Helicobacter pylori Eradication Does Not Exacerbate Reflux Symptoms in Gastroesophageal Reflux Disease

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1 GASTROENTEROLOGY 2001;121: Helicobacter pylori Eradication Does Not Exacerbate Reflux Symptoms in Gastroesophageal Reflux Disease PAUL MOAYYEDI, CHANDU BARDHAN, LYNNE YOUNG, MICHAEL F. DIXON, LORNA BROWN, and ANTHONY T.R. AXON The General Infirmary at Leeds, Leeds, West Yorkshire, England Background & Aims: Observational studies have suggested that Helicobacter pylori may protect against gastrointestinal reflux disease (GERD), but these results could be due to bias or confounding factors. We addressed this in a prospective, double blind, randomized, controlled trial. Methods: H. pylori positive patients with at least a 1-year history of heartburn with a normal endoscopy or grade A esophagitis were recruited. Patients were randomized to 20 mg omeprazole, 250 mg clarithromycin, and 500 mg tinidazole twice a day for 1 week or 20 mg omeprazole twice a day and identical placebos. A second concurrently recruited control group of H. pylori negative patients were given open label 20 mg omeprazole twice a day for 1 week. All patients received 20 mg omeprazole twice a day for the following 3 weeks and 20 mg omeprazole once daily for a further 4 weeks. Omeprazole was discontinued at 8 weeks and patients were followed up for a further 10 months. A relapse was defined as moderate or severe reflux symptoms. H. pylori eradication was determined by 13 C-urea breath test. Results: The H. pylori positive cases were randomized to antibiotics (n 93) or placebo (n 97). Relapse of GERD occurred in 83% of each of the antibiotic, placebo, and H. pylori negative groups during the 12-month study period. Life tables revealed no statistical difference between the 2 H. pylori positive groups (log rank test, P 0.84) or between the 3 groups (log rank test, P 0.94) in the time to first relapse. Two patients in each group developed grade B esophagitis at 12 months. Conclusions: H. pylori eradication therapy does not seem to influence relapse rates in GERD patients. The relationship between Helicobacter pylori infection, acid suppression, and gastroesophageal reflux disease (GERD) is complex. 1 Patients with H. pylori infection are at risk of developing gastric mucosal atrophy, and a cohort study suggested that long-term proton pump inhibitor (PPI) therapy for GERD may accelerate this process. 2 This work has been supported by randomized controlled trials, 3,4 although not all have given statistically significant results. 4 Some investigators therefore have recommended that H. pylori should be treated in GERD patients in whom long-term antisecretory therapy is planned. Case control studies, however, have suggested that H. pylori eradication may result in an increased incidence of GERD in duodenal ulcer patients, 5,6 although results are conflicting. 7,8 The severity of GERD has also been reported to be lower in H. pylori infected patients. 9 H. pylori infection may enhance the ability of PPIs to reduce intragastric acidity, 10 and patients with H. pylori positive esophagitis heal faster with PPIs than uninfected individuals. 11 Furthermore, rebound acid hypersecretion has been observed in H. pylori negative subjects after stopping PPI therapy. 12 There are concerns, therefore, that treatment of H. pylori in GERD patients may exacerbate the disease, reduce the ability of PPIs to treat symptoms effectively, and promote rebound acid hypersecretion once the drug is discontinued. The suggestion that H. pylori may protect against GERD has been derived from case control or cohort studies, and the results could be due to bias or confounding factors. We have therefore evaluated the effect of H. pylori eradication on reflux symptoms in GERD patients in a prospective, double blind, randomized, controlled trial. Materials and Methods This was a double blind, single dummy, parallel group randomized trial performed by 2 centers (Leeds and Rotherham) in the United Kingdom between July 1995 and August Patients over the age of 17 years were considered for recruitment if they had recurrent heartburn for at least 1 year as a dominant complaint and at least moderate symptoms for a minimum of 2 days each week for the previous 2 weeks. Subjects with grade A esophagitis or a normal endoscopy were enrolled. Exclusion criteria included grades B D esophagitis, Abbreviations used in this paper: GERD, gastroesophageal reflux disease; PPI, proton pump inhibitor by the American Gastroenterological Association /01/$35.00 doi: /gast

2 November 2001 H. PYLORI THERAPY & SYMPTOMS IN GERD PATIENTS 1121 past or present peptic ulcer, previous esophageal or gastric surgery, pregnancy, and alcohol dependence. Patients taking warfarin or phenytoin, allergy to study drugs, treatment with antibiotics, or bismuth salts within the previous month and PPIs, H 2 receptor antagonists, sucralfate, or prokinetic agents within a day before randomization were also excluded. Assessment of H. pylori Status One antral and 1 corpus biopsy specimen was obtained for rapid urease test and 2 antral and 2 corpus biopsy specimens for histology. The histology biopsy sections were stained with H&E for classification of gastritis according to the Sydney system and with Alcian Blue/periodic acid Schiff for intestinal metaplasia. A modified Giemsa stain was used to assess H. pylori status. Participants were invited to attend for 13 C-urea breath test up to 7 days after the endoscopy. Four grams of citric acid was dissolved in 200 ml of water, and the fasted patient was given 150 ml of the solution to delay gastric emptying. A baseline breath sample was obtained in duplicate and then the patient was given the remaining 50 ml of citric acid solution, to which 100 mg of 13 C-urea (Boston Isotopes, Boston, MA) had been added. A further duplicate breath sample was obtained at 30 minutes in exetainers, and the samples were analyzed by mass spectrometry (ABCA-NT Europa Scientific, Crewe, Cheshire, UK) at the Leeds General Infirmary. The 13 C-urea breath test was considered positive if there was a greater than 5 per 1000 of 13 CO 2 difference over baseline. This protocol has a sensitivity of 96% and specificity of 98% in our population. 13 Patients were defined as H. pylori positive if the 13 C-urea breath test and at least 1 biopsy-based test was positive, and defined as negative if all tests were negative. Study Design GERD patients infected with H. pylori were randomized to 1 week of 20 mg omeprazole, 250 mg clarithromycin, and 500 mg tinidazole twice a day or to 20 mg omeprazole twice a day and identical antibiotic placebos (Figure 1). All patients were then given 20 mg open label omeprazole twice a day for 3 weeks and 20 mg omeprazole once a day for a further 4 weeks. Randomization was performed using a computergenerated list, and the investigators assessing the patient were not involved in administering the medication. A further group of H. pylori negative GERD patients were given 20 mg open label omeprazole twice a day for 4 weeks and 20 mg omeprazole once a day for the subsequent 4 weeks. The relative proportion of H. pylori infected subjects in this trial does not reflect the prevalence in the population because recruitment of H. pylori negative subjects was discontinued after 61 uninfected patients were enrolled. These individuals were aware of their H. pylori negative status, so this additional arm of the study was not masked. This uninfected cohort was analyzed separately and acted as a second but unrandomized control group. Omeprazole was discontinued in all groups after 8 weeks. Patients were given Maalox antacid preparation (Rhône-Poulenc Rorer, Kings Hill, Kent, UK) to take as rescue medication. No other antacid, antisecretory, or prokinetic therapy was permitted. Outcome Assessment Participants were followed up every month for the first 3 months and every 3 months thereafter until month 12 (Figure 1). The presence of heartburn, epigastric pain, acid regurgitation, and dysphagia was assessed by questionnaire. These were classified as mild if the patient was aware of the symptom but it was easily tolerated, moderate if the discomfort was sufficient to interfere with normal activities, and severe if the patient was unable to perform normal activities. All symptom assessments were obtained by a face-to-face interview. GERD symptoms were assessed by questionnaire at each visit using the same questionnaire that was administered at Figure 1. Summary of the trial design.

3 1122 MOAYYEDI ET AL. GASTROENTEROLOGY Vol. 121, No. 5 baseline. A 13 C-urea breath test was performed at 3 and 12 months (Figure 1). An endoscopy was also performed at 12 months to evaluate the presence of esophagitis. A relapse was defined as the recurrence of moderate or severe GERD symptoms for 2 or more days per week. This was the primary endpoint of the trial. Patients that relapsed were given 20 mg omeprazole twice a day for 1 month followed by 20 mg omeprazole once daily until month 12. Patients were withdrawn from the trial if they continued to have at least moderate symptoms despite PPI therapy, and a 13 C-urea breath test and endoscopy were performed at the exit visit. Participants that failed to attend follow up were censored at the time of their last visit. All patients in remission at 12 months were followed up for a further 6 months. Patients prescribed 20 mg omeprazole once daily for symptom relapse were instructed to discontinue therapy, and this group was analyzed separately as a prospectively planned subgroup analysis. Relapse rates were compared between the antibiotic, placebo, and H. pylori negative arms of the trial during the month phase of the trial. The rationale for this part of the trial is that rebound acid hypersecretion may occur in H. pylori negative subjects and this could increase relapse rates in patients discontinuing PPI therapy. Local ethics committees approved the study and all participants gave written informed consent. Statistical Analysis We assumed that 80% of the patients receiving antibiotic placebos would have relapsed by the 12-month visit. 14 A total of 188 H. pylori positive GERD patients (94 in each group) would give the power to detect a 20% difference in relapse rates at the 80% power and 5% significance level assuming a 20% drop out rate. A smaller number of H. pylori negative patients were also recruited to the study. This group was not randomized or masked and was not used in the primary statistical analyses. The data from this group was for descriptive purposes, so the results from the H. pylori infected groups randomized to antibiotics or placebo could be put into perspective. The primary endpoint of the trial was time to first relapse. The data were analyzed using life table methods and the remission curves of the groups were compared using the log rank test. A secondary endpoint was relapse rates at months. Patients that had relapsed in the first 12 months but had remained asymptomatic on 20 mg omeprazole once daily were asked to discontinue therapy, and the month relapse rate of this group was analyzed separately. The proportion of patients discontinuing because of relapse on 20 mg omeprazole once daily and the proportion of participants with esophagitis at 12 months was compared using the 2 test. The GERD symptom scores were compared between the randomized groups at the beginning and end of the study using the Mann Whitney U test. All analyses were intention-to-treat, and a P value of 0.05 was taken as statistically significant. Results Two hundred fifty-one patients were recruited to the study; 190 were H. pylori positive and 61 were H. pylori negative. The H. pylori positive cases were randomized to antibiotics (n 93) or placebo antibiotics (n 97). The baseline characteristics were similar between the 2 groups (Table 1). Four patients in the placebo arm, 8 from the antibiotic arm, and 7 from the H. pylori negative arm were excluded from the intention-to-treat analysis (Figure 2) because of disagreements between tests as to H. pylori status, no study drug taken, or no efficacy data after baseline. The H. pylori eradication rate was 82% in the antibiotic arm according to the 13 C-urea breath test at 3 and 12 months. An H. pylori eradication rate of 13% was observed in the placebo arm, but this may be artefactual because some patients were taking omeprazole before the 13 C-urea breath test. Relapses From 0 to 12 Months The relapse rates at 12 months were 83% in each of the placebo, antibiotic, and H. pylori negative groups. Life tables revealed no statistical difference between the 2 H. pylori positive groups (log rank test, P 0.84) or between the 3 groups (log rank test, P 0.94) in the time to first relapse (Figure 3). Eleven of 85 (13%) of the Table 1. Baseline Characteristics of the Intention to Treat Antibiotic, Placebo, and H. pylori Negative Groups Variable Placebo group (n 93) Antibiotic group (n 85) H. pylori negative group (n 54) No. of males (%) 45 (48%) 38 (45%) 29 (54%) Grade A esophagitis (%) 19 (20%) 20 (24%) 18 (33%) Overall GERD symptoms Moderate (%) 80 (86%) 72 (85%) 41 (76%) Severe (%) 13 (14%) 13 (15%) 13 (24%) Current smoker (%) 32 (34%) 27 (32%) 14 (26%) Current alcohol consumption 71 (76%) 56 (66%) 43 (80%) Body mass index (mean SD) kg/m (3.9) 26.5 (4.6) 26.7 (4.0) Age (mean SD) yr 50.8 (11.6) 47.4 (12.5) 45.0 (12.3) Corpus atrophy present 20 (23%) 15 (18%) 0 (0%) Intestinal metaplasia present 4 (5%) 1 (1%) 0 (0%)

4 November 2001 H. PYLORI THERAPY & SYMPTOMS IN GERD PATIENTS 1123 Table 2. Comparison of GERD Symptoms and Endoscopic Diagnosis at 12 Months Between the Antibiotic, Placebo, and H. pylori Negative Groups Variable Placebo group Antibiotic group H. pylori negative group Heartburn None Mild Moderate Severe Regurgitation None Mild Moderate Severe Overall symptoms None Mild Moderate Severe Esophagitis None Grade A Grade B P a Figure 2. Flow diagram of the progress of participants. a Mann Whitney U test in antibiotic vs. placebo groups only. H. pylori negative group shown for comparison. antibiotic group, 11 of 93 (12%) of the placebo group, and 10 of 54 (19%) of the H. pylori negative group withdrew from the study within the first 2 months because of relapse of symptoms during this period. Symptom and Endoscopy Assessment at 12 Months There were no statistically significant differences in heartburn, regurgitation, overall GERD symptoms, or rates of esophagitis between the randomized H. pylori positive groups at 12 months (Table 2) with most patients having no or mild symptoms. Results for the H. pylori negative group were also similar (Table 2). Relapses From 12 to 18 Months Patients without GERD symptoms or esophagitis at 12 months including patients who had relapsed and been restarted on omeprazole were eligible for further follow up. Fifty-six participants remained in remission at 12 months (placebo group, n 20; antibiotic group, n 22; and H. pylori negative group, n 14). The relapse rates in these patients were 12% in the placebo Figure 3. Gastroesophageal remission curves from 0 to 12 months for the antibiotic, placebo, and H. pylori negative groups.

5 1124 MOAYYEDI ET AL. GASTROENTEROLOGY Vol. 121, No. 5 Figure 4. Remission curves from 12 to 18 months for the antibiotic, placebo, and H. pylori negative groups in patients with no previous relapse. group, 23% in the antibiotic group, and 37% in the H. pylori negative group (Figure 4). Fifty-nine patients had relapsed during the previous 12 months but had then remained asymptomatic on 20 mg omeprazole once daily (placebo group, n 20; antibiotic group, n 20; H. pylori negative group, n 19). In these groups, omeprazole was discontinued and the patients were followed up for a further 6 months. The relapse rates were 82% in the placebo group, 55% in the antibiotic group, and 70% in the H. pylori negative group (Figure 5). Discussion This is the first randomized controlled trial to evaluate the effect of H. pylori eradication on reflux symptoms and esophagitis in GERD patients. There was an 83% relapse rate in GERD symptoms at 12 months in the antibiotic and placebo groups. This relapse rate is consistent with the previous literature 14 and was also seen in the H. pylori negative controls. These data suggest that H. pylori infection does not have a clinically important impact on relapse rates in Los Angeles grade A esophagitis or endoscopy-negative reflux disease. The results may not be applicable to patients with more severe esophagitis, although our study is representative of the majority of patients presenting in primary care with reflux symptoms. The drop out rates were relatively high, and this may reduce the power of the trial to show a difference between the H. pylori eradication and placebo antibiotic groups. All analyses were intention-to-treat using life table methods, so patients contributed to the results until the point that they were lost to follow up or withdrawn. The remarkably similar relapse rates in all 3 arms of the study Figure 5. Remission curves from 12 to 18 months for the antibiotic, placebo, and H. pylori negative groups in patients with previous relapse.

6 November 2001 H. PYLORI THERAPY & SYMPTOMS IN GERD PATIENTS 1125 suggest there is little difference between the groups for this primary outcome. Rebound acid hypersecretion has been reported in H. pylori negative patients after discontinuation of highdose omeprazole given for 8 weeks. 12 This is not seen in all H. pylori positive individuals, with some showing persistent acid suppression. 12 The clinical importance of this observation is uncertain. Our data do not support a clinically significant increase in relapse rates in infected GERD patients allocated to antibiotic therapy after receiving 20 mg omeprazole twice daily for 4 weeks followed by once daily for a further 4 weeks. It remains possible that rebound hypersecretion may be more pronounced in H. pylori negative patients given longer course of acid suppression. We found no statistically significant difference in relapse rates in H. pylori positive patients allocated to antibiotic or placebo after the omeprazole was discontinued at 12 months in those requiring long-term acid suppression. This, however, was a secondary outcome measure and the numbers of patients eligible for this part of the trial were relatively small. We therefore cannot exclude the possibility that H. pylori eradication therapy may cause a modest change in relapse rates once long-term PPI therapy is discontinued. Intragastric ph is positively correlated with healing of reflux esophagitis, 15 and PPI therapy is more effective at reducing acid output in the presence of H. pylori. 10 Treatment of H. pylori may therefore be expected to reduce the efficacy of PPI in GERD patients. Some studies have suggested that healing rates are higher in H. pylori positive esophagitis patients compared with uninfected controls after antisecretory therapy, 11,16 whereas others have not found this relationship These contradictory results may be caused by confounding factors because there are differences in age and socioeconomic circumstances between H. pylori positive and negative patients. 20 These studies also cannot exclude the possibility that an independent factor may cause a decrease in the prevalence of H. pylori infection and an increase in GERD. Bile reflux, for example, inhibits H. pylori 21 and has been associated with GERD. 22 A randomized controlled trial overcomes these problems, and we found the symptomatic response to omeprazole was similar in H. pylori positive patients randomized to antibiotic therapy compared with placebo. H. pylori eradication is therefore unlikely to reduce the efficacy of PPI therapy in GERD patients. The majority of patients in this study had a normal endoscopy and the diagnosis of GERD mainly relied on symptoms. These have been shown to be reasonably accurate, 23 although some patients without GERD may have been included in the study. 24 A positive response to PPI therapy may be a more accurate method of identifying GERD patients. 25,26 There was no difference in relapse rate when patients not responding to PPI therapy were excluded at the 2-month visit. The putative protective effect of H. pylori on GERD is said to be more marked in caga-positive 27 and vaca S1 strains. 28 We did not assess this and it is possible that more virulent strains of H. pylori have a protective effect in GERD patients. We evaluated patients with GERD and it remains possible that H. pylori eradication therapy may change the risk of GERD in non-ulcer dyspepsia or peptic ulcer patients. A systematic review, however, found no evidence that H. pylori eradication therapy increase esophagitis in non-ulcer dyspepsia patients, 29 and we found no increase in reflux symptoms in a large, double blind, randomized, controlled trial of H. pylori eradication in the general population. 30 H. pylori infection can cause gastric mucosal atrophy leading to reduced gastric acid output, which in turn may reduce reflux esophagitis. 31 This is likely to be more of a problem in elderly patients, and this was confirmed by a case control study. 32 Patients enrolled in this trial had a mean age of 48 years, and it is possible that results would have been different in an older population with a greater proportion of pan-gastritis and gastric atrophy. H. pylori eradication leads to a recovery of acid secretion in a proportion of these individuals, and this could increase reflux in predisposed patients. We have shown that H. pylori eradication therapy does not increase relapse rates in endoscopy-negative reflux disease and Los Angeles grade A esophagitis patients. We have also demonstrated that treating H. pylori infection does not dramatically impair the efficacy of PPI therapy. Therefore, the decision as to whether H. pylori eradication therapy should be offered to infected GERD patients rests on the individual beliefs of clinicians about the risks of developing corpus atrophy and intestinal metaplasia during prolonged acid suppression. References 1. Dent J. Helicobacter pylori and reflux disease. Eur J Gastroenterol Hepatol 1999;11(suppl 2):S51 S Kuipers EJ, Lundell L, Klinkenberg-Knol EC, Havu N, Festen HP, Liedman, Lamers CB, Jansen JB, Dalenback J, Snel P, Nelis GF, Meuwissen SG. Atrophic gastritis and Helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication. 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Gastroenterology 1999;116: Klauser AG, Schindlbeck NE, Muller-Lissner SA. Symptoms in gastro-oesophageal reflux disease. Lancet 1990;335: Moayyedi P, Axon AT. The usefulness of the likelihood ratio in the diagnosis of dyspepsia and gastroesophageal reflux disease. Am J Gastroenterol 1999;94: Fass R, Ofman JJ, Sampliner RE, Camargo L, Wendel C, Fennerty MB. The omeprazole test is as sensitive as 24-h oesophageal ph monitoring in diagnosing gastro-oesophageal reflux disease in symptomatic patients with erosive oesophagitis. Aliment Pharmacol Ther 2000;14: Ofman JJ, Gralnek IM, Udani J, Fennerty MB, Fass R. The costeffectiveness of the omeprazole test in patients with noncardiac chest pain. Am J Med 1999;107: Vicari JJ, Peek RM, Falk GW, Goldblum JR, Easley KA, Schnell J, Perez-Perez GI, Halter SA, Rice TW, Blaser MJ, Richter JE. The seroprevalence of caga-positive Helicobacter pylori strains in the spectrum of gastroesophageal reflux disease. Gastroenterology 1998;115: Fallone CA, Barkun AN, Gottke MU, Best LM, Loo VG, Veldhuyzen VZ, Nguyen T, Lowe A, Fainsilber T, Kouri K, Beech R. Association of Helicobacter pylori genotype with gastroesophageal reflux disease and other upper gastrointestinal diseases. Am J Gastroenterol 2000;95: Moayyedi P, Soo S, Deeks J, Forman D, Mason J, Innes M, Delaney B. Systematic review and economic evaluation of Helicobacter pylori eradication treatment for non-ulcer dyspepsia. BMJ 2000;321: Moayyedi P, Feltbower R, Brown J, Mason S, Mason J, Nathan J, Richards IDG, Dowell AC, Axon ATR. The effect of population H. pylori screening and treatment on dyspepsia and quality of life in the community: results of a randomised controlled trial. Lancet 2000;355: Koike T, Ohara S, Sekine H, Iijima K, Kato K, Shimosegawa T, Toyota T. Helicobacter pylori infection inhibits reflux esophagitis by inducing atrophic gastritis. Am J Gastroenterol 1999;94: Haruma K, Hamada H, Mihara M, Kamada T, Yoshihara M, Sumii K, Kajiyama, Kawanishi M. Negative association between Helicobacter pylori infection and reflux esophagitis in older patients: case-control study in Japan. Helicobacter 2000;5: Received April 2, Accepted July 26, Address requests for reprints to: Paul Moayyedi, Ph.D., FRCP, Gastroenterology Unit, City Hospital NHS Trust, Dudley Road, Winson Green, Birmingham, B18 7QH England. p.moayyedi@bham. ac.uk; fax: (44) Supported by a research grant from AstraZeneca. Dr. Moayyedi is currently funded by a UK Medical Research Council Training Fellowship in Health Services Research. Dr. Brown is an employee of AstraZeneca.