THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 93, No. 10, 1998 Copyright 1998 by Am. Coll. of Gastroenterology ISSN /98/$19.

Transcription

1 THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 93, No. 10, 1998 Copyright 1998 by Am. Coll. of Gastroenterology ISSN /98/$19.00 Published by Elsevier Science Inc. PII S (98) Cure of Helicobacter pylori Infection and Healing of Duodenal Ulcer: Comparison of Pantoprazole-Based One-Week Modified Triple Therapy Versus Two-Week Dual Therapy Romuald J. Adamek, M.D., Thomas D. Bethke, M.D., and The International Pantoprazole HP Study Group Department of Medicine, St. Josef-Hospital, Ruhr-University, Bochum, Germany; Department of International Clinical Research, Byk Gulden, Konstanz, Germany; and The International Pantoprazole HP Study Group: in Austria, B. Brandstätter, L. Kasses, P. Kratochvil, W. Weiss, H. Wurzer; in Germany, G. Beetz, H. Bock, G. Bretzke, G. Büttner, K. Eichhorn, H. Hebbeln, E. Hommel, D. Hüppe, W. Hüttemann, M. Kirchhof, H. Klann, J. Labenz, W. Martens, C. Naumann, B. Pfaffenbach, I. Rehmann, H. G. Rohner, U. Schink, W. Schmeisser, E. Schütz, G. Tangerding, H. Wübbolding; in Switzerland, C. Beglinger, R. Meier Objective: Eradication of Helicobacter pylori (H. pylori) is recommended as the first-line therapeutic concept for reliable long-term prevention of duodenal ulcer (DU) relapse. Current treatment regimens vary in efficacy, complexity, and compliance. To assess the efficacy of pantoprazole in in parallel groups of patients using two eradication regimens. Methods: Patients, (18 85 yr old; intention-to-treat, n 286) with proven DU, positive rapid urease test (biopsy), and 13 C-urea breath test (UBT) were included in a prospective, randomized, multicenter study. Modified triple therapy consisted of 40 mg pantoprazole b.i.d., 500 mg clarithromycin t.i.d., and 500 mg metronidazole t.i.d. for 7 days (PCM therapy); dual therapy consisted of 40 mg pantoprazole b.i.d. and 500 mg clarithromycin t.i.d. for 14 days (PC therapy). In both groups 40 mg pantoprazole o.d. was given until day 28 when healing of DU was evaluated endoscopically; H. pylori status was assessed by UBT on day 56. Results: rate was 95% in PCM versus 60% in PC therapy groups (perprotocol population, p < 0.001), and 82% in PCM versus 50% in PC therapy in the intention-to-treat patient population (p < 0.001). The DU healing rate was 98% in the PCM and 95% in the PC therapy groups (per-protocol population). Both regimens were similarly well tolerated. Adverse events in both regimens included taste disturbance, diarrhea, and increased serum concentration of liver enzymes, at an incidence of < 10%. Conclusions: Compared to 2-wk PC therapy (pantoprazole and clarithromycin), the 1-wk PCM therapy (pantoprazole, clarithromycin, and metronidazole) is a significantly superior and highly promising strategy for eradication of H. pylori. (Am J Gastroenterol 1998;93: by Am. Coll. of Gastroenterology) Received Dec. 29, 1997; accepted June 1, INTRODUCTION Based on evidence from interventional trials it is now well accepted that the spiral Gram-negative bacterium Helicobacter pylori (H. pylori), which colonizes gastric mucosa in humans, is not only a causative agent in chronic active gastric diseases but also contributes to the pathogenesis of chronic relapsing duodenal ulcer disease (for review, see Reference (1). Eradication of H. pylori by medications administered for a limited period is recommended as the first-line therapeutic approach, leading to reliable long-term prophylaxis of duodenal ulcer relapse (2 5). Indeed, the eradication of this microorganism has accelerated healing of duodenal ulcers even in patients refractory to some of the antisecretory drugs (6, 7), prevented ulcer complications, and significantly improved the quality of life of those affected (8 10). In addition, cure of H. pylori represents the most economic approach in the long-term management of duodenal ulcers and has become the recommended treatment in all patients with this disease (9, 11, 12). In view of the frequency of duodenal ulcers in the general population and the health costs involved in treating them, numerous therapies have been investigated using several combinations of medications. Such work, however, often yielded contradictory results, which became a matter of controversy and debate (1, 13, 14). A regimen consisting of 1-wk triple therapy using a proton-pump inhibitor and two antibiotics has consistently shown high eradication rates and good tolerability (13, 15 20). In contrast, recent clinical studies have indicated that a 2-wk dual therapy with a proton-pump inhibitor and one antibiotic was less effective than a 1-wk triple therapy (13, 17, 21 23). A direct comparison of a modified 1-wk triple therapy consisting of the proton-pump inhibitor pantoprazole, clarithromycin, and metronidazole (PCM therapy) and a 2-wk dual therapy consisting of pantoprazole and clarithromycin (PC therapy) has, however, not been reported so far in a large patient population. Thus, the aim of the present study was to

2 1920 ADAMEK et al. AJG Vol. 93, No. 10, 1998 assess the efficacy of a 1-wk PCM therapy in comparison to a 2-wk PC therapy, using parallel groups of patients in a prospective, randomized, multicenter study. PATIENTS AND METHODS The study was designed as a prospective and randomized trial, involving centers (n 27) in Austria, Germany, and Switzerland. The investigation was conducted according to the Declaration of Helsinki and the guidelines for Good Clinical Practice. The study protocol was approved by the respective ethics committees. All patients gave their written informed consent to participate in the study. Inclusion and exclusion criteria Mobile male and female patients (median age, 48 yr; range, yr) were enrolled in the study. All patients had endoscopically proven duodenal ulcer (diameter 5mm and 20 mm) and H. pylori infection. At each study center all endoscopies were performed by the same endoscopist. During the initial examination a single biopsy was taken from the corpus and one from the antrum for use in the rapid urease test, indicating infection with H. pylori (Jatrox H. p. test, Röhm Pharma GmbH, Weiterstadt, Germany). In addition, the presence of H. pylori was confirmed with the 13 C-urea breath test (INFAI HPT, INFAI GmbH, Bochum, Germany). The breath samples were analyzed as described elsewhere (24). The breath sample was classified as positive if the excess Delta was 4% 13 CO 2. Exclusion criteria to enter the study were the presence of additional gastric ulcers, gastrointestinal malignancy, previous gastric surgery, pregnancy, lactation, concurrent severe diseases, concomitant treatment with potentially ulcerogenic medications such as nonsteroidal antiinflammatory drugs, suspected poor compliance, a known allergy to one of the study drugs, or treatment with proton-pump inhibitors, antibiotics, or bismuth salts during the last 4 wk before start of the study. Gastrointestinal symptoms Gastrointestinal symptoms experienced by the patients were assessed on entry into the study and at follow-up visits (days 7, 14, and 28 of the treatment). The symptoms included ulcer pain during the day and night, vomiting, nausea, retching, acid regurgitation, and heartburn; presence of these symptoms was conveyed by the patients and graded as mild, moderate, or severe. Hematological and biochemical parameters, as well as dipstick urine analysis, were performed at the individual study sites during the initial visit and then on days 7 and 14 of therapy for the PCM therapy and PC therapy groups, respectively. Study medications and protocol Study medications were oral tablets: 40 mg pantoprazole, 500 mg metronidazole, and 500 mg clarithromycin. To aid compliance the tablets were packed in blister packs and labeled morning, midday, and evening. Patients were randomized into two parallel treatment groups. Those in the PCM therapy group received, for 7 days, one pantoprazole, one clarithromycin, and one metronidazole tablet each morning and each evening before meals, and one metronidazole and one clarithromycin tablet each day before the midday meal. Subsequently, these patients took one pantoprazole tablet each morning until day 28 of the treatment schedule. Patients in the PC therapy group were treated, for 14 days, with one pantoprazole and one clarithromycin tablet each morning and each evening before meals and one clarithromycin tablet each day before lunch. Patients in the PC therapy group took one pantoprazole tablet each morning until day 28 of the treatment schedule. Patients were asked to report any adverse events to the physician. Eligibility for statistical evaluation included a compliance criterion whereby the consumption of the study medication had to be 75% for and 70% for the duodenal ulcer healing; this was checked by counting the study pills. Efficacy assessment was examined endoscopically on day 28; healing was defined as a complete reepithelialization of the ulcer crater with or without scarring; ulcer-related pain relief was judged by the severity of gastrointestinal symptoms on days 7, 14, and 28 of treatment. Eradication of H. pylori was checked by 13 C-urea breath test as described by Labenz et al. (24) on day 56 (4 wk after the cessation of treatment). Statistical analysis The number of patients required for the study was calculated to detect a difference of 20% in the eradication rates between the two study groups (Fisher s Exact Test). Based on a two-sided test, a significance level of 5%, and a power of 0.8, at least 100 patients per group were required to detect this difference. Results include the binomial 95% lower and upper confidence intervals (CI). Patient populations For both treatment regimens the statistical analysis of results was performed in three patient populations: intention-to-treat, per-protocol, and key point available. Definition of these terms and the investigated clinical parameters that these were applied to are shown in Table 1. The main analysis of rates and duodenal ulcer healing was performed per-protocol. Patients were excluded from this analysis if they had major protocol violations (such as not achieving the specified compliance with study medications or those whose follow-up visits fell outside the defined ranges). Patients who discontinued the study prematurely for reasons possibly related to the study medication were included in this analysis and classified as

3 AJG October 1998 PANTOPRAZOLE-BASED CURE FOR H. PYLORI 1921 TABLE 1 Definition of Patient Populations and the Evaluated Parameters Patient Population Definition Evaluated Parameter Intention-to-treat Ingestion of at least one dose of test medication Adverse events Per-protocol Completion of the entire treatment regimen, including medications, tests, and follow-up visits Symptoms Key point available Availability of test results for the 13 C-UBT at pretreatment and at the follow-up visit on day 56 Definitions of patient populations used for the statistical analysis of results obtained for the respective test parameters. 13 C-UBT, 13 C-urea breath test. TABLE 2 Demographic and Anthropometric Data Parameter/Protocol PCM Therapy PC Therapy Number of patients Median age (yr) Range Median height (cm) Range Median weight (kg) Range Median body mass index (kg/m 2 ) Range No previous history of duodenal 41 (29%) 48 (33%) ulcer (%) Duodenal ulcer relapse One (%) 15 (11%) 15 (11%) More than one (%) 86 (60%) 81 (56%) No previous diagnosis of H. pylori 115 (81%) 117 (81%) infection (%) Smokers (%) 76 (54%) 74 (51%) PCM therapy, triple therapy consisting of 40 mg pantoprazole b.i.d., 500 mg clarithromycin t.i.d., and 500 mg metronidazole t.i.d. for 7 days; PC therapy, dual therapy consisting of 40 mg pantoprazole b.i.d. and 500 mg clarithromycin t.i.d. for 14 days. treatment failures. and duodenal ulcer healing rates were compared between the treatment groups by the Cochran-Mantel/Haenszel test using the method of odds ratios; the study centers were included in the analysis as a covariable. The possible influence by other factors, including the age, gender, smoking habits, body mass index, frequency of ulcer recurrence and duration of H. pylori infection upon eradication, and healing rates, were also investigated. Rates of complete ulcer pain relief were compared on days 7, 14, and 28 of the treatment using Fisher s Exact Test. RESULTS A total of 286 patients were enrolled into the study; their demographic and anthropometric data as well as patients histories are summarized in Table 2. At entry, almost all patients complained of epigastric pain or discomfort. There were no significant differences among the patients with respect to demographic and clinical parameters at the time of enrollment. TABLE 3 Patients Included in the Per-Protocol Statistical Evaluation* Parameter/Protocol PCM Therapy PC Therapy Number of patients Male/female 80/42 77/43 Number of patients Male/female 84/42 78/45 PCM therapy, triple therapy consisting of 40 mg pantoprazole b.i.d., 500 mg clarithromycin t.i.d., and 500 mg metronidazole t.i.d. for 7 days; PC therapy, dual therapy consisting of 40 mg pantoprazole b.i.d. and 500 mg clarithromycin t.i.d. for 14 days. * The number of patients entered for evaluation of and duodenal ulcer healing differed slightly. This was due to either insufficient compliance or missed follow-up visits, making some patients ineligible for the evaluation of both parameters. The patients were randomized such that 142 received the PCM therapy and 144 the PC therapy. These patients represented the intention-to-treat population. Due to insufficient compliance or missed follow-up visits, some patients were not eligible for the evaluation of as well as duodenal ulcer healing. For this reason the actual patient numbers for the two investigated clinical parameters were not identical (Table 3). For the per-protocol analysis of and duodenal ulcer healing, respectively, 44 and 37 patients were excluded. Thus, a total of 242 patients were in the per-protocol analyses for the eradication of H. pylori; 122 were in the PCM and 120 in the PC therapy groups (Table 3). For the analysis of duodenal ulcer healing a total of 249 patients were included in the per-protocol analysis; of these 126 were in the PCM and 123 in the PC therapy groups (Table 3). In the per-protocol analysis, 116 of 122 patients (95% confidence interval [CI]: 90 98%) in the PCM therapy group demonstrated eradication of H. pylori, compared with 72/120 (60% CI: 51 69%) in the PC therapy group (p 0.001) (Fig. 1). Comparable differences between the two treatment schedules for rates were also observed for the other evaluated patient populations, namely, the key point available (116/119 [97% CI: 93 99%]

4 1922 ADAMEK et al. AJG Vol. 93, No. 10, 1998 FIG. 1. Comparison of rates after PCM and PC therapy. Statistical evaluation was performed from results in the following patient populations: intention-to-treat, per-protocol, and key point available. The number of patients (N) in each patient population, eradication rate (%), and p values are indicated. The Cochran-Mantel/Haenszel test was used to calculate the p values. in the PCM therapy and 72/113 [64% CI: 54 73%) in the PC therapy groups; p 0.001), as well as in the intentionto-treat (116/142 [82% CI: 74 88%] in the PCM therapy and 72/144 [50% CI: 42 58%] in the PC therapy groups; p 0.001) (Fig. 1). Other evaluated factors, including the age, gender, smoking, body mass index, frequency of ulcer recurrence or duration of H. pylori infection before entry into the study, had no effect upon the eradication rates in the PCM therapy group. In the PC therapy group, the eradication rates were higher for male than for the female patients (64% vs 53%) and in patients with relapsing ulcer disease, as compared with those with no previous ulcer history (65% vs 47%). The difference in the latter may possibly be due to higher compliance in patients suffering from duodenal ulcer disease for a longer time. For duodenal ulcer healing the rates were not significantly different between the two groups. After 28 days of treatment, complete ulcer healing occurred in 123/126 (98% CI: %) patients in the PCM therapy group and in 117/123 (95% CI: 90 98%) in the PC therapy group, p The results were similar when per-protocol and intention to treat patient populations were evaluated. Other factors such as age, gender, smoking habits, body mass index, previous history of ulcers, and H. pylori infection showed no effect upon the duodenal ulcer healing rates. Symptoms Relief from duodenal ulcer pain was also similar between the two study groups after 1, 2, and 4 wk of treatment. The differences between the two treatment regimens were not statistically significant. Of the patients who reported ulcer pain at entry, 101/122 (83% CI: 75 89%) in the PCM therapy and 100/120 (83% CI: 75 90%) in the PC therapy group were free from pain after 1 wk; after 2 wk the values were 111/121 (92% CI: 85 96%) and 106/118 (90% CI: 83 95%) in the PCM therapy and PC therapy groups, respectively; and by the fourth wk of treatment these values were 116/121 (96% CI: 91 99%) and 114/117 (97% CI: 93 99%), respectively. Adverse events, discontinuations, and laboratory analysis The most frequent adverse events observed during the course of this study included taste disturbance, diarrhea, and increased serum concentration of liver enzymes (Table 4). Patients in the PCM and PC therapy groups showed no other changes in their tested laboratory parameters after 1 and 2 wk of treatment, respectively. A total of 10 patients (3.4%) discontinued the study and were considered drop-outs. Of these, seven patients (three in the PCM and four in the PC therapy groups) discontinued due to adverse events that were likely related to the treatment, and three patients (all in the PC therapy group) discontinued due to lack of efficacy in the criterion of ulcer healing. These patients were evaluated as not healed and not eradicated in the per-protocol

5 AJG October 1998 PANTOPRAZOLE-BASED CURE FOR H. PYLORI 1923 TABLE 4 Incidence of Adverse Events in PCM and PC Therapy Groups* Parameter/Protocol PCM Therapy PC Therapy Number of patients Taste disturbance 12 (9%) 13 (9%) Diarrhea 11 (8%) 4 (3%) SGOT increased 9 (6%) 7 (5%) SGPT increased 9 (6%) 7 (5%) Nausea 4 (3%) 1% Abdominal pain 4 (3%) 1% * Adverse events reported at an incidence of 3% in patients who were treated according to PCM and PC therapy regimens. The calculations are based on the intention-to-treat patient population. PCM therapy, triple therapy consisting of 40 mg pantoprazole b.i.d., 500 mg clarithromycin t.i.d., and 500 mg metronidazole t.i.d. for 7 days; PC therapy, dual therapy consisting of 40 mg pantoprazole b.i.d. and 500 mg clarithromycin t.i.d. for 14 days. SGOT, serum glutamic-oxaloactetic transaminase; SGPT, serum glutamate pyruvate transaminase. analysis of data. Other patients were excluded from the per-protocol analysis due to protocol violations (insufficient compliance or missed assessment visits). In the statistical evaluation of data, these patients were part of the intentionto-treat population. DISCUSSION Acceptance of a treatment schedule for the eradication of H. pylori depends on efficacy, tolerability, adverse events, complexity, and patient compliance. Several published clinical studies investigating schedules for effective eradication of H. pylori infections from the gastric mucosa have in the past provoked debate, often resulting in contentious recommendations (1, 11, 25 30). In a classic triple therapy consisting of bismuth and two antibiotics administered for 2 wk, the cure rates of H. pylori infection were high but the compliance was low (26, 27). In other protocols involving a proton-pump inhibitor together with amoxycillin or clarithromycin, the cure rates varied between 23 91%, depending on the study population and geographic region (1, 10, 31 33). On the other hand, recent studies have indicated that a 1-wk course of PCM therapy may be a reasonable and simple approach able to achieve reliable and consistent cure of H. pylori infection (15, 16, 18 20, 34). This proved correct in investigations with 1-wk PCM therapy in which more than 90% of patients were cured; the medications used included a proton pump inhibitor, together with the antibiotics clarithromycin and tinidazole (13) or clarithromycin and metronidazole (17). Because direct comparison of the PCM and PC therapies have not been reported heretofore, a prospective, multicenter study in two parallel groups of randomized patients was conducted. The present results show that the eradication rate of H. pylori was 95% after a 1-wk course of PCM therapy with pantoprazole, clarithromycin, and metronidazole. We found that this was significantly superior to a 2-wk PC therapy consisting of pantoprazole and clarithromycin, which achieved eradication of H. pylori in about 60% of patients (Fig. 1). The cure rates of H. pylori by the PCM therapy compare well with the highest eradication rates observed in other studies using triple regimens (25, 26). With respect to pretreatment resistance of H. pylori to antibiotics, it could be argued that resistance to metronidazole in particular may affect the efficacy of the 1-wk PCM therapy. Indeed, previous investigations showed that H. pylori resistance to metronidazole occurs in about 20 25% of patients; the cure rates, however, were not affected when clarithromycin was incorporated into the PCM therapy (21, 35). The high eradication rates of H. pylori observed by the PCM therapy in the present study suggests that resistance to metronidazole does not necessarily influence the success of the treatment (36). This study showed that 4 wk after the start of treatment, patients in both PCM and PC therapy regimens had similarly high rates of ulcer healing (PCM therapy, 98%; PC therapy, 95%). Such healing rates compare well with those observed in studies using 40 mg pantoprazole alone (18, 37 39). The treatment schedules were well tolerated and both the type and frequency of adverse events were equivalent. In conclusion, it could be shown that a 1-wk course of PCM therapy (comprising pantoprazole, clarithromycin, and metronidazole) is a simple, well-tolerated, highly potent regimen for the eradication of H. pylori infection. Hence, the PCM therapy represents a significantly superior schedule in comparison to the PC therapy (consisting of pantoprazole and clarithromycin). Our results support the concept that the 1-wk PCM therapy could become the standard therapeutic strategy for effective eradication of H. pylori infections in patients with duodenal ulcers. ACKNOWLEDGMENTS We thank the following persons: R. Dietrich, H. Dold, H. Khalil, P. Mateyka, G. Mönch, C. Riesenhuber, K. Rose, and G. Schilling for organizational activities involved with this multicenter and multinational study; R. Lühmann and A. Wiedemann for statistical evaluation; and C. Cain, R. Fischer, A. Schneider, K. B. Thomas, and W. Wurst for discussions, critical reading, and editing of the manuscript. This study was supported by a grant from Byk Gulden, Konstanz, Germany. Reprint requests and correspondence: PD Dr. R. J. Adamek, Medizinische Universitätsklinik St. Josef-Hospital, Gudrunstrasse 56, D-4479 Bochum, Germany. REFERENCES 1. Penston JG, McColl KE. Eradication of Helicobacter pylori: An objective assessment of current therapies. Br J Clin Pharmacol 1997;43: Marshall BJ, Goodwin CS, Warren JR, et al. Prospective double-blind trial of duodenal ulcer relapse after eradication of Campylobacter pylori. Lancet 1988;2: Rauws EA, Tytgat GNJ. Cure of duodenal ulcer associated with eradication of Helicobacter pylori. Lancet 1990;335:

6 1924 ADAMEK et al. AJG Vol. 93, No. 10, Graham DY, Lew GM, Klein PD, et al. Effect of treatment of Helicobacter pylori infection on the long-term recurrence of gastric or duodenal ulcer. A randomized, controlled study. Ann Intern Med 1992;116: Forbes GM, Glaser ME, Cullen DJ, et al. Duodenal ulcer treated with Helicobacter pylori eradication: Seven-year follow-up. Lancet 1994; 343: Hentschel E, Brandstatter G, Dragosics B, et al. Effect of ranitidine and amoxicillin plus metronidazole on the eradication of Helicobacter pylori and the recurrence of duodenal ulcer. N Engl J Med 1993;328: Bianchi Porro G, Parente F, Lazzaroni M. Short and long term outcome of Helicobacter pylori positive resistant duodenal ulcers treated with colloidal bismuth subcitrate plus antibiotics or sucralfate alone. Gut 1993;34: Graham DY, Hepps KS, Ramirez FC, et al. Treatment of Helicobacter pylori reduces the rate of rebleeding in peptic ulcer disease. Scand J Gastroenterol 1993;28: Labenz J, Borsch G. Role of Helicobacter pylori eradication in the prevention of peptic ulcer bleeding relapse. Digestion 1994;55: Tytgat GNJ. Treatments that impact favourably upon the eradication of Helicobacter pylori and ulcer recurrence. Aliment Pharmacol Ther 1994;8: (review article). 11. Wilhelmsen I, Berstad A. Quality of life and relapse of duodenal ulcer before and after eradication of Helicobacter pylori. Scand J Gastroenterol 1994;29: Sonnenberg A. Cost-benefit analysis of testing for Helicobacter pylori in dyspeptic subjects. Am J Gastroenterol 1996;91: Goddard A, Logan RP. One-week low-dose triple therapy: New standards for Helicobacter pylori treatment. Eur J Gastroenterol Hepatol 1995;7: Harris AW, Misiewicz JJ. Treating Helicobacter pylori The best is yet to come? Gut 1996;39: Jaup BH, Norrby A. Low dose, short-term triple therapy for cure of Helicobacter pylori infection and healing of peptic ulcers. Am J Gastroenterol 1995;90: Moayyedi P, Sahay P, Tompkins DS, et al. Efficacy and optimum dose of omeprazole in a new 1-week triple therapy regimen to eradicate Helicobacter pylori. Eur J Gastroenterol Hepatol 1995;7: Labenz J, Stolte M, Ruhl GH, et al. One-week low-dose triple therapy for the eradication of Helicobacter pylori infection. Eur J Gastroenterol Hepatol 1995;7: Fitton A, Wiseman L. Pantoprazole. A review of its pharmacological properties and therapeutic use in acid-related disorders. Drugs 1996; 51: Bardhan KD. Triple therapy as a cure for Helicobacter pylori infection. Eur J Clin Pharmacol 1996;8:S Frevel M, Daake H, Janisch HD, et al. Pantoprazole plus claritromycin and metronidazole versus pantoprazole plus claritromycin and amoxycillin for therapy of H. Pylori infection. Gastroenterology 1997;112:(4, supplement)a119b. 21. Adamek RJ, Szymanski C, Pfaffenbach B, et al. Kurzzeit-Tripel- Therapie mit Pantoprazol, Clarithromycin und Metronidazol zur Heilung der Helicobacter-pylori-Infektion. (Short-term triple treatment of Helicobacter pylori infection with pantoprazole, clarithromycin and metronidazole.) Dtsch Med Wochenschr 1995;120: Adamek RJ, Opferkuch W, Wegener M. Modified short-term triple therapy ranitidine, clarithromycin, and metronidazole for cure of Helicobacter pylori infection. Am J Gastroenterol 1995;90:168 9 (letter). 23. Delchier JC, Elamine I, Goldfain D, et al. Comparison of omeprazole amoxicillin versus omeprazole amoxicillin clarithromycin in the eradication of Helicobacter pylori (Hp) results from a randomized study involving 120 patients. Gastroenterology 1995;108:(4 suppl)a81 (abstract). 24. Labenz J, Stolte M, Aygen S, et al. Qualitative und semiquantitative invasive und nicht-invasive Diagnostik der Helicobacter pylori-kolonisation der gastralen Mukosa. (Qualitative and semiquantitative invasive and noninvasive diagnosis of Helicobacter pylori colonization of gastric mucosa.) Z Gastroenterol 1993;31: Pajares-Garcia J, Bazzoli F. Eradication. In: Malfertheiner P, Megraud F, Michetti P, Price A, eds. The year in Helicobacter pylori Curr Opin Gastroenterol 1996;12 (suppl 1): Chiba N, Rao BV, Rademaker JW, et al. Meta-analysis of the efficacy of antibiotic therapy in eradicating Helicobacter pylori. Am J Gastroenterol 1992;87: Labenz J, Gyenes E, Ruhl GH, et al. Amoxicillin plus omeprazole versus triple therapy for eradication of Helicobacter pylori in duodenal ulcer disease: A prospective, randomized, and controlled study. Gut 1993;34: de Boer WA, Driessen WM, Potters VP, et al. Randomized study comparing 1 with 2 weeks of quadruple therapy for eradicating Helicobacter pylori. Am J Gastroenterol 1994;89: de Boer WA. Re: [ 13 C]urea breath test. Am J Gastroenterol 1995;90: Penston JG, Mistry KR. Eradication of Helicobacter pylori in general practice. Aliment Pharmacol Ther 1996;10: Axon ATR. The role of acid inhibition in the treatment of Helicobacter pylori infection. Scand J Gastroenterol 1994;29 (suppl 201): Penston JG. Helicobacter pylori eradication understandable caution but no excuse for inertia. Aliment Pharmacol Ther 1994;8: (review article). 33. Delchier JC, Elamine I, Goldfain D, et al. Omeprazole-amoxycillin versus omeprazole-amoxycillin-clarithromycin in the eradication of Helicobacter pylori. Aliment Pharmacol Ther 1996;10: Bazzoli F, Zagari R, Fossi S, et al. Efficacy and tolerability of a short term, low dose triple therapy for eradication of Helicobacter pylori. Gastroenterology 1993;104(No. 4 suppl):a40 (abstract). 35. Adamek RJ, Opferkuch W, Pfaffenbach B, et al. Cure of Helicobacter pylori infection: Role of duration of treatment with omeprazole and amoxicillin. Am J Gastroenterol 1996;91: Tytgat GN. Antimicrobial therapy for Helicobacter pylori infection. Helicobacter 1997;2 (suppl 1):S Schepp W, Classen M. Pantoprazole and ranitidine in the treatment of acute duodenal ulcer. A multicentre study. Scand J Gastroenterol 1995;30: Bader JP, Delchier JC. Clinical efficacy of pantoprazole compared with ranitidine. Aliment Pharmacol Ther 1994;8 (suppl 1): Beker JA, Bianchi Porro G, Bigard MA, et al. Double-blind comparison of pantoprazole and omeprazole for the treatment of acute duodenal ulcer. Eur J Gastroenterol Hepatol 1995;7: