Publications on Helicobacter pylori and nonmalignant

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1 Volume 7 Supplement HELICOBACTER Blackwell Science, Ltd Helicobacter pylori and nonmalignant disease Paul Moayyedi * and Peter Malfertheiner *City Hospital NHS Trust, Winson Green, Birmingham, UK; Otto-von-Guericke-Universität Magdeburg, Zentrum für Innere Medizin, Klinik für Gastroenterologie, Hepatologie und Infektiologie, Magdeburg, Germany ABSTRACT Helicobacter pylori eradication has become the recognized standard and widely adopted therapy to cure peptic ulcer disease. Other H. pylori associated conditions with potential benefit from eradication therapy are still subject to clinical investigations. The current state of evidence for these indications is summarized in this article. For NSAID associated peptic ulcer disease the current evidence needs to be grouped in three subsets of clinical conditions: a) H. pylori eradication for prevention of ulcers before starting NSAIDs therapy is advisable; b) eradication during PPI treatment for NSAID associated active ulcer shows no advantage on healing; and c) eradication alone is not sufficient for secondary prevention of ulcer complications induced by NSAID, however it appears to protect from further episodes of aspirin induced bleeding. In nonulcer dyspepsia the latest Cochrane collaboration review supports a small benefit in favour of H. pylori eradication. New insight in the relationship of H. pylori with GERD is provided from clinical trials which show that H. pylori eradication does not influence the clinical course of patients with reflux esophagitis. Finally important new data are presented regarding the management of dyspepsia at the primary care level with the confirmation that the H. pylori test and treat strategy in the appropriate setting is more costeffective than endoscopy. Publications on Helicobacter pylori and nonmalignant upper gastrointestinal disease have been on the increase until recently. This seems surprising, as the role of H. pylori in peptic ulcer disease has been well established. The main reason for this is the controversy surrounding the role of H. pylori in other upper gastrointestinal diseases. This article will outline the progress that has been achieved during the past 12 months in the relationship between H. pylori and peptic ulcer disease, nonulcer dyspepsia, gastro-esophageal reflux disease and undiagnosed dyspepsia. Peptic ulcer disease NonNSAID related peptic ulcer disease It is now accepted that successful H. pylori eradication therapy leads to long-term remission from peptic ulcer disease. The Maastricht 2 Correpondence: Paul Moayyedi, City Hospital NHS Trust, Dudley Road, Winson Green, Birmingham B18 7QH, UK. p.moayyedi@bbham.ac.uk 2000 Consensus Report strongly recommended H. pylori eradication therapy for gastric and duodenal ulcers in infected patients [1]. The dyspepsia symptoms in patients with peptic ulcer and are not always exclusively related to the underlying ulcer diathesis. Dyspepsia symptoms remain in about 40% of peptic ulcer patients after eradication therapy but a randomized controlled trial suggested this was similar to that achieved by maintenance proton pump inhibitor therapy [2]. The benefits of H. pylori eradication persisted for at least 6 years [3] with statistically significant reductions in requirement in the eradications. NSAID related peptic ulcer disease The role of H. pylori infection in patients with nonsteroidal anti-inflammatory drugs (NSAIDs) is more controversial. A systematic review of observational studies reported that NSAIDs and H. pylori were both strong risk factors for peptic ulcer disease [4]. H. pylori increased the odds of peptic ulcer (odds ratio = 3.53; 95% CI = ) in patients taking NSAIDs. The effect of 30

2 H. pylori and nonmalignant disease 31 H. pylori infection was stronger for duodenal ulcer than gastric ulcer although the relatively small size of this subgroup analysis made it difficult to draw any definitive conclusions. Similarly, the odds of bleeding peptic ulcer was higher in H. pylori infected patients (odds ratio = 6.1; 95% CI = ) than in H. pylori negative subjects (odds ratio = 4.8; 95% CI = ) taking NSAIDs. The results of observational studies can be due to confounding and/or bias and synthesizing the results of many trials in a meta-analysis may magnify these problems. Double-blind randomized controlled trials avoid confounding or bias and these have suggested the relationship between H. pylori, NSAIDs and peptic ulcer disease is complex. H. pylori eradication may reduce the rate of healing NSAID associated gastric ulcers according to one randomized trial, possibly by enhancing the acid suppressing effect of proton pump inhibitors [5]. Although another randomized-controlled trial could not confirm this finding [6]. The Maastricht Consensus Report suggested it was advisable to eradicate H. pylori before commencing NSAID therapy [1]. The evidence for this was from a trial that randomized H. pylori positive, NSAID naive patients with dyspepsia or past history of peptic ulcer disease to eradication therapy or placebo. Peptic ulcers occurred more frequently in the placebo [34%] than in the eradication [12%] group during 6-months follow-up with similar statistically significant differences seen in the probability of complicated peptic ulcer disease [7]. This trial confirmed the results of an earlier trial by the same group indicating that H. pylori eradication reduced peptic ulcer occurrence in a lower risk group not previously taking NSAID [8]. It is unlikely, however, that this in isolation is insufficient to reduce peptic ulcer disease to normal population rates in patients taking NSAIDs. A trial in patients with a previous upper gastrointestinal bleed taking naproxen 500 mg bd found that ulcer recurrence was higher in the group randomized to H. pylori eradication than in those randomized to long-term proton pump inhibitor therapy (absolute difference = 14%; 95% CI = 4 24%) [9]. The same trial found that ulcer recurrence was not statistically different for H. pylori eradication compared with longterm proton pump inhibitor therapy in patients taking low-dose aspirin [9]. The event rates in patients taking aspirin were much lower than for those taking naproxen and the lack of statistical significance for low-dose aspirin patients could be due to the study having insufficient power to detect a clinically meaningful difference. A larger trial in low-dose aspirin patients is currently being undertaken [10]. Nonulcer dyspepsia H. pylori eradication has revolutionized the management of peptic ulcer disease but this accounts for only a small proportion of dyspepsia in the community [11]. The majority of patients have nonulcer dyspepsia and the role of H. pylori in this disorder has been the subject of vociferous debate. Randomized controlled trials evaluating H. pylori eradication in nonulcer dyspepsia have reached different conclusions [12,13] suggesting that if there is any effect on symptoms it is likely to be modest. Usually systematic reviews allow results of many randomized trials to be synthesized so that a definitive conclusion can be reached but in this case they have added to the confusion. A US systematic review suggested H. pylori eradication had no effect on the symptoms of nonulcer dyspepsia [14] whilst a Cochrane Collaboration systematic review found that treating H. pylori had a small but statistically significant effect in curing this disorder [15]. The advantage of systematic reviews is that their methods are reproducible. It is, therefore possible to evaluate the reasons why two wellconducted systematic reviews reached opposite conclusions. The main reason appears to be the date at which the search was completed. The US systematic review assessed trials until December 1999 and identified seven trials involving 1544 patients. The Cochrane Collaboration review evaluated studies until May 2000 and identified nine trials assessing 2541 patients [16]. The extra power achieved by involving approximately 1000 extra patients in the meta-analysis allowed the small difference between H. pylori eradication and placebo antibiotics to become highly statistically significant [Fig. 1]. The question remains, however, whether a statistically significant result in favor of H. pylori eradication in nonulcer dyspepsia is clinically important. Fifteen H. pylori positive nonulcer dyspepsia patients (95% CI = patients) need eradication therapy to achieve symptom resolution that would not have occurred with placebo [15]. This is similar to the effect seen with proton pump inhibitors but the results are

3 32 Moayyedi et al. Risk ratio (95% CI) % Weight Blum 0.92 (0.81,1.03) 15.0 McColl 0.85 (0.77,0.93) 16.5 Koelz 0.95 (0.81,1.11) 8.3 Talley (Orchid) 0.97 (0.85,1.11) 12.4 Talley (USA) 1.07 (0.86,1.34) 8.5 Miwa 0.91 (0.70,1.18) 3.6 Malfertheiner 0.87 (0.77,0.99) 21.6 Bruley des Varannes 0.83 (0.68,1.00) 10.1 Froehlich 0.86 (0.60,1.24) 4.0 Overall (95% CI) 0.91 (0.86,0.96) Risk ratio Figure 1 Meta-analysis of randomized controlled trials of H. pylori eradication vs. placebo antibiotics in nonulcer dyspepsia, from [15]. more robust for H. pylori eradication as more patients have been evaluated in trials [17]. H. pylori eradication involves a 1 week treatment whereas patients responding to acid suppression will often need to take this medication long-term. A health economic model has also suggested that the cost of H. pylori eradication per person achieving symptom resolution is similar to treating patients with gastro-esophageal reflux disease with proton pump inhibitors [15]. These data have led the Maastricht Consensus Report to suggest that H. pylori eradication in nonulcer dyspepsia is advisable [1]. The factors that predict response to H. pylori eradication in nonulcer dyspepsia are uncertain. An observational study following nonulcer dyspepsia patients for 12 months after H. pylori eradication therapy suggested the presence of prominent acute inflammation and a low incidence of lymphoid follicles at pretreatment gastric histology were good predictors of a successful outcome [18]. This interesting work needs further evaluation. Gastro-esophageal reflux disease There has been a fall in H. pylori prevalence over the last few decades and this has been mirrored by a rise in gastro-esophageal reflux disease (GERD) in developed countries [19]. This has led to the suggestion that H. pylori infection protects against the development of GERD. This is supported by some observational studies [20,21] although others found no association between H. pylori and reflux disease [22,23]. Two randomized controlled trials have reported that H. pylori eradication does not worsen reflux symptoms in patients with GERD compared with placebo [24,25] and proton pump inhibitor requirements do not increase. It will be impossible to prove that H. pylori eradication does not influence GERD but these trials either showed identical relapse rates [24] or a result in favor of H. pylori eradication protecting against acid reflux [25]. It is therefore very unlikely that there is a clinically important relationship between H. pylori and GERD. Theoretically H. pylori infection should increase the ability of proton pump inhibitors to reduce acid output and it remains possible that eradication therapy may make GERD more difficult to treat but again any clinical impact is likely to be small [24,26]. It remains possible that Cag + strains of H. pylori may protect against reflux [27,28] and that this may be particularly important in countries with a high background prevalence of atrophic gastritis and gastric cancer [29]. This will give researchers in the save the H. pylori corner something to still argue about [30] although the only people that seem likely to benefit from the infection are those at highest risk of distal gastric cancer. There is also an important distinction between patients with esophagitis, patients with endoscopynegative reflux disease and uninvestigated patients with predominant reflux symptoms. The majority of studies have evaluated patients in the first two groups whereas the uninvestigated reflux patient is the most common clinical

4 H. pylori and nonmalignant disease 33 Figure 2 A meta-analysis of dyspepsia cure rates in randomized controlled trials of test and treat vs. early endoscopy. Random effects model using data from [32,33]. problem. Two trials which randomized infected subjects in primary care [11,31] have found H. pylori eradication to reduce symptoms significantly better than placebo antibiotics. Both trials found those with predominant reflux symptoms responding better than patients with epigastric pain [11,31]. This suggests some patients with peptic ulcer disease, or perhaps patients with nonulcer dyspepsia that are more likely to respond to anti-h. pylori therapy, have predominant heartburn symptoms. Management of undiagnosed dyspepsia The management of dyspepsia is expensive and in the UK it is estimated that over $1.5 billion is spent on this condition annually. Endoscopy is a significant contributor to these costs and the need for this procedure in young dyspeptic patients without alarm symptoms has been challenged since noninvasive tests for H. pylori have been readily available. Initially testing for H. pylori and only endoscoping those infected was suggested but a randomized trial has shown this is less cost-effective than usual management [32]. Screening for H. pylori and treating those infected is a more logical approach as most peptic ulcer cases will be cured and a proportion of nonulcer dyspepsia patients may also benefit [15]. Theoretically endoscopy can therefore be avoided in all young patients with uncomplicated dyspepsia symptoms. The definition of young will vary depending on the local incidence of gastric cancer. Figure 3 A meta-analysis of endoscopy rates in randomized controlled trials of test and treat vs. early endoscopy. Random effects model using data from [32,33].

5 34 Moayyedi et al. This approach is recommended by the Maastricht 2 consensus report [1] and is supported by a meta-analysis of three randomized controlled trials comparing H. pylori test and treat with early endoscopy [33]. Pooling the data of all three trials suggested symptomatic benefit was similar for each strategy [Fig. 2] although one trial did suggest endoscopy was more effective. This trial was based in primary care and used a near patient blood test [34] whereas the other trials were based in secondary care and used the more accurate urea breath test [35,36]. All trials reported significantly less endoscopy in the H. pylori test and treat group with approximately 70% of endoscopies avoided [Fig. 3]. The results of this systematic review are supported by a further randomized controlled trial of early endoscopy vs. H. pylori test and treat in 708 dyspepsia patients < 55 years old [37]. This trial had an 80% follow-up rate at one year and found no difference in mean dyspepsia scores or proportion of patients symptom-free between the two strategies. Only 8% of patients randomized to H. pylori test and treat had an endoscopy in the subsequent 12 months [37]. Strong leadership from secondary care advising that further investigation was unnecessary in patients having H. pylori test and treat, even if symptoms persist may have achieved this remarkably low endoscopy rate. Markov models supports the concept that patients do not need endoscopy even if symptoms persist [38 40]. Trials have not reported formal economic analyses but a meta-analysis suggested there were no significant differences between strategies in other health care costs [33]. H. pylori test and treat is therefore likely to be more cost-effective than endoscopy as it achieves similar symptomatic improvement whilst avoiding 70% of endoscopies. Patient satisfaction is another important consideration in evaluating the most appropriate strategy for managing dyspepsia. Trials have shown that patient satisfaction is high with both early endoscopy or H. pylori test and treat. One trial highlighted that satisfaction was reduced in a subset of H. pylori negative patients [35] but this was not confirmed by another randomized controlled trial [37]. The absolute benefit H. pylori positive dyspepsia patients will gain from eradication therapy has also been evaluated. A Canadian study randomized 294 infected patients to eradication therapy or placebo antibiotics. At 12 months, 50% of the treatment group had successful treatment compared with 36% of the controls (number needed to treat = 7; 95% CI = 4 63) [31]. The study was not powered to detect a difference in health service related dyspepsia costs but there was a trend for the group receiving H. pylori eradication to incur less costs over the next 12 months. There is therefore compelling evidence that H. pylori test and treat is more cost-effective than endoscopy. Conclusion The indications for H. pylori eradication for nonmalignant upper gastrointestinal disease are increasing. As a consequence of this H. pylori test and treat is likely to remain the recommended approach for managing dyspepsia over the next few years. Once the infection becomes rare in developed countries it is possible that empirical acid suppression will be the most costeffective strategy. The discovery of H. pylori may therefore facilitate the clinical community in coming full circle in our approach to dyspepsia. References 1 Malfertheiner P, Mégraud F, O Morain C, et al. The European Helicobacter pylori Study Group. Current concepts in the management of H. pylori infection The Maastricht Consensus Report. Aliment Pharmacol Ther 2002;16: Bytzer P, Aalykke C, Rune S, et al. and the Danish Ulcer Study Group. Eradication of Helicobacter pylori compared with long-term acid suppression in duodenal ulcer disease. Scand J Gastroenterol 2000;10: van der Wouden EJ, Thijs JC, van Zwet AA, Kleibeuker JH. Six-year follow-up after successful triple therapy for H. pylori infection in patients with peptic ulcer disease. Eur J Gastroenterol Hepatol 2001;13: Huang J-Q, Sridhar A, Hunt RH. Role of H. pylori infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease: a meta-analysis. Lancet 2002;359: Hawkey CJ, Tulassay Z, Szczepanski L et al. Randomised controlled trial of H. pylori eradication in patients on non-steroidal inflammatory drugs. HELP NSAIDS Study. Lancet 1998;352: Chan FKL, Sung JJY, Suen R, et al. Does eradication of H. pylori impair healing of nonsteroidal anti-inflammatory drug associated bleeding peptic ulcers? A prospective randomised study. Aliment Pharmacol Ther 1998;12: Chan FKL, To KF, Wu JCY, et al. Eradication of H. pylori and risk of peptic ulcers in patients

6 H. pylori and nonmalignant disease 35 starting long-term treatment with non-steroidal anti-inflammatory drugs: a randomised trial. Lancet 2002;359: Chan FK, Sung JY, Chung SC, et al. Randomised trial of eradication of H. pylori before nonsteroidal anti-inflammatory drug therapy to prevent peptic ulcers. Lancet 1997;350: Chan FK, Chung Sc, Suen Bym Lee YT, et al. Preventing recurrent upper gastrointestinal bleeding in patients with H. pylori infection who are taking low-dose aspirin or naproxen. New Engl J Med 2001;344: Peek RM, Chan FKL. Elimination of H. pylori or acid in high-risk users of aspirin or non-steroidal medications: final answer? Gastroenterology 2002;122: Moayyedi P, Feltbower R, Brown J, Mason S, Mason J, Nathan J, Richards ID, Dowell AC, Axon AT. Effect of population screening and treatment for Helicobacter pylori on dyspepsia and quality of life in the community: a randomised controlled trial. Leeds HELP Study Group. Lancet 2000;355: Froehlich F, Gonvers JJ, Wietlisbach V, et al. and the Eradication in Dyspepsia Study Group. H. pylori Eradication treatment does not benefit patients with non-ulcer dyspepsia. Am J Gastroenterol 2001;96: Bruley des Varannes S, Fléjou JF, Colin R, Zaïm M, Meuniers A, Bidaut-Mazel C. There are some benefits for eradication H. pylori in patients with non-ulcer dyspepsia. Aliment Pharmacol Ther 2001;15: Laine L, Schoenfeld P, Fennerty MB. Therapy for H. pylori in patients with non-ulcer dyspepsia. Ann Int Med 2001;134: Moayyedi P, Soo S, Deeks J, et al. on behalf of the Dyspepsia Review Group. Systematic review and economic evaluation of H. pylori eradication treatment for non-ulcer dyspepsia. BMJ 2000; 321: Moayyedi P, Deeks J, Forman D. H. pylori eradication therapy for non-ulcer dyspepsia. Ann Int Med 2002;136:555. Letter. 17 Soo S, Moayyedi P, Deeks J, Delaney B, Innes M, Forman D. Pharmacological interventions for non-ulcer dyspepsia (Cochrane Review). In: The Cochrane Library. Issue 2. Oxford: Update Software, Sheu B-S, Yang H-B, Wang Y-L, Chuang C-H, Huang A-H, Wu J-J. Pre-treatment gastric history is helpful to predict the symptomatic response after H. pylori eradication in patients with non-ulcer dyspepsia. Dig Dis Sci 2001;46: Xia HH-X, Phung N, Altiparmak E, Berry A, Methson M, Talley N. Reduction of peptic ulcer disease and H. pylori infection but increase in reflux esophagitis in Western Sydney between 1990 and Dig Dis Sci 2001;46: Fallone CA, Barkun AN, Gottke MU, et al. Association of Helicobacter pylori genotype with gastroesophageal reflux disease and other upper gastrointestinal diseases. Am J Gastroenterol 2000;95: El-Serag HB, Sonnenberg A, Jamal MM, Inadomi JM, Crooks LA, Feddersen RM. Corpus gastritis is protective against reflux oesophagitis. Gut 1999;45: Kim N, Lim SH, L KH. No protective role of H. pylori in the pathogenesis of reflux esophagitis in patients with duodenal or benign gastric ulcer in Korea. Dig Dis Sci 2001;46: Öberg S, Peters JH, Nigro JJ, et al. H. pylori is not associated with the manifestations of gastroesophageal relfux disease. Arch Surg 1999;134: Moayyedi P, Bardhan C, Young L, Dixon MF, Brown L, Axon AT. Helicobacter pylori eradication does not exacerbate reflux symptoms in gastroesophageal reflux disease. Gastroenterology 2001;121: Schwizer W, Thumshirn M, Dent J, Guldenschuh I, Menne D, Cathomas G, Fried M. Helicobacter pylori and symptomatic relapse of gastrooesophageal reflux disease: a randomised controlled trial. Lancet 2001;357: Armstrong D, Pare P, Pericak D, Pyzyk M, Canadian Pantoprazole GERD Study Group. Symptom relief in gastroesophageal reflux disease: a randomized, controlled comparison of pantoprazole and nizatidine in a mixed patient population with erosive esophagitis or endoscopynegative reflux disease. Am J Gastroenterol 2001; 96: Warburton-Timms VJ, Charlett A, Valori RM, Uff JS, Shepherd NA, Barr H, McNulty CA. The significance of caga (+) Helicobacter pylori in reflux oesophagitis. Gut 2001;49: Rokkas T, Ladas SD, Triantafyllou K, Liatsos C, Petridou E, Papatheodorou G, Karameris A, Raptis SA. The association between CagA status and the development of esophagitis after the eradication of Helicobacter pylori. Am J Med 2001;110: Koike T, Ohara S, Sekine H, Iijima K, Abe Y, Kato K, Toyota T, Shimosegawa T. Helicobacter pylori infection prevents erosive reflux oesophagitis by decreasing gastric acid secretion. Gut 2001;49: Richter JE. H pylori: the bug is not all bad. Gut 2001;49: Chiba N, Veldhuyzen van Zanten SJO, Sinclair P, Ferguson RA, Escobedo S, Grace E. Treating Helicobacter pylori infection in primary care patients with uninvestigated dyspepsia: the Canadian adult dyspepsia empiric treatment Helicobacter pylori positive (CADET-Hp) randomised controlled trial. BMJ 2002;324:012 9.

7 36 Moayyedi et al. 32 Delaney BC, Wilson S, Roalfe A, Roberts L, Redman V, Wearn A, Hobbs FD. Randomised controlled trial of Helicobacter pylori testing and endoscopy for dyspepsia in primary care. BMJ 2001;322: Delaney BC, Innes MA, Deeks J, et al. Initial management strategies for dyspepsia (Cochrane Review). In: The Cochrane Library. Issue 2. Oxford: Update Software, Duggan AE, Elliott CA, Hawkey CJ, Logan RFA. Does initial management of patients with dyspepsia alter symptom response and patient satisfaction? Results from a randomised trial. Gastroenterology 1999;116:G Lassen AT, Pedersen FM, Bytzer P, Schaffalitzky de Muckadell OB. Helicobacter pylori test-anderadicate versus prompt endoscopy for management of dyspeptic patients: a randomised trial. Lancet 2000;356: Heaney A, Collins JS, Watson RG, McFarland RJ, Bamford KB, Tham TC. A prospective randomised trial of a test and treat policy versus endoscopy based management in young Helicobacter pylori positive patients with ulcer-like dyspepsia, referred to a hospital clinic. Gut 1999;45: McColl KEL, Murray LS, Gillen D, et al. Randomised trial of endoscopy with testing for Helicobacter pylori compared with non-invasive H. pylori testing alone in the management of dyspepsia. BMJ 2002;324: Delaney B, Moayyedi P, Deeks J, et al. The management of dyspepsia: a systematic review. Health Technol Assessment 2000;4: Spiegel BMR, Vakil NB, Ofman JJ. Dyspepsia management in primary care: a reappraisal of competing strategies. Gastroenterology 2002;122: Talley NJ. Dyspepsia management in the millennium the death of test and treat? Gastroenterology 2002;122: