¼ 2.97, 95% CI: 1.70 5.20, P < 0.001). Conclusions: The prevalence of peptic ulcer disease, mainly duodenal ulcers, was reduced in association with a decreasing trend in the prevalence of H. pylori infection and non-steroidal anti-inflammatory drug use from 1997 to 2003. INTRODUCTION Correspondence to: Dr B. C. Y. Wong, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China. E-mail: bcywong@hku.hk Prevalence of peptic ulcer diseases (PUD) differs within countries. In China between 1977 and 1986, the average prevalence of duodenal ulcer in patients Ó 2005 Blackwell Publishing Ltd 243

244 B. XIA et al. undergoing upper endoscopy was 23% in the South and 9.7% in the North, with the average rate of duodenal ulcer almost doubling that of gastric ulcer. 1 It has been established that Helicobacter pylori infection is a major cause for PUD. 2 4 Approximately half of the world s populations are infected with H. pylori, according to the estimate by the World Health Organization. 3 Pooled data obtained in 1991 showed that the prevalence of H. pylori infection in patients with dyspepsia was reported to be about 60% in China. 5 Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used for various indications; 6 NSAID use increases with age, with 10 20% of the elderly having a current or recent NSAID prescription. 6 The use of NSAIDs is associated with various adverse events. Studies have shown that NSAID use is a major risk factor for non-h. pylori-associated PUD, especially gastric ulcer. 7, 8 Moreover, NSAIDs increase the risk of peptic ulcer complications by three to fivefold, and responsible for 15 35% of all peptic ulcer complications. 9, 10 Helicobacter pylori eradication therapy has become part of routine clinical practice for infected patients with PUD. 11, 12 Permanent cure of ulcers is achieved in most cases where H. pylori infection is successfully eradicated. 4 Following wide spread anti- H. pylori therapy in both primary practice and the hospital setting and particularly, the improvement of socio-economic and living conditions, the prevalence of H. pylori infection and PUD, especially duodenal ulcers, are decreasing in many countries. 4, 13, 14 The case is unknown in the Hong Kong Chinese population. Therefore, this study was carried out to investigate the trend in prevalence of PUD, H. pylori infection and frequency of NSAID use in uninvestigated dyspeptic patients referred by family physicians in Hong Kong Chinese. PATIENTS AND METHODS Source and collection of data Consecutive Chinese patients who were referred by family physicians to our open access endoscopy service, Medical Endoscopy Unit, Queen Mary Hospital from January 1997 to December 2003 with dyspeptic symptoms (defined as intermittent epigastric pain or discomfort) were analysed. Our open access endoscopy service was previously reported. 15 Briefly, family physicians in government general out-patient clinics were able to directly refer patients with uninvestigated dyspepsia to our open access endoscopy without prior consultation with a specialist. A special session was allocated to the open access service and over 90% of the cases were performed by a single endoscopist. 15 Data was collected using the computerized endoscopyreporting system established in 1993 in our unit. This system was specifically designed to collect the required information prospectively. Clinical information was recorded on a standard questionnaire before endoscopy, and entered into the reporting system, together with endoscopic findings after endoscopy. The clinical information included patient age and gender, major indication for upper endoscopy, duration of the symptoms, smoking and drinking history, concomitant diseases, use of aspirin and non-aspirin NSAIDs. Dosage and duration of NSAID use were also included. Endoscopic information included current endoscopic findings, lesion site, size and number if present. Helicobacter pylori status was determined using a rapid urease test on antral biopsy specimens, histological detection of Helicobacter-like organisms on biopsies taken from gastric antrum and body and/or 13 C-urea breath test. 16, 17 The rapid urease test as a single test for diagnosis of H. pylori infection has been validated in our centre with sensitivity, specificity, positive and negative predictive value of 99, 100, 100 and 99% respectively. 17 As some patients had more than one endoscopy performed during the period of study, the first endoscopy was used as an index endoscopy. However, when a patient had PUD or gastric cancer, the first endoscopy at which PUD or gastric cancer was diagnosed was used as an index endoscopy. Thus, each patient had one representative endoscopy. Patients with peptic ulcers (visible mucosal defect with diameter of 3 mm and depth 0.5 mm) and healed ulcers (ulcer scarring and/or duodenal deformity) in the stomach or duodenum were defined as having peptic ulcers. 18 The diagnosis of gastric cancer must be histologically confirmed. Patients who had used NSAIDs for at least 3 days at any dosage within 3 months prior to the index endoscopy were considered to be NSAID users. 7 All demographic, clinical and endoscopic data were retrieved. The cohort was divided into two groups based on the time period with roughly equal number in both groups, i.e. those between 1997 and 2000 (n ¼ 1369) and those between 2001 and 2003 (n ¼ 1331).

TRENDS IN PEPTIC ULCER DISEASE AND H. PYLORI 245 Statistical analysis The trend in the prevalence of PUD, gastric cancer, H. pylori infection, NSAID use, and the association among PUD, H. pylori infection and NSAID use in dyspeptic patients were analysed using the chi-squared test (with Yates correction if required), or the Fisher s exact test. Odds ratios (OR) and 95% confidence intervals (CI) were estimated where appropriate. Moreover, a multivariate logistic regression analysis including age and gender of patients, H. pylori infection and NSAID use was used to identify independent predictor (or risk) factor(s) for PUD. Difference in numeric data such as age between the groups was performed using the t-test or preformed using logistic regression analysis. All P-values calculated were two-tailed. The alpha level of significance was set at P < 0.05. Statistical analyses were performed using SPSS11.5 software (SPSS, Inc., Chicago, IL, USA). RESULTS Overall trend in the prevalence of peptic ulcer, gastric cancer, Helicobacter pylori infection and non-steroidal anti-inflammatory drug use in dyspeptic patients During 1997 and 2003, data from 2700 patients referred by family physicians to our open access upper endoscopy were analysed. Among these patients, 405 (15.0%) were diagnosed as having PUD; 260 (9.6%) with duodenal ulcer, 129 (4.8%) with gastric ulcer and 16 (0.6%) with both duodenal and gastric ulcer. The overall prevalence of symptomatic PUD, gastric cancer, H. pylori infection and NSAIDs use in this population was 15.0, 0.5, 42.8 and 5.1%, respectively. There was a reduced trend in the prevalence of PUD (P ¼ 0.016), H. pylori infection (P < 0.001) and NSAIDs use (P < 0.001) (Table 1 and Figure 1). Comparison of the demographic, clinical and endoscopic data of dyspeptic patients between 1997 2000 and 2001 2003 The mean age of the patients was significantly younger between 2001 and 2003 than that between 1997 and 2000 (46.0 ± 15.6 vs. 51.3 ± 16.4 years old, P ¼ 0.011). However, there was no change in the gender distribution during the two periods of time. The prevalence of PUD between 2001 and 2003 were significantly lower than that between 1997 and 2000 (16.6% vs. 13.4%, OR ¼ 0.78, 95% CI: 0.63 0.96, P ¼ 0.020). Table 1. Trend in the prevalence of peptic ulcer disease, gastric cancer, Helicobacter pylori infection and non-steroidal anti-inflammatory drug (NSAID) use in dyspeptic patients referred by general practitioners between 1997 and 2003 v 2 for trend P value Total (n ¼ 2700) 2003 (n ¼ 329) 2002 (n ¼ 534) 2001 (n ¼ 468) 2000 (n ¼ 433) 1999 (n ¼ 365) 1998 (n ¼ 365) 1997 (n ¼ 206) Peptic ulcer disease 35 (17.0) 72 (19.7) 50 (13.7) 70 (16.2) 61 (13.0) 72 (13.5) 45 (13.7) 405 (15.0) 5.795 0.016 Duodenal ulcer* 24 (11.7) 51 (14.0) 37 (10.1) 46 (10.6) 45 (9.6) 47 (8.8) 26 (7.9) 276 (10.2) 8.091 0.004 Gastric ulcer* 12 (5.8) 23 (6.3) 13 (3.6) 29 (6.7) 19 (4.1) 30 (5.6) 19 (5.8) 145 (5.3) 0.069 0.793 Gastric cancer 1 (0.5) 1 (0.3) 4 (1.1) 2 (0.5) 1 (0.2) 2 (0.4) 3 (0.9) 14 (0.5) 4.471 0.583 Helicobacter pylori 42/95 (44.2) 136/275 (49.5) 128/161 (49.0) 148/338 (43.8) 158/396 (39.9) 134/334 (40.2) 98/273 (35.9) 844/1971 (42.8) 13.547 < 0.001 infection NSAID use 26/194 (13.4) 16/344 (4.7) 18/344 (5.2) 21/385 (5.5) 14/438 (3.2) 17/441 (3.9) 13/314 (4.1) 125/2460 (5.1) 13.608 <0.001 The numbers in parentheses are percentages. * 16 cases had both gastric and duodenal ulcer. Data were not available for some cases.

246 B. XIA et al. 50% 45% 40% Prevalence 35% 30% 25% 20% 15% 10% 5% 0% 1997 1998 1999 2000 2001 2002 2003 Year H. pylori infection Peptic ulcer disease Duodenal ulcer Gastric ulcer NSAID use Gastric cancer Figure 1. Trend in the prevalence of peptic ulcer disease, gastric cancer, Helicobacter pylori infection and non-steroidal antiinflammatory drugs use in dyspeptic patients between 1997 and 2003. While the prevalence of duodenal ulcer was significantly reduced, the prevalence of gastric ulcer remained stable (Table 2). The prevalenceof H. pylori infection and NSAID use between 2001 and 2003 was significantly lower than that between 1997 and 2000 (46.9% vs. 38.9%, OR ¼ 0.73, 95% CI: 0.60 0.86, P < 0.001 for H. pylori infection; 6.4% vs. 3.7%, OR ¼ 0.56, 95% CI: 0.39 0.82, P ¼ 0.002 for NSAID use) (Table 2). No change in the prevalence of gastric cancer was observed (Table 2). Association of peptic ulcer disease with gender, and age of patients, Helicobacter pylori infection and non-steroidal anti-inflammatory drug use The prevalence of PUD was significantly higher in men than in women (54.1% vs. 35.5%, OR ¼ 2.09, 95% CI: 1.62 2.70, P < 0.001). Patients with PUD were significantly older than those without PUD (51.2 ± 14.9 vs. 47.3 ± 16.4 years old, P ¼ 0.01). Helicobacter pylori infection was significantly associated with PUD (OR ¼ 9.46, 95% CI: 7.15 12.52, P < 0.001) including both duodenal ulcer (OR ¼ 15.87, 95% CI: 10.60 23.76, P < 0.001) and gastric ulcer (OR ¼ 3.12, 95% CI: 2.15 4.53, P < 0.001). Although NSAID use was not associated with overall PUD (OR ¼ 1.35, 95% CI: 0.85 2.14, P ¼ 0.201) and duodenal ulcer, it was significantly associated with gastric ulcer (OR ¼ 2.97, 95% CI: 1.70 5.20, P < 0.001) (Table 3). Moreover, patients with H. pylori infection and/or NSAID use were more likely to have PUD (OR ¼ 9.541, 95% CI: 7.05 12.92, P < 0.001), including both duodenal ulcer (OR ¼ 16.86, 95% CI: 10.68 26.60, P < 0.001) and gastric ulcer (OR ¼ 3.34, 95% CI: 2.25 4.97, P < 0.001). Table 2. Demographic and clinical data of dyspeptic patients between 1997 and 2000 and between 2001 and 2003 1997 2000 (n ¼ 1369) 2001 2003 (n ¼ 1331) Total (n ¼ 2700) Gender Male 509 (37.2%) 512 (38.5%) 1021 (37.8%) Female 860 (62.8%) 819 (61.5%) 1679 (62.2%) Age (year) Mean age (mean ± SD) 51.3 ± 16.4 46.0 ± 15.6 48.7 ± 16.2 Range 17 94 16 87 16 94 NSAID users* 81/1267 (6.4%) 44/1193 (3.7%)à 125/2460 (5.1%) Helicobacter pylori positive cases* 454/969 (46.9%) 390/1002 (38.9%) 844/1971 (42.8%) Peptic ulcer disease 227 (16.6%) 178 (13.4%) 405 (15.0%) Duodenal ulcer 150 (11.0%) 110 (8.3%) 260 (9.6%) Gastric ulcer 69 (5.0%) 60 (4.5%) 129 (4.8%) Duodenal/gastric ulcer 8 (0.6%) 8 (0.6%) 16 (0.6%) Gastric cancer 8 (0.6%) 6 (0.5%) 14 (0.5%) Other gastrointestinal diseases 12 (0.9%) 4 (0.3%) 16 (0.6%) * Data were not available for some cases. Compared with 1997 2000, P < 0.05. à Compared with 1997 2000, P < 0.01. Compared with 1997 2000, P < 0.001.

TRENDS IN PEPTIC ULCER DISEASE AND H. PYLORI 247 Table 3. Association of peptic ulcer disease (PUD), including duodenal ulcer (DU) and gastric ulcer (GU), with Helicobacter pylori infection and non-steroidal anti-inflammatory drug (NSAID) use in dyspeptic patients between 1997 and 2003 1997 2000 2001 2003 1997 2003 Total PUD DU* GU* Total PUD DU* GU* Total PUD DU* GU* Helicobacter pylori status Positive 454 186 (41.0%) 142 (31.3%) 51 (11.2%) 390 136 (34.9%) 101 (25.9%) 42 (10.8%) 844 322 (38.2%) 243 (28.8%) 93 (11.0%) Negative 515 35 (6.8%) 14 (2.7%) 22 (4.3%) 612 34 (5.6%) 14 (2.3%) 21 (3.4%) 1127 69 (6.1%) 28 (2.5%) 43 (3.8%) NSAID use Yes 81 17 (21.0%) 10 (12.3%) 9 (11.1%)à 44 7 (15.9%) 0 (0%) 7 (15.9%) 125 24 (19.2%) 10 (8%) 16 (12.8%) No 1186 201 (16.9%) 146 (12.3%) 60 (5.1%) 1149 148 (12.9%) 103 (9.0%) 50 (4.4%) 2335 349 (14.9%) 249 (10.7%) 110 (4.7%) 218 156 69 155 103 57 373 259 126 Helicobacter pylori infection and/or NSAID use Yes 514 192 (37.4%) 145 (28.2%) 55 (10.7%) 420 139 (33.1%) 101 (24.0%) 45 (10.7%) 934 331 (35.4%) 246 (26.3%) 100 (10.7%) No 463 29 (6.3%) 11 (2.4%) 18 (3.9%) 548 26 (4.7%) 10 (1.8%) 17 (3.1%) 1011 55 (5.4%) 21 (2.1%) 35 (3.5%) * Some cases had both gastric and duodenal ulcer. Compared with H. pylori negative cases, non-nsaid users or H. pylori negative non-nsaid users, where appropriate, P < 0.001; à Compared with non-nsaid users, P ¼ 0.020. Using the multivariate logistic regression analysis, male gender (OR ¼ 2.09, 95% CI: 1.63 2.70, P < 0.001), increasing age (OR ¼ 0.99, 95% CI: 0.98 1.00, P ¼ 0.026) of the patients and positive H. pylori infection (OR ¼ 5.41, 95% CI: 2.96 12.67, P < 0.001), but not NSAID use, were identified as independent risk factors for PUD. Non-steroidal anti-inflammatory drug users were significantly older than non-nsaid users (59.8 ± 15.9 vs. 48.4 ± 15.9 years old, P < 0.001), although NSAID use was not associated with gender of patients. There was no significant difference in the prevalence of H. pylori infection between NSAID users and non- NSAID users (38.9% vs. 43.0%, OR ¼ 0.84, 95% CI: 0.55 1.30, P ¼ 0.444). However, in patients with PUD, the prevalence of H. pylori infection in NSAID users was significantly lower than that in non-nsaid users (65.2% vs. 84.0%, OR ¼ 0.36, 95% CI: 0.15 0.89, P ¼ 0.021). DISCUSSION In the present study, the prevalence of duodenal ulcer, H. pylori infection and NSAID use all decreased from 1997 to 2003 in uninvestigated dyspeptic patients in Hong Kong, but that of gastric ulcer and gastric cancer remained unchanged. This phenomenon after widespread application for H. pylori eradication therapy was also observed in other studies. 19 Our study confirms that the decreased trend in prevalence of PUD, mainly duodenal ulcer, is associated with a decrease in H. pylori infection. We did not find any association between NSAID use and overall prevalence of PUD, after adjusting for confounding factors including age, gender of the patients and H. pylori infection. However, our further analysis showed that NSAID use was associated with gastric ulcer, but not with duodenal ulcer. This observation is in agreement with a previous study demonstrating that NSAIDs are associated with the development of gastric ulcers, independent of H. pylori infection. 8 Many previous studies have shown that H. pylori infection is inversely associated with NSAID use. 20 23 In a recent large cross-sectional endoscopic trial, the prevalence of H. pylori infection was significantly lower in NSAID users with gastric ulcers than in those without ulcers. 20 Indeed, previous studies have also shown that between 30 and 75% of H. pylori negative ulcer patients are NSAID users, whereas <30% of H. pylori positive ulcer patients are NSAID users. 21 23

248 B. XIA et al. The reason for such inverse association is unknown, but it is likely to be explained by the observations that NSAIDs have bacteriostatic or inhibitory activity against H. pylori, 24, 25 and thus occasionally eliminate the organism with or without use of one or more antimicrobial agents. In the present study, we also found in patients with PUD, the prevalence of H. pylori infection in NSAID users was significantly lower than in non-nsaid users, which is consistent with the crosssectional endoscopic trial. It has been reported in a meta-analysis that H. pylori infection and NSAIDs independently and significantly increase the relative risk of PUD. 26 Moreover, H. pylori infection significantly increases the risk of ulcer in NSAID users compared with non-nsaid users. Eradication of H. pylori has been recommended for the management of PUD. 27 However, there are controversies regarding eradication therapy in patients on longterm NSAID treatment for the prevention of PUD and the associated complications. Sung 28 showed that eradication of H. pylori infection reduced the risk of ulcer and the complications in patients requiring NSAIDs and aspirin. Lanas 29 showed that proton pump inhibitors or H. pylori eradication seemed the best option to reduce the incidence of upper gastrointestinal bleeding in patients taking low-dose aspirin. However, Lai et al. 30, 31 reported that the eradication of H. pylori infection in patients receiving long-term NSAID treatment was not sufficient to prevent ulcer development, and proton pump inhibitors are required. In the present study, there was no reduction in the prevalence of gastric cancer and gastric ulcer over 7 years, despite an active H. pylori eradication in Hong Kong. In a high-risk region of China, eradication of H. pylori infection in individuals without precancerous lesions significantly decreases the incidence of gastric cancer during 7.5-year follow-up period. 32 However, the sample size of the present study was not adequate (n ¼ 2700), and the follow-up period (7 years) was also insufficient for the determination of the trend in the incidence of gastric cancer after some eradication of H. pylori infection. Also for these reasons, it is not feasible to assess the association between gastric cancer and other factors such as H. pylori infection and NSAID use in the present study. In conclusion, the prevalence of PUD, mainly duodenal ulcers, was reduced, in association with a decreasing trend in the prevalence of H. pylori infection and NSAID use from 1997 to 2003. ACKNOWLEDGEMENTS Prof. B. Xia was a visiting professor, financially supported by the Sun Yat Sen Foundation Fund for Academic Exchanges with China, Faculty of Medicine, The University of Hong Kong, for this study. We thank nurse specialist M. Chong, and endoscopy nurses V.S.Y. Tang, D.K.K. Chang, and W.P. Yung, and technician Mr Hess Cheung for assistance; and Mr James Ma of Queen Mary Hospital, Hong Kong, for the computer endoscopy reporting system. REFERENCES 1 Wong BCY, Ching CK, Lam SK, et al. Differential north to south gastric cancer duodenal ulcer gradient in China. J Gastroenterol Hepatol 1998; 13: 1050 7. 2 Warren JR, Marshall B. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet 1983; 1: 1273 5. 3 International Agency for Research on Cancer, World Health Organization. Infection with Helicobacter pylori, schistosomes, liver flukes and Helicobacter pylori, IARC, Lyon, 1994 Monogr. Eval Carcinog Risks Hum 1994; 60: 177 240. 4 Consensus Development Panel on Helicobacter pylori in Peptic Ulcer Disease. Helicobacter pylori in peptic ulcer disease. JAMA 1994; 272: 65 9. 5 Li YY, Hu PJ, Du GG, Hazell SL. The prevalence of Helicobacter pylori infection in the Peoples Republic of China. Am J Gastroenterol 1991; 86: 446 9. 6 Griffin MR, Piper JM, Daugherty JR, Snowden M, Ray WA. Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons. Ann Intern Med 1991; 114: 257 63. 7 Xia HHX, Kalantar JS, Mitchell HM, Talley NJ. Can Helicobacter pylori serology still be a surrogate marker to identify peptic ulcer disease in dyspepsia? Aliment Pharmacol Ther 2000; 14: 615 24. 8 Laine L, Marin-Sorensen M, Weinstein WM. Nonsteroidal antiinflammatory drug-associated gastric ulcers do not require Helicobacter pylori for their development. Am J Gastroenterol 1992; 87: 1398 402. 9 Henry D, Lim LLY, Garc a Rodr guez LA, et al. Variability in risk of gastrointestinal complications with individual nonsteroidal anti-inflammatory drugs: results of a collaborative meta-analysis. BMJ 1996; 312: 1563 6. 10 Luis AGR, Sonia HD. Risk of uncomplicated peptic ulcer among users of aspirin and nonaspirin nonsteroidal antiinflammatory drugs. Am J Epidemiol 2004; 159: 23 31. 11 Xia HHX, Wong BCY, Talley NJ, Lam SK. Helicobacter pylori infection current treatment practice. Expert Opin Pharmacother 2001; 2: 253 66. 12 Xia HHX, Wong BCY, Talley NJ, Lam SK. Alternative and rescue treatment regimens for Helicobacter pylori eradication. Expert Opin Pharmacother 2002; 3: 1301 11.

TRENDS IN PEPTIC ULCER DISEASE AND H. PYLORI 249 13 Sonnenberg A. Temporal trends and geographical variations of peptic ulcer disease. Aliment Pharmacol Ther 1995; 9(Suppl. 2): 3 12. 14 Xia HHX, Phung N, Altiparmak E, Berry A, Matheson M, Talley NJ. Reduction of peptic ulcer disease and Helicobacter pylori infection but increase of reflux esophagitis in western Sydney between 1990 and 1998. Dig Dis Sci 2001; 46: 2716 23. 15 Wong BCY, Wong KW, Chan CK, et al. Evaluation of a new referral system for the management of dyspepsia in Hong Kong: role of open access upper endoscopy. J Gastroenterol Hepatol 2000; 15: 1251 6. 16 Wong BCY, Xiao SD, Hu FL, et al. Comparison of lansoprazolebased triple therapy for treatment of Helicobacter pylorirelated duodenal ulcer: an Asian multicentre double-blind randomized placebo controlled study. Aliment Pharmacol Ther 2000; 14: 217 24. 17 Wong BCY, Wong WM, Wang WH, et al. An evaluation of invasive and non-invasive tests for the diagnosis of Helicobacter pylori infection in Chinese. Aliment Pharmacol Ther 2001; 15: 505 11. 18 Xia HHX, Wong BCY, Wong KW, et al. Clinical and endoscopic characteristics of non-helicobacter pylori, non- NSAID duodenal ulcers: a long-term prospective study. Aliment Pharmacol Ther 2001; 15: 1875 82. 19 Kearney DJ, Liu CF, Crump C, Brousal A. The effect of a Helicobacter pylori treatment strategy on health care expenditures in patients with peptic ulcer disease and dyspepsia. Am J Gastroenterol 2003; 98: 1952 62. 20 Matsukawa Y, Aoki M, Nishinarita S, et al. Prevalence of Helicobacter pylori in NSAID users with gastric ulcer. Rheumatology (Oxford) 2003; 42: 947 50. 21 Nensey YM, Schubert TT, Bologna SD, Ma CK. Helicobacter pylori-negative duodenal ulcer. Am J Med 1991; 91: 15 8. 22 Borody TJ, George LL, Brandl S, et al. Helicobacter pylorinegative duodenal ulcer. Am J Gastroenterol 1991; 86: 1154 7. 23 Kemppainen H, Raiha I, Kujari H, Sourander L. Characteristics of Helicobacter pylori-negative and -positive peptic ulcer disease. Age Ageing 1998; 27: 427 31. 24 Wang WH, Wong WM, Dailidiene D, et al. Aspirin inhibits the growth of Helicobacter pylori and enhances its susceptibility to antimicrobial agents. Gut 2003; 52: 490 5. 25 Gu Q, Xia HHX, Wang WH, et al. Effect of cyclo-oxygenase inhibitors on Helicobacter pylori susceptibility to metronidazole and clarithromycin. Aliment Pharmacol Ther 2004; 20: 675 81. 26 Huang JQ, Sridhar S, Hunt RH. Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in pepticulcer disease: a meta-analysis. Lancet 2002; 8: 124 31. 27 Kuipers EJ, Malfertheiner P. Helicobacter pylori and nonmalignant diseases. Helicobacter 2004; 9(Suppl. 1): 29 34. 28 Sung JJY. Should we eradicate Helicobacter pylori in nonsteroidal anti-inflammatory drug users? Aliment Pharmacol Ther 2004; 20(Suppl. 2): 65 70. 29 Lanas A. Prevention of aspirin-induced gastroduodenal damage: H. pylori infection eradication versus proton pump inhibitors or both. Dig Liver Dis 2004; 36: 655 7. 30 Lai KC, Lau CS, Ip WY, et al. Effect of treatment of Helicobacter pylori on the prevention of gastroduodenal ulcers in patients receiving long-term NSAIDs: a double-blind, placebo-controlled trial. Aliment Pharmacol Ther 2003; 17: 799 805. 31 Lai KC, Lam SK, Chu KM, et al. Lansoprazole reduces ulcer relapse after eradication of Helicobacter pylori in nonsteroidal anti-inflammatory drug users a randomized trial. Aliment Pharmacol Ther 2003; 18: 829 36. 32 Wong BC, Lam SK, Wong WM, et al. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA 2004; 291: 187 94.