SUMMARY INTRODUCTION. Aliment Pharmacol Ther 1997; 11: 515±522. Accepted for publication 27 January 1997

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1 Aliment Pharmacol Ther 1997; 11: 515±522. Doubling the omeprazole dose (40 mg b.d. vs. 20 mg b.d.) in dual therapy with amoxycillin increases the cure rate of Helicobacter pylori infection in duodenal ulcer patients J. LABENZ*, J.A. BEKER, C.P.M. DEKKERSà A. FARLEY, H.-U. KLOÈ R± & A. JOÈ NSSON** * Elisabeth Hospital, Essen, Germany; St. Antonius Hospital, Leidschendam, the Netherlands; à Ignatius Hospital, Breda, the Netherlands; Centre de Gastro-enteÂrologie et d EÁndoscopie de MontreÂal, Canada; ± University of Giessen, Germany; and ** Clinical Research Management, Astra HaÈssle, MoÈlndal, Sweden Accepted for publication 27 January 1997 SUMMARY Background: Several studies have shown that dual therapy with omeprazole and amoxycillin may cure Helicobacter pylori infection. However, the optimum dose of omeprazole has still to be established. Methods: An international, randomized, double-blind multicentre trial was conducted in patients with duodenal ulcers to compare the H. pylori cure rates obtained by dual therapy consisting of either omeprazole 20 mg b.d. plus amoxycillin 750 mg b.d. or omeprazole 40 mg b.d. plus amoxycillin 750 mg b.d. for 2 weeks. Dual therapy was followed by omeprazole 20 mg once daily for 2 weeks. Before entering the trial and 4 weeks after cessation of treatment H. pylori infection was assessed by histology and a 13 C-urea breath test. Results: 381 patients were randomized into the study, of whom 345 were evaluable for the all-patients-treated analysis of ef cacy and 378 were valid for the evaluation of safety. Histology results showed that H. pylori infection was cured in 64 out of 174 patients treated with omeprazole 20 mg b.d. plus amoxycillin and in 102 out of 171 patients treated with omeprazole 40 mg b.d. plus amoxycillin (37% vs. 60%; P < 0.001). Both treatment regimens were well tolerated, with adverse events reported by 29 (15.2%) and 35 patients (18.7%), respectively. Conclusions: This study has shown that dual therapy with amoxycillin 750 mg b.d. and omeprazole 40 mg b.d. is superior to dual therapy with amoxycillin and omeprazole 20 mg b.d. in patients with H. pyloripositive duodenal ulcers. Thus, a true dose±response relationship exists between omeprazole and treatment success. However, a combination of omeprazole with two of amoxycillin, clarithromycin and a nitroimidazole is a preferable alternative for routine clinical use. INTRODUCTION Helicobacter pylori, a spiral-shaped bacterium, causes chronic active gastritis that is the underlying disease in the majority of duodenal ulcers. Cure of the infection heals ulcers without acid suppression, 1 prevents ulcer recurrences 2 and probably ulcer complications as Correspondence to: Dr J. Labenz, Elisabeth Hospital, Moltkestrasse 61, D Essen, Germany. well. 3±5 Antibiotics coupled with antisecretory drugs accelerate duodenal ulcer healing. 6 In addition, treating duodenal ulcers by curing the infection is associated with an improvement in the quality of life of the patients. 7 Moreover, a therapy aiming at cure of the infection is by far the most cost-effective approach to the long-term management of duodenal ulcer disease. 8 Considering the overwhelming evidence from intervention trials, Helicobacter treatment is now recommended in all ulcer patients infected with H. pylori, whether on rst presentation or with an ulcer relapse. 9,10 Ó 1997 Blackwell Science Ltd 515

2 516 J. LABENZ et al. Cure of the infection has proved dif cult. Oral triple therapy consisting of a bismuth salt, metronidazole and tetracycline was earlier considered the standard for Helicobacter treatment. However, frequently occurring side-effects, a high number of tablets, and a loss of ef cacy in patients harbouring H. pylori strains resistant to metronidazole are major drawbacks. In 1989, Unge et al. reported that a simple treatment regimen comprising omeprazole and amoxycillin may cure H. pylori infection. 11 During subsequent years, some authors have con rmed encouraging results with this novel treatment option while others have reported rather disappointing outcomes. 12 Since the minimal inhibitory concentration of amoxycillin substantially decreases with increasing ph and since the effect of omeprazole on acid secretion, and thus on the ph gradient across the mucus layer is dose dependent, it was tempting to speculate that a higher dose of omeprazole would improve the H. pylori cure rate of dual therapy with omeprazole and amoxycillin. The present international, randomized, double-blind multicenter study was designed to test the hypothesis that omeprazole 40 mg b.d. in combination with amoxycillin is superior to omeprazole 20 mg b.d. plus amoxycillin in the cure of H. pylori infection in duodenal ulcer patients. METHODS Patient population Patients (n = 381) from 33 centres in eight countries (Canada, Finland, Germany, Italy, Netherlands, Norway, Portugal, UK) participated in the study. Patients with at least one endoscopically-proven duodenal ulcer of ³5 mm in diameter were eligible for the study. Patients were excluded if they: were below 18 years of age; had contraindications to the study drugs; had severe concomitant diseases, concurrent gastric ulcer or re ux oesophagitis; were suffering current complications of peptic ulcer disease, had a history of gastric surgery apart from a simple closure of a perforation, were in pregnancy or lactation, had been pre-treated with bismuth within 6 months prior to enrolment or with proton pump inhibitors or antibiotics during the preceding month; were pre-treated regularly with NSAIDs; were on phenytoin or warfarin, or if there was a suspected lack of compliance (e.g. chronic alcoholism). The study was conducted according to GCP guidelines and the Declaration of Helsinki. The protocol was approved by all local ethics committees. Study design The study was performed as a randomized double-blind study with parallel groups. The randomization was performed by computer and carried out separately for each centre and within blocks of two consecutive patient numbers. Before enrolment and 4 weeks after cessation of any medication a gastroscopy was performed and H. pylori infection was assessed by histology and 13 C-urea breath test (UBT). Cure of the infection was established 4 weeks after cessation of any medication. A summary of all assessments used during the study is given in Table 1. Treatment Patients who were eligible for the study and who had given written informed consent were randomly treated with either omeprazole 20 mg b.d. plus amoxycillin 750 mg b.d. or omeprazole 40 mg b.d. plus amoxycillin 750 mg b.d. for 2 weeks. In both groups, Helicobacter Table 1. Assessments used during the study Entry 2 weeks 4 weeks 8 weeks* 8(12*) weeks Endoscopy + biopsies UBT Symptoms * Physical examination * Laboratory screen * Adverse events * Compliance * * Patients judged not to be in remission after 4 weeks. UBT, 13 C-urea breath test.

3 DUAL THERAPY FOR H. PYLORI 517 treatment was followed by omeprazole 20 mg o.m. for 2 weeks. Treatment was stopped after 4 weeks if a patient was judged to be in remission. Patients with ongoing symptoms were treated with omeprazole 20 mg o.m. for an additional 4 weeks. Compliance was checked by counting the returned drugs. Assessment of H. pylori infection At each endoscopy three biopsies from the antrum and two biopsies from the corpus of the stomach were taken and placed in separate tubes containing formalin. The biopsies were stained with Giemsa and in doubtful cases additionally with the Warthin & Starry and immunoperoxidase methods for assessment of H. pylori infection. The severity of gastritis was graded according to the Sydney system 13 after haematoxylin-eosin staining. The breath test was performed with 100 mg 13 C-urea. A sandwich, liquid nutrition or a chocolate bar served as the test meal. Breath samples were collected before the test meal was given, 15, 30, 45 and 60 min after intake of the labelled urea. The breath samples were stored at room temperature and later analysed by isotope ratio mass spectrometry. A patient was considered to be infected with H. pylori if the d 13 CO 2 passed 5&. Since the breath test had not been validated before the start of the trial, patients were classi ed to be infected with H. pylori if typical bacteria were seen on histology. Cure of the infection was de ned as no evidence of ongoing infection by histology at least 4 weeks after cessation of any medication. Analysis of ef cacy We used two approaches to the analysis of data, allpatients-treated (APT) and per-protocol (PP) 14. The APT approach addresses the question: `How does the drug work in patients prescribed the drug?', while the PP approach is based on the question: `How effective is the drug in patients who take the drug as prescribed?' Patients who were not treated with the combination therapy, who did not have a duodenal ulcer, who were H. pylori-negative at entry, who received an unknown study drug, who were discontinued due to baseline characteristics, without assessment of ef cacy, were excluded from the APT analysis. Data from patients affected by major deviations from the protocol, e.g. intake of less than 75% of the study medication during weeks 1 and 2, were excluded from the PP analysis. Patients eligible for adverse event evaluation were those who took at least one dose of the study drug and for whom subsequent study information was available. Statistical analysis The sample size estimation was based on the assumption that the true H. pylori cure rates were 65% and 80% for the two treatment groups. Then 360 randomized patients with a drop-out rate of 15% would give a two-sided test at 5% signi cance level a power of 80% to detect a signi cant difference between the two treatments. Cure of H. pylori infection was analysed with Mantel± Haenszel test strati ed by centre. The treatment groups were compared with respect to overall symptoms and epigastric pain at visit 2 and at visit 5 with a Wilcoxon rank sum test. All tests were two-sided, considering signi cance at a 5% probability level. A multiple logistic regression analysis was performed with the dosage of omeprazole, patients' age, smoking habits, and compliance as explanatory variables and cure of H. pylori infection as the dependent variable. The assessments of H. pylori status by histology and the 13 C-urea breath test were compared by crosstabulation. During the study, the type of vial for collecting the breath samples had to be changed. The rst type had a rubber stopper, which was found to be de cient and did not keep the samples intact. Therefore, the comparison between histology and UBT was made only between the samples collected in screw cap vials and their corresponding histology samples. RESULTS There were 381 patients randomized into the study, 194 into the study arm treated with omeprazole 20 mg b.d. combined with amoxycillin and 187 into the study arm treated with omeprazole 40 mg b.d. plus amoxycillin. Overall, 345 patients could be included in the APT analysis of ef cacy. Thirty-six patients were excluded because: they were H. pylori-negative at entry (n = 31); they did not receive study medication (n = 2); the H. pylori status was unknown at entry (n = 2); or they were lost to follow-up (n = 1). The characteristics of the patients included in the APT approach are summarized in Table 2. Additionally, 27 patients were excluded from the PP analysis because of: major deviations in inclusion or exclusion criteria (n = 2);

4 518 J. LABENZ et al. Table 2. Demographic and clinical characteristics of the study patients included in the all-patients-treated analysis of ef cacy OME 20 mg b.d. OME 40 mg b.d. n = 175 n = 170 Mean age (s.d.), years 49 (14) 49 (13) Male/female, n 122/53 102/68 Caucasian, n Current smokers, n Current alcohol drinkers, n Duration of ulcer disease: <1 year ±5 years >5 years Previous ulcer complications, n Mean ulcer size (s.d.), mm 8.7 (3.1) 8.5 (3.0) OME 20 mg b.d., combination therapy with omeprazole 20 mg b.d. and amoxycillin 750 mg b.d.; OME 40 mg b.d., combination therapy with omeprazole 40 mg b.d. and amoxycillin 750 mg b.d. discontinuation due to adverse events (n = 5); lost to follow-up or unwillingness to continue (n = 11); noncompliance (n = 8); and inadequate biopsies at visit 5 (n = 1). At one centre, one patient received omeprazole 40 mg b.d. instead of omeprazole 20 mg b.d. because the hospital pharmacy dispensed study drugs from another trial. This mistake was detected after completion of the analysis of the study and so the H. pylori cure rates have been re-analysed. H. pylori infection was cured in 64 out of 174 patients treated with omeprazole 20 mg b.d. plus amoxycillin and in 102 out of 171 patients treated with the higher dosage of omeprazole (37% vs. 60%; P < 0.001). The PP analysis gave similar results (40% vs. 64%; P < 0.001) (Figure 1). Cure of the infection was associated with an improvement of grade and of activity of gastritis both in the antrum and in the corpus of the stomach in the biopsies taken 4 weeks after end of Figure 1. Cure of H. pylori infection obtained by dual therapy consisting of either omeprazole (OME) 20 mg b.d. or omeprazole 40 mg b.d. with amoxycillin 750 mg b.d. Figure 2. Mean score of antral (A, B) and corpus gastritis (C, D) (grade of gastritis: d-d; activity of gastritis: s-s) in patients with cure of the infection (A, C) and in patients with post-therapeutically ongoing infection (B, D).

5 DUAL THERAPY FOR H. PYLORI 519 treatment. In patients with ongoing infection we observed a slight improvement in the antrum gastritis, while grade and activity remained unchanged in the corpus in the biopsies taken 4 weeks after end of treatment (Figure 2). Compliance with the treatment regimens was excellent: 327 out of the 345 patients included in the APT analysis (95%) took more than 90% of the combination therapy. Only three patients took less than 75% of the study drugs during the rst 2 weeks. There were no indications by the Breslow±Day test that the treatment differences varied signi cantly between countries (Table 3) and centres. Among the prognostic factors tested (dose of omeprazole, age, smoking habits, compliance), the age of patients proved to have an in uence (APT: P < 0.001, PP: P < 0.001), with a higher age being associated with a higher rate of H. pylori cure (Figure 3). The dose of omeprazole also had a signi cant impact on H. pylori eradication (P < in both the APT and PP analysis). As Table 3. Cure rates of H. pylori infection by country OME 20 mg b.d. OME 40 mg b.d. HP cure HP cure HP cure HP cure n/n % n/n % Canada 8/ /20 55 Finland 4/ /10 70 Germany 8/ /33 55 Italy 8/ /14 43 Netherlands 17/ /47 68 Norway 17/ /37 59 Portugal 2/7 29 2/5 40 UK 1/3 33 3/4 75 OME 20 mg b.d., 2 weeks treatment with omeprazole 20 mg b.d. and amoxycillin 750 mg b.d.; OME 40 mg b.d., 2 weeks treatment with omeprazole 40 mg b.d. and amoxycillin 750 mg b.d. HP, H. pylori Figure 3. H. pylori cure rates in relation to the age of patients. compliance was good it was not relevant to perform an analysis. Smoking (P = 0.93) did not affect the treatment success. Also, the pre-treatment H. pylori density, grade and activity of gastritis were not obviously related to the outcome of treatment. The relief from dyspeptic symptoms by treatment group and by post-treatment H. pylori status is given in Table 4. Overall, about 80% of patients were free of symptoms immediately after stopping the combination therapy and at the end of the trial. The dose of omeprazole during combination therapy as well as the post-therapeutic H. pylori status did not affect the relief from dyspeptic symptoms. However, 4 weeks after stopping treatment 95% (95% CI: 91±98%) of patients with cured infection had healed ulcers as compared to 82% (95% CI: 75±87%) of patients with ongoing infection (P < 0.001). Since we did not check ulcer healing at the end of active treatment, it is not clear whether this difference is due to failed ulcer healing or early ulcer relapse. Regarding safety, 378 patients were eligible for adverse event evaluation. Two patients never took the study Table 4. Relief from dyspeptic symptoms after combination therapy with omeprazole and amoxycillin (2 weeks) and 4 weeks after cessation of any medication (8 weeks) in relation to the post-treatment H. pylori status and to the treatment group (omeprazole 20 mg b.d. combined with amoxycillin or omeprazole 40 mg b.d. with amoxycillin) Percentage of patients without symptoms At entry After 2 weeks After 8 weeks By post-treatment H. pylori status H. pylori cured H. pylori persistent By treatment group Omeprazole 20 mg b.d Omeprazole 40 mg b.d

6 520 J. LABENZ et al. drug and in one patient no information about adverse events was available. During combination therapy, 29 patients (15.2%) treated with omeprazole 20 mg b.d. plus amoxycillin and 35 patients (18.7%) treated with omeprazole 40 mg b.d. plus amoxycillin reported adverse events. Three patients had serious adverse events (chills, melaena, mononucleosis infection plus allergic reaction, respectively). The most frequently reported adverse events during combination therapy were diarrhoea (n = 23) and headache (n = 7). In six patientsðtwo of whom had serious adverse eventsð combination therapy was stopped prematurely due to these adverse events. New onset adverse events were observed during open treatment with omeprazole in 38 patients. Comparing the laboratory results at entry and 4 weeks later, a small statistically signi cant but clinically insigni cant decrease was found in both treatment groups with respect to the concentration of haemoglobin ()0.3 g/dl and )0.1 g/dl, respectively), the white blood cell count ()0.6/nL and )0.5/nL, respectively) and the bilirubin levels ()1.5 lmol/l and )1.8 lmol/l respectively). Creatinine, alkaline phosphatase, ALAT and ASAT were not affected. In this study histology was the gold standard. The percentage of false negative breath tests was 6.0% (19/318) while the percentage of false positive tests was 3.9% (6/152). In 95% (445/470) of all tests, histology and UBT gave the same results. The sensitivity and speci city of the UBT was similar before treatment (94% and 96%, respectively) and 4 weeks after cessation of the study medication (96% and 91%, respectively). DISCUSSION This international, randomized, double-blind multicentre study with parallel groups has shown that doubling the dose of omeprazole (40 mg b.d. vs. 20 mg b.d.) increases the H. pylori cure rate obtained by 2-week combination therapy consisting of omeprazole plus amoxycillin 750 mg b.d. (APT analysis: 60% vs. 37%; PP analysis: 64% vs. 40%). Thus, a true dose±response relationship exists. Both treatment regimens were safe and well tolerated, with <20% of patients experiencing adverse events. Serious adverse events (<1%) and premature cessation of combination therapy (<2%) were infrequent. Omeprazole combined with amoxycillin may cure H. pylori infection. During the last 7 years many authors have published results obtained with this dual therapy. The reported cure rates, however, vary widelyðwhilst some authors have claimed high H. pylori cure rates, others have reported rather disappointing treatment results. Including the present report there are now ve large, randomized, double-blind multicentre studies available. In 1993, Unge et al. randomly treated duodenal ulcer patients with either omeprazole alone or with omeprazole 40 mg once daily in combination with amoxycillin 750 mg b.d. H. pylori infection was cured in 54% of patients. 15 In 1995, Koelz et al. reported the results of their Swiss multicentre trial in which 223 patients were treated with omeprazole 40 mg b.d. combined with amoxycillin 1 g b.d. Patients received randomly a 2-week course with omeprazole 20 mg either before or after Helicobacter treatment or no additional antisecretory medication. The H. pylori cure rates were 57%, 62% and 63%, with no differences between the study groups. 16 BayerdoÈrffer and colleagues randomly treated duodenal ulcer patients with omeprazole 40 mg t.d.s. plus amoxycillin 750 mg t.d.s. or omeprazole alone. Based on an intention-to-treat analysis of ef cacy, cure of H. pylori infection succeeded in 89% of cases. 17 Recently, Pommerien et al. tried to nd the optimal dose of omeprazole for dual therapy. They randomly treated 231 duodenal ulcer patients with amoxycillin 1 g b.d. in combination with omeprazole 20 mg b.d., 40 mg b.d. or 80 mg b.d. The H. pylori cure rates were 47%, 53% and 69%. 18 From the results of these high quality studies and a further dose- nding study, 19 it can be concluded that omeprazole 40± 80 mg/day combined with amoxycillin 1.5±2 g/day cures H. pylori infection in about 50±60% of ulcer patients, with the higher dose of omeprazole being more effective. Increasing the dose of omeprazole to 120 mg or more will probably improve the treatment results. This does not come as a surprise, since independent studies have shown that the intragastric acidity is related to the success of dual therapy 20, 21 and that a high dose of omeprazole (³90 mg) is required to consistently produce ph values close to neutral and to overcome interindividual differences in the ph response to omeprazole. 22, 23 However, none of the studies have investigated the dose±response relationship of amoxycillin and cure of the infection. A recent meta-analysis suggested that increasing the dosage of amoxycillin in dual therapy may improve the treatment success. 24 This has been con rmed by a randomized study in 120 duodenal ulcer patients who were treated with omeprazole 20 mg b.d. combined with amoxycillin 500 mg

7 DUAL THERAPY FOR H. PYLORI 521 t.d.s., 1 g b.d. or 1 g t.d.s. H. pylori infection was cured in 51%, 62% and 79% of cases, respectively. 25 Based on this nding and the now established dose±response relationship between omeprazole and cure of H. pylori infection, a large-scale double-blind multicentre trial seems to be warranted, in order to investigate the effectiveness of different dosages of amoxycillin combined with high-dose omeprazole. In our opinion, dual therapy should not be ignored, since all other currently recommended treatment schedules for H. pylori may be affected by resistance of the bacteria to nitroimidazoles 2, 26, 27 or clarithromycin. Ignoring trials from all over the world, 28±31 it has been claimed that high success rates of dual therapy are a `German phenomenon'. The present study is the rst international trial with omeprazole plus amoxycillin. The trial gives no indication that the treatment results varied signi cantly between countries and centres. In previous studies, it has been shown that pre-treatment with omeprazole 20 mg once daily does not affect the outcome of dual therapy. 16 Also, the relationship of amoxycillin to meals does not explain differing treatment results. 32 Other studies have suggested that compliance, smoking, age and the severity of gastritis 15, 16, 32±34 are related to the success of dual therapy. The age factor has now been con rmed by our large multicentre trial, with a higher age being associated with higher cure rates. However, the dose of omeprazole was important in all age groups. It is conceivable that lack of compliance is associated with failure to cure the infection whatever treatment regimen is applied. In the present study, however, only very few patients had insuf cient compliance. This might explain why drug compliance was not signi cantly related to the outcome. Interestingly, smoking did not affect the outcome of dual therapy in this study. This nding is in line with the study by Pommerien et al. 18 but in contradiction to 15, 16, 21, 33, 34 the results reported by others. In conclusion, increasing the dose of omeprazole in dual therapy with amoxycillin improves the cure of H. pylori infection. In view of the documented excellent results obtained by simple one-week regimens consisting of omeprazole, clarithromycin and a nitroimidazole or amoxycillin, 35,36 dual therapy should be reserved for patients harbouring H. pylori strains resistant to nitroimidazoles and clarithromycin. Considering the current literature, these patients should be treated with highdose omeprazole (e.g. 40 mg t.d.s.) combined with highdose amoxycillin (750±1000 mg t.d.s.). Further studies are urgently needed to de ne the optimum dose of amoxycillin. ACKNOWLEDGEMENTS Financial support for this study was provided by Astra HaÈssle AB, MoÈlndal, Sweden. The following physicians also contributed to this study: Germany: Dr Ahrens, Dr Pannewick, Dr Hanhoff, Dr Reichelt, Professor Dr von Kleist, Dr Breitkreuz, Dr Doppl, Dr Glaum, Dr Bade, Dr Domian, Professor Dr Stange, Dr Reimann, Dr WoÈrdehoff, Dr Henkel. Finland: Dr Nyman, Dr GroÈnfors, Dr Wingren, Dr Nikus Dr Isomaa D SoÈdervik. United Kingdom: Dr Chapman, Dr Linacker, Dr Spiller, Dr Isaacs, Dr Morgan, Dr Long, Dr Fine, Dr McKinley. Netherlands: Dr van Spreeuwel, Dr Stronkhorst, Dr van Ditzhuijsen, Dr Poen, Dr Wolff, Dr Smals, Dr van Gorp. Italy: Dr Prada, Dr Bortoli, Dr Minoli, Dr Spinzi, Dr Terruzzi, Dr Ferrini, Dr Semperlotti, Dr Carcinese, Professor Bianchi Porro, Dr Parente. Norway: Dr Pytte, Dr Tonnessen, Dr Torp, Dr Kydland, Dr Nydal, Dr Sauar, Dr Olafsson, Dr Thiis-Evensen, Dr Hamre, Dr Hareide, Dr Tholfson, Dr Skogestad, Dr Kittang, Dr Breder, Dr Vetvik. Portugal: Professor G. Rodrigues Peixe, Dr P. Rodrigues Peixe, Dr Silveira Saragoca, Dr Valente. 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