*Department of Gastroenterology, Moscow Regional Research Clinical Institute (MONIKI), Moscow, Russia; ... controlled trials on H. pylori eradication in patients.
Volume 8 • Supplement 1 • 2003 H E L I C O B AC T E R
Helicobacter pylori and nonmalignant diseases Blackwell Publishing Ltd.
Vassili Isakov* and Peter Malfertheiner† *Department
of Gastroenterology, Moscow Regional Research Clinical Institute (MONIKI), Moscow, Russia; für Innere Medizin, Klinik für Gastroenterologie, Hepatologie und Infectiologie, Magdeburg, Germany
†Otto-von-Guericke-Universität, Magdeburg, Zentrum
ABSTRACT
Eradication of Helicobacter pylori has lead to a significant decrease in the prevalence of peptic ulcer disease world-wide. Despite the fact that H. pylori eradication is the only way to cure peptic ulcer disease, a substantial number of patients still need antisecretory agents to be symptoms-free after eradication. During the past year several randomized controlled trials on H. pylori eradication in patients taking NSAIDs have been published but contradictory results have been obtained. In certain parts of the world, NSAIDs are becoming the main cause of peptic ulcer disease complications such as bleeding or perforation. Some patients with nonulcer dyspepsia do benefit from eradication of H. pylori as was shown in several studies. Long-term trials with cost/efficacy analysis are still needed to demonstrate the benefit of H. pylori eradication over acid inhibition in this group of patients. H. pylori prevalence is
lower in patients with gastro-esophageal reflux disease, but according to recent systematic reviews it varies geographically. There are more data now to show that eradication of H. pylori in duodenal ulcer patients does not increase the incidence of GERD. The ‘test and treat’ strategy for patients with uninvestigated dyspepsia was strongly supported by both meta-analysis and the results of recent randomized controlled trials. Even in developed countries where the prevalence of H. pylori decreases, this strategy allows resolution of symptoms in a larger number of patients with dyspepsia compared to empirical treatment with proton pump inhibitors and reduces the endoscopic workload. Keywords. gastro-esophageal reflux disease, nonsteroidal anti-inflammatory drug-related peptic ulcer, nonulcer dyspepsia, peptic ulcer disease, unvestigated dyspepsia.
Peptic ulcer disease
based on a sample of dyspeptic patients examined with upper endoscopy and 13C-urea breath test (UBT) during the period of 1996–2001 a decrease in the incidence of H. pylori in 7920 patients from 72.8% to 53.8% as well as in the prevalence of peptic ulcer from about 44% to 8% were demonstrated [2]. Interestingly, there was no decrease found in the incidence of ulcer complications such as bleeding and perforation which could be explained by the increase of NSAID use in that group from 15.8% in 1999 to 19.4% in 2001. The prevalence of H. pylori infection in peptic ulcer disease complicated by gastric outlet obstruction according to a recent review is lower (69%) than that reported in uncomplicated PUD, but varied in the range from 33% to 91% in the individual studies [3]. The authors of this review conclude that H. pylori eradication therapy should be considered as the first step in the treatment of duodenal or pyloric H. pylori-positive stenosis, whereas
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espite the decrease in prevalence of H. pylori in developed countries, it is still a major causative factor of peptic ulcer disease (PUD). According to the data of the first populationbased prospective cohort study which assessed the impact of multiple risk factors on the incidence of peptic ulcer disease in a random sample of 2416 Danish adults with no history of peptic ulcer, the main risk factor for PUD was H. pylori infection (OR = 4.3 (95% CI 2.2–8.3) [1]. In those who were serologically positive for H. pylori, tobacco smoking (12.7 (2.8–56.8)) and intake of spirits (2.4 (1.1–5.4)) additionally increased the risk of PUD. In another study,
Correspondence: Vassili A. Isakov, Department Gastroenterology, MONIKI, Schepkin st., 61/2, Moscow, 129110, Russia. Tel./Fax: + 709 5971 7258; E-mail: Vassili.Isakov @rambler.ru © 2003 Blackwell Publishing Ltd, Helicobacter, 8 (Suppl. 1), 36 – 43
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H. pylori and nonmalignant diseases dilatation or surgery should be reserved for patients who do not respond to medical therapy. It is well known that gastric ulcers are less frequently associated with H. pylori than duodenal ulcers because of a high proportion of NSAID induced ulcers. To elucidate the relationship among disparate ulcer risk factors in three subtypes of gastric ulcer, a stratification analysis was performed in 159 age-matched controls, 30 patients with ulcer in the gastric body, 55 with coexistent gastroduodenal ulcer, and 69 with ulcer in the prepyloric region who were examined for potential risk factors [4]. Among all gastric ulcer subsets, cigarette smoking, NSAID use and H. pylori infection were independent risk factors. For ulcers in the gastric body, smoking and NSAID use raised the likelihood of ulceration. H. pylori infection carried the strongest association with gastroduodenal ulcer, and NSAID use generated the highest possibility of prepyloric ulcers (OR = 11.3; 95% CI 3.49–36.5). NSAID use also markedly raised the likelihood of multiple gastric ulcers In spite of the predominant role of H. pylori in ulcer pathogenesis, NSAIDs and other permissive factors continue to substantially contribute to the heterogeneity of this disease. The Maastricht 2–2000 Consensus Report strongly recommends H. pylori eradication in all patients with peptic ulcer as it permits a definite cure of the disease [5]. There are only few reports about a long-term follow-up in patients after H. pylori eradication. In a large prospective trial 445 H. pylori-positive patients (88 duodenal ulcers, 357 gastric ulcers) were randomly divided into three groups. In the first group, patients received ‘conventional treatment’ including therapy with a histamine H2-receptor antagonist or proton pump inhibitor (PPI). In the second group, patients received ‘dual therapy’ and in the third group, triple therapy with PPI plus amoxicillin and clarithromycin. Eradication of H. pylori infection was assessed at 4 weeks, and 6 and 12 months after the end of therapy. Endoscopy examinations continued to be performed at intervals of 6 months for 5 years. No recurrence was noted in the duodenal ulcer patients and only in 4% of gastric ulcer patients after successful eradication during 5-year follow-up. In contrast, in patients with persistent H. pylori infection all DU and 92% of gastric ulcers recurred [6]. This study confirms once more that eradication of H. pylori infection changes the natural course of PUD. It should be noted that not all the patients in whom eradication was © 2003 Blackwell Publishing Ltd, Helicobacter, 8 (Suppl. 1), 36–43
achieved became symptoms-free. In one uncontrolled study 2 years after successful H. pylori eradication 42.2% of patients were still requiring maintenance therapy with H2-blockers or PPI [7]. Predictors of symptomatic response and no further requirement of acid inhibitory therapy after 2 years were: younger age at onset of PUD; absence of concomitant gastro-esophageal reflux disease or hiatus hernia. In another study with a similar design it was shown that 1 year following eradication, 44% (18/41) of patients still required acid suppressors. The majority of these patients (11/18; 61%) continued to remain on acid-suppressor treatment during 4 years of follow-up (95%CI 38%–83%) [8]. In a further study a group of patients with dyspeptic symptoms (PUD in 58%) on maintenance therapy with H2-receptor antagonists after successful H. pylori eradication, at the end of the 1-year period, could either stop or significantly reduce the intake of H2-receptor antagonists [9]. In a comparative study of 183 patients with PUD or gastritis and/or duodenitis (G/D) H. pylori was eradicated and GI symptoms were evaluated after 1 year by means of Gastrointestinal Symptom Rating Scale (GSRS) and the Ulcer Esophagitis Subjective Symptoms Scale (UESS) questionnaires. One year after H. pylori eradication, 99% of the PUD patients and 75% of the G/ D patients reported a significant improvement of their main upper GI complaint. Abdominal pain score decreased by 48% as measured by GSRS and by 78% as measured by UESS in the PUD group and by 25% and 47%, respectively, in the G/D group. Reflux symptoms decreased by 41% and 63% in PUD patients and by 28% and 45% in G/D patients; All individual symptoms were significantly improved compared to baseline, but only abdominal pain improved significantly more in PUD than in G/D patients [10]. The results of these studies indicate that there is more than one cause to contribute to upper gastrointestinal symptoms and this needs to be considered in the patient’s management. Nonsteroidal-anti-inflammatory drug-related peptic ulcer The Maastricht 2–2000 Consensus Report advises the eradication of H. pylori before starting longterm therapy with nonsteroidal-anti-inflammatory drugs (NSAIDs) [5], based on the evidence from randomized placebo-controlled trials that showed that the eradication of H. pylori is associated
38 with lower rate of gastroduodenal lesions in patients taking NSAIDs. However, even recent double-blind placebo controlled trials continue to report contradictory findings on this intriguing NSAID–H. pylori relationship. In one study 140 H. pylori-positive patients, whilst receiving long-term NSAID therapy but with no ulcers at baseline endoscopy, were randomized to have triple therapy or placebo during 1 week. After 12 weeks, peptic ulcer had developed in five (7%) of the patients who received triple therapy and in six (9%) of those who had received placebo ( p = 1.00). Over time no difference in the development of ulcers was observed between patients with persistent H. pylori infection (9%) and those with successful eradication of H. pylori (8%) [11]. In another study, 660 H. pylori-positive patients requiring NSAID therapy with no past or current peptic ulcer received diclofenac 50 mg twice daily for 5 weeks in combination with one of the four randomly assigned treatments: triple therapy for 1 week followed by placebo for 4 weeks (OAC-P); triple therapy followed by antisecretory treatment with omeprazole 20 mg once daily for 4 weeks (OAC-O); omeprazole 20 mg once daily for 5 weeks (OO); or placebo for 5 weeks (P-P). The occurrence of peptic ulcers in the four treatment groups during the study period was: 1.2% for OAC-P, 1.2% for OAC-O, 0% for O-O, and 5.8% for P-P ( p < 0.05 between placebo and all active treatment groups). Patients who received active treatment had dyspeptic symptoms requiring medication less frequently than those who received placebo [12]. Two studies demonstrated the influence of H. pylori eradication in healing of ulcers in patients receiving NSAIDs. In one study healing rates of gastric ulcers at 8 weeks were statistically significantly greater among H. pylori-positive patients (n = 181) than among-negative patients (n = 497) (70% vs. 61%, respectively; p < 0.05), especially among those with large ulcers (> 10 mm) and in younger patients (< 60 years old) [13]. The presence of H. pylori infection enhanced gastric ulcer healing with acid suppressants such as ranitidine, but it did not affect duodenal ulcer healing [14]. An analysis of factors that influence dyspeptic symptoms was performed in two studies. In one study no relationship was found between H. pylori infection and dyspepsia or any of its surrogate markers (use of antisecretory drug or NSAID intolerance). Female gender and treatment with antisecretory
Isakov and Malfertheiner drugs were found to be independent predictors for the appearance and severity of dyspeptic symptoms. The only independent predictive variables of the requirement for antisecretory drugs were age, previous ulcer disease, taking NSAIDs with a medium or high anti-inflammatory potential, and the symptoms score [15]. In a comparative study, 919 patients received NSAIDs and were treated with triple therapy or omeprazole monotherapy: H. pylori eradication did not appear to influence the incidence and severity of dyspeptic symptoms in infected patients [16]. An interesting observation was that of 226 dyspeptic patients who received NSAIDs the prevalence of H. pylori was lower for those with gastric ulcer in comparison to those without [17,18]. H. pylori infection was found to be less prevalent in patients with bleeding ulcers compared to controls (66.7 vs. 89.6%). The issue of the interaction between H. pylori and NSAIDs remains controversial and complex, with much support from these recent studies that the harmful potential, especially on the gastric mucosa, is independent rather than synergistic. Nonulcer dyspepsia Nonulcer dyspepsia (NUD) is defined as persistent or recurrent pain/discomfort in the upper abdomen, where no structural explanation for the symptoms is found. Maastricht 2–2000 Consensus Report advises the eradication of H. pylori in patients with NUD [5], based on the evidence of the last meta-analysis. Since Maastricht 2–2000 five meta-analyses have been performed. According to their results the Odds Ratio of symptom relief in the control groups relative to the treated groups varied between 0.30 (95% CI = 0.2– 0.5) to 0.88 (95% CI = 0.7– 1.2) and the proportion of patients becoming symptom free due to treatment varied between 11% and 38% [19]. Fifteen randomized controlled trials were included in the Cochrane Collaboration systematic review. Thirteen trials compared antisecretory dual or triple therapy with placebo antibiotics+/–antisecretory therapy, and evaluated dyspepsia at 3 –12 months. There was a 9% relative risk reduction in the H. pylori eradication group (95% CI = 5% to 14%) compared to placebo. The number needed to treat to cure one case of dyspepsia was 15 (95% CI = 10 – 28) [20]. Therefore, H. pylori eradication therapy has a small but statistically significant effect in H. pylori-positive NUD. © 2003 Blackwell Publishing Ltd, Helicobacter, 8 (Suppl. 1), 36–43
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H. pylori and nonmalignant diseases The effect of H. pylori infection on the natural history of functional dyspepsia was investigated in several recent studies. In one study 201 patients (118 H. pylori-positive and 83 H. pylori-negative) were enrolled in to follow-up during 7 years. Only four cases of PUD were found in H. pyloriinfected patients, i.e. an annual incidence of less than 1% during the follow-up period. H. pylori-positive patients were investigated by endoscopy more often (47%) than H. pylorinegative patients (29%) (p = 0.011) with comparable findings in follow-up examinations [21]. In another study with similar design peptic ulcers occurred in 16 of 209 NUD patients during the 2-year follow-up period. The rates for peptic ulcer and erosion development were significantly higher in H. pylori-positive patients than in H. pylori-negative patients (ulcer 12.6% vs. 3.5%; erosion, 23.2% vs. 12.3%) [22]. A 5-year follow-up of 64 patients who were included in a randomized placebo controlled trial showed that there was a significant difference between patients who were H. pylori-negative and those who remained positive with regard to complete symptom resolution, consumption of relevant medications and PUD development, in favour of active treatment [23]. The findings of these studies support the use of H. pylori eradication in symptomatic patients with NUD both to induce symptom resolution and to prevent disease progression. A double-blind placebo-controlled study demonstrated that in a selected group of 197 patients from which the patients with symptoms indicating gastro-oesophageal reflux disease or irritable bowel syndrome were excluded, treatment with omeprazole was better than placebo, but H. pylori status did not significantly influence the response to therapy during 2 weeks [24]. In a further double-blind randomized trial with a 6-month follow-up 181 H. pylori-positive patients resistant to conventional therapy with H2-blockers or PPI were randomized to receive double-therapy or omeprazole alone for 2 weeks. The response rates defined as no need for further therapy or investigations for dyspeptic symptoms 4 –6 months after treatment were 66% vs. 62% (NS) [25]. The findings of this study do not support a superiority of H. pylori therapy in functional dyspepsia over a short-term use of acid inhibitor. There is still need for a definitive large study to prove the benefit of H. pylori eradication in NUD, which should include a cost/efficacy analysis. © 2003 Blackwell Publishing Ltd, Helicobacter, 8 (Suppl. 1), 36–43
Figure 1 Odds ratios (95% confidence intervals) for prevalence of H. pylori infection, grouped by geographical location, from [26 ].
Gastro-esophageal reflux disease The evidence for an association between H. pylori and gastro-esophageal reflux disease (GERD) remains uncertain and the studies evaluating the presence or absence of H. pylori on GERD have given conflicting results. Recent systematic review of 20 studies has demonstrated a lower prevalence of H. pylori in patients with GERD with an Odds Ratio for prevalence of 0.60 (95% CI: 0.47–0.78) [26]. Substantial heterogeneity was observed between studies. Location seemed to be an important factor, with a much lower prevalence of H. pylori in patients with GERD in studies from the Far East, despite a higher overall prevalence of infection than in Western Europe and North America [ Fig. 1]. Does this low prevalence of H. pylori mean that infection could protect from GERD? In the study of patients with an endoscopic diagnosis of hernia, 507 patients were divided into three
40 groups: A ≤ 45 years; B 46–60 years; C ≥ 61 years. A significant increase in H. pylori prevalence and corpus gastritis scores with age, and a parallel decrease of GERD symptom prevalence was found: 66.6% in group A, 52.1% in B, and 46.8% in C ( p < 0.01). Taking the three groups together, the prevalence of H. pylori infection was higher in patients without GERD than with GERD (66.4 vs. 57.3%, p < 0.05), and higher in patients with nonerosive than erosive GERD (62.8 vs. 48.6%, p = 0.02); corpus gastritis scores were significantly higher in patients without GERD than those with GERD and in those with nonerosive than erosive GERD [27]. In another comparative study of 73 reflux esophagitis patients and 132 controls it was shown that the prevalence of H. pylori infection was significantly lower in patients with reflux oesophagitis than in the nonreflux group. Grade of inflammation and glandular atrophy in the antrum and body were higher in patients in the nonreflux group compared with those in the reflux esophagitis group [28]. Therefore, H. pylori infection protects against development of GERD, but this effect is significantly more evident in the elderly where, in spite of the high prevalence of hernia, only a small number of individuals develop GERD. The development of a corpus-predominant gastritis is probably responsible for this effect. This influence of age and atrophic gastritis on the development of GERD could partly explain the difference in the results of epidemiological studies and should motivate new studies considering these two cofactors. If some kind of protection from GERD in H. pylori-positive patients exists, does it mean that eradication could induce or exacerbate GERD? It was shown that at least 27.8% of duodenal ulcer patients have associated endoscopic evidence of oesophagitis and 17% nonerosive reflux disease [29]. Therefore it is possible that the data on the development of GERD following eradication of H. pylori represent the unmasking of existing disease rather than de novo development. To date there is a body of evidence showing that the eradication of H. pylori in duodenal ulcer patients does not increase the incidence of GERD. In a multicenter trial program in the EC and Canada, 1497 gastric or duodenal ulcer patients were randomized to an omeprazole triple therapy group or to a control group, and were followed up for 1–6 months after treatment. In patients with duodenal ulcer, there
Isakov and Malfertheiner was a significantly lower prevalence of heartburn after successful eradication of H. pylori compared with that in cases of eradication failure (estimated OR = 0.48). The reduction in the prevalence of heartburn in patients with gastric ulcer was independent of the post-treatment H. pylori status. The observed incidence of esophagitis at the last visit was not influenced by H. pylori status [30]. Results of eight doubleblind prospective trials of H. pylori therapy in 1165 duodenal patients revealed no development or worsening of GERD symptoms and endoscopic evidence of erosive esophagitis [31]. Erosive esophagitis developed in 24 (4%) of 621 patients with cure vs. 14 (3%) of 544 with persistent H. pylori. In the longest study (28–30week follow-up), esophagitis developed in two (7%) of 28 patients with cure vs. five (7%) of 76 with persistent infection. New GERD symptoms developed in 13 (14%) of 92 patients with cure vs. seven (20%) of 35 with persistent infection. GERD worsened in 20 (7%) of 269 with cure vs. 20 (15%) of 137 with persistent H. pylori (OR = 0.47, 95% CI = 0.24–0.91; p = 0.02). In a case-control study in which 241 pairs of PUD patients matched for age, gender, and type of ulcer were evaluated 3 years after H. pylori eradication, the rates of patients with improved reflux symptoms in the case and control groups were 65.4% and 30.4% ( p < 0.001) respectively. On the contrary, the rates of those with worsened reflux symptoms were similar (5.1% and 7.6%) [32]. Carditis, a new entity for GERD/H. pylori link, was found to be strongly associated with H. pylori but not with GERD in two studies [33,34]; different results were demonstrated in another study [35]. These data need further evaluation, and studies on the cardia should include careful consideration of clinical, endoscopic and histological criteria. Uninvestigated dyspepsia The Maastricht 2–2000 Consensus Report defined ‘test and treat’ approach as a key management strategy in primary care for patients with uninvestigated dyspepsia under the age of 45 years, without predominant GERD symptoms, without alarm symptoms, and not using NSAIDs [5]. This approach was strongly supported by meta-analysis of previous studies [36] as well as by several recent randomized controlled trials [37,38] that compared ‘test and treat’ © 2003 Blackwell Publishing Ltd, Helicobacter, 8 (Suppl. 1), 36–43
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H. pylori and nonmalignant diseases with endoscopy. The more challenging comparison is a ‘test and treat’ strategy with empirical PPI therapy for patients with uninvestigated dyspepsia because PPI therapy is often the first approach and likely to be more cost-effective in developed countries with low prevalence of H. pylori. The first randomized controlled trial of a ‘test and treat’ strategy vs. empirical therapy with omeprazole during 4 weeks in 219 young dyspeptic patients showed that fewer patients had endoscopy in the ‘test and treat’ group than in the omeprazole group (55% vs. 88%), because of persisting or recurrent symptoms [39]. Eradication of H. pylori achieved resolution of symptoms in a larger number of patients with dyspepsia and reduced the endoscopic workload. PPI empirical treatment is likely to mask an appreciable number of peptic ulcers and cases of esophagitis. Similar data were shown in a study performed in Hong Kong in which 460 patients with predominant reflux type symptoms were evaluated with a structured questionnaire followed by endoscopy [40]. In 82 (18%) patients PUD was found and 95% of these cases were H. pylori-positive. Concomitant erosive esophagitis was found in 26 (32%) of these patients. Of the remaining 378 patients, 218 (58%) had erosive esophagitis and one had esophageal cancer. Among the 159 patients with no endoscopic lesion, 148 (93%) symptoms were relieved with a PPI. Multivariate analysis showed that male gender, age older than 60 years and H. pylori infection were significantly associated with a diagnosis of PUD. Coexisting dyspeptic symptom was not a predictor for PUD. Therefore, in populations with a high prevalence of H. pylori infection, a significant proportion of patients with reflux symptoms have concomitant PUD, and empirical treatment based on symptoms does not appear to be appropriate. Conclusion
Eradication of H. pylori is indicated for all patients with nonmalignant diseases associated with this pathogen. However, its effect is variable, ranging from the highest benefit in the cure of PUD to a small benefit in patients with NUD. The controversies over the benefit of H. pylori eradication in NSAID users continue, and the benefit very much depends on the selection of patients and type of drugs. There is a strong body of evidence that eradication of H. pylori in duodenal ulcer patients neither increases © 2003 Blackwell Publishing Ltd, Helicobacter, 8 (Suppl. 1), 36–43
incidence of GERD, nor enhances pre-existing esophagitis or heartburn even in long-term studies. Management of patients with uninvestigated dyspepsia in primary care using ‘test and treat’ strategy is still cost-effective even in developed countries in which prevalence of H. pylori decreases. References 1 Rosenstock S, Jorgensen T, Bonnevie O, Andersen L. Risk factors for peptic ulcer disease: a population based prospective cohort study comprising 2416 Danish adults. Gut 2003;52:186– 93. 2 Bobrzynski A, Beben P, Budzynski A, et al. Incidence of complications of peptic ulcers in patients with Helicobacter pylori (Hp) infection and/or NSAID use in the era of Hp eradication. Med Sci Monit 2002;8:CR554–7. 3 Gisbert JP, Pajares JM. Review article. Helicobacter pylori infection and gastric outlet obstruction – prevalence of the infection and role of antimicrobial treatment. Aliment Pharmacol Ther 2002;16:1203–8. 4 Chen MH, Wu MS, Lee WC, Wang HP, Lin JT. A multiple logistic regression analysis of risk factors in different subtypes of gastric ulcer. Hepatogastroenterology 2002;49:589–92. 5 Malfertheiner P, Megraud F, O’Morain C, et al. Current concepts in the management of Helicobacter pylori infection – the Maastricht 2–2000 Consensus Report. Aliment Pharmacol Ther 2002;16:167–80. 6 Tomita T, Fukuda Y, Tamura K et al. Successful eradication of Helicobacter pylori prevents relapse of peptic ulcer disease. Aliment Pharmacol Ther 2002;16:204–9. 7 Forrest EH, MacKenzie JF, Stuart RC, Morris AJ. Helicobacter pylori eradication for peptic ulceration: an observational study in a Scottish primary care setting. Scott Med J 2002;47:28–33. 8 Khan Z, Nair P, O’Shea C, et al. Does Helicobacter pylori eradication reduce the long-term requirements for acid suppressants in patients with a history of peptic ulcer disease in general practice? Results from a four-year longitudinal study. Scand J Gastroenterol 2002;37:144–7. 9 Verma S, Giaffer MH. Helicobacter pylori eradication in patients on long-term H2 receptor antagonists. Economic and symptomatic benefits. A large prospective study in primary care. Helicobacter 2002;7:91–8. 10 Olafsson S, Hatlebakk JG, Berstad A. Patients with endoscopic gastritis and/or duodenitis improve markedly following eradication of Helicobacter pylori, although less so than patients with ulcers. Scand J Gastroenterol 2002;37:1386–94.
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Isakov and Malfertheiner 24 Bolling-Sternevald E, Lauritsen K, Aalykke C, et al. Effect of profound acid suppression in functional dyspepsia: a double-blind, randomized, placebo-controlled trial. Scand J Gastroenterol 2002;37:1395–402. 25 Koelz HR, Arnold R, Stolte M, Fischer M, Blum AL. Treatment of Helicobacter pylori in functional dyspepsia resistant to conventional management: a double blind randomised trial with a six month follow up. Gut 2003;52:40–6. 26 Raghunath A, Hungin AP, Wooff D, Childs S. Prevalence of Helicobacter pylori in patients with gastro-oesophageal reflux disease: systematic review. BMJ 2003;326:737. 27 Manes G, Pieramico O, Uomo G, et al. Relationship of sliding hiatus hernia to gastroesophageal reflux disease: a possible role for Helicobacter pylori infection? Dig Dis Sci 2003;48:303–7. 28 Jang TJ, Kim NI, Suh JI, Yang CH. Reflux esophagitis facilitates low Helicobacter pylori infection rate and gastric inflammation. J Gastroenterol Hepatol 2002;17:839–43. 29 McNamara D, Buckley M, O’Morain C. Helicobacter pylori-induced duodenal ulcer frequently coincides with gastro-oesophageal reflux disease. Dig Liver Dis 2002;34:542–6. 30 Malfertheiner P, Dent J, Zeijlon L, et al. Impact of Helicobacter pylori eradication on heartburn in patients with gastric or duodenal ulcer disease – results from a randomized trial programme. Aliment Pharmacol Ther 2002;16:1431–42. 31 Laine L, Sugg J. Effect of Helicobacter pylori eradication on development of erosive esophagitis and gastroesophageal reflux disease symptoms: a post hoc analysis of eight double blind prospective studies. Am J Gastroenterol 2002;97:2992–7. 32 Miwa H, Sugiyama Y, Ohkusa T, et al. Improvement of reflux symptoms 3 years after cure of Helicobacter pylori infection: a case-controlled study in the Japanese population. Helicobacter 2002;7:219–24. 33 Jang TJ, Kim NI, Yang CH. Carditis is associated with Helicobacter pylori-induced gastritis and not reflux esophagitis. J Clin Gastroenterol 2003;36:26–9. 34 McNamara D, Buckley M, Crotty P, et al. Carditis: all Helicobacter pylori or is there a role for gastro-oesophageal reflux? Scand J Gastroenterol 2002;37:772–7. 35 Oksanen A, Sipponen P, Karttunen R, Rautelin H. Inflammation and intestinal metaplasia at the squamocolumnar junction in young patients with or without Helicobacter pylori infection. Gut 2003;52:194–8. 36 Delaney B, Moayyedi P, Forman D. Initial management strategies for dyspepsia (Cochrane Review). Cochrane Database Syst Rev 2003 CD001961. 37 Chiba N, Van Zanten SJ, Sinclair P, et al. Treating Helicobacter pylori infection in primary care © 2003 Blackwell Publishing Ltd, Helicobacter, 8 (Suppl. 1), 36–43
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43 39 Manes G, Menchise A, De Nucci C, Balzano A. Empirical prescribing for dyspepsia. randomised controlled trial of test and treat versus omeprazole treatment. BMJ 2003;326:1118. 40 Wu JC, Chan FK, Ching JY, et al. Empirical treatment based on ‘typical’ reflux symptoms is inappropriate in a population with a high prevalence of Helicobacter pylori infection. Gastrointest Endosc 2002;55:461–5.
