Eradicating Helicobacter Pylori in Functional Dyspepsia

GASTROENTEROLOGY 2012;142:1613–1619

SELECTED SUMMARIES Philip S. Schoenfeld, Section Editor John Y. Kao, Associate Section Editor

STAFF OF CONTRIBUTORS Nuzhat A. Ahmad, Philadelphia, PA Darren M. Brenner, Chicago, IL Andrew T. Chan, Boston, MA Francis K. L. Chan, Hong Kong, China Lin Chang, Los Angeles, CA Tsutomu Chiba, Kyoto, Japan Massimo Colombo, Milan, Italy B. Joseph Elmunzer, Ann Arbor, MI Alex Ford, Leeds, United Kingdom

Timothy B. Gardner, Lebanon, NH Lauren B. Gerson, Stanford, CA Colin W. Howden, Chicago, IL W. Ray Kim, Rochester, MN Paul Y. Kwo, Indianapolis, IN Edward V. Loftus, Rochester, MN Josep M. Llovet, New York, NY Julian Panes, Barcelona, Spain Joel Rubenstein, Ann Arbor, MI

ERADICATING HELICOBACTER PYLORI IN FUNCTIONAL DYSPEPSIA Mazzoleni LE, Sander GB, de Magalhaes Francesconi CF, et al. Helicobacter pylori eradication in functional dyspepsia. HEROES trial. Arch Intern Med 2011;171:1929 –1936. Dyspepsia is common in the community, with a population prevalence as high as 40% (Br Med J 1989;298:30 – 32). Most individuals have no structural explanation for their symptoms (Clin Gastroenterol Hepatol 2010;8:830 – 837), and therefore are labeled as having functional dyspepsia. This condition is a chronic, relapsing and remitting disorder, and the pathogenesis is not fully understood. Higher rates of Helicobacter pylori infection have been reported in patients with functional dyspepsia, compared with healthy controls (Gastroenterology 1988;94:33– 40). In a pooled analysis of nonrandomized studies of eradication therapy in H pylori-positive functional dyspepsia patients, rates of symptom improvement appeared higher in those achieving successful eradication (Aliment Pharmacol Ther 1996;10:843– 850). As a result, eradication of H pylori has been advocated as a treatment for individuals with functional dyspepsia infected with the bacterium. The Helicobacter Eradication Relief of Dyspeptic Symptoms trial was a randomized, double-blind, single-center trial conducted in primary care in Brazil, with 12 months of follow-up. Eligible patients were aged ⱖ18 years with dyspepsia according to the Rome III criteria, a structurally normal upper gastrointestinal (GI) endoscopy, and H pylori infection (confirmed by positive rapid urease testing and histology). Subjects were randomized to receive either 10 days of proton pump inhibitor (PPI) triple therapy (omeprazole 20 mg, amoxicillin 1 g, and clarithromycin 500 mg all twice daily) or 10 days of PPI alone (omeprazole 20 mg and placebo antibiotics twice daily). Participants were allowed rescue medication with metoclopramide for postprandial distress, and famotidine for epigastric pain, throughout the study period.

Sameer Saini, Ann Arbor, MI Shiv K. Sarin, New Delhi, India Shamita B. Shah, Stanford, CA Amit Singal, Dallas, TX Jan Tack, Leuven, Belgium Michael L. Volk, Ann Arbor, MI Akbar Waljee, Ann Arbor, MI Kenneth K. Wang, Rochester, MN Alastair J. M. Watson, Norwich, UK

Follow-up was at 4, 8, and 12 months, and upper GI endoscopy was performed at baseline and 12 months. The primary end point was the proportion of patients with a ⱖ50% decrease in dyspeptic symptom scores, measured using a questionnaire validated locally. Other outcomes of interest included the proportion of patients reporting complete resolution of symptoms, the mean decrease in symptom scores, use of rescue medications in the 30 days before study completion, patient global assessment of symptoms (improved, unchanged, or deteriorated), and patient-reported quality of life. In total, 404 eligible patients were randomized, with 201 assigned to PPI triple therapy, and 203 allocated to PPI and placebo antibiotics. The 2 arms of the trial were reasonably well matched with respect to demographics, and duration and severity of symptoms. Complete follow-up data were obtained in 389 (96.3%) patients. At 12-month follow-up, 49% of those assigned to PPI triple therapy achieved the primary end point of a ⱖ50% decrease in dyspeptic symptom scores, compared with 36.5% of those receiving PPI and placebo antibiotics. This 12.5% difference in absolute effect was significant (P ⫽ .01); the number needed to treat was 8. In terms of secondary outcomes, a greater proportion of patients reported a global improvement in symptoms in the triple therapy arm (78% vs 67.5%; P ⫽ .02), and the mean decrease in symptom score was also significantly greater in those receiving triple therapy (P ⫽ .008). However, no differences were detected in rates of complete symptom relief, and differences in quality of life data were not consistently better with eradication therapy. Finally, rescue medication use was not different between the 2 therapies, although there was a trend toward lower consumption in those allocated to triple therapy. Adverse events were significantly more frequent in the triple therapy patients, although the majority of these were short lived according to the investigators. Comment. Functional dyspepsia is common and, as is the case in most of the functional GI disorders, the medical

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treatment of the condition is considered unsatisfactory. It therefore represents a considerable burden to the health service, owing to consultations, repeated investigations, and the use of prescription medications. Previous randomized, controlled trials (RCTs) of H pylori eradication therapy in functional dyspepsia have demonstrated conflicting results in terms of efficacy (N Engl J Med 1998; 339:1869 –1874; N Engl J Med 1999;341:1106 –1111). Even systematic reviews and meta-analyses of the available trials have reached differing conclusions regarding the benefit of eradication therapy in this disorder (Br Med J 2000;321:659 – 664; Ann Intern Med 2001;134:361–369). From the results of the meta-analysis in the British Medical Journal, it seemed that H pylori eradication therapy conferred a small but significant benefit in functional dyspepsia. In an update of this meta-analysis (Am J Gastroenterol 2003;98:2621–2626), further eligible trials were identified and incorporated without affecting the pooled efficacy of eradication therapy. However, the majority of the RCTs included in these meta-analyses were conducted in secondary or tertiary care settings, meaning that the population studied may represent a more severe spectrum of disease than those encountered in primary care, and the results may therefore not be generalizable to patients consulting a physician in this setting. The present study is, therefore, important because it was conducted entirely in primary care, and still demonstrates a clear benefit of eradication therapy in functional dyspepsia. The fact that a 10-day treatment course can have a significant, although modest, benefit in terms of an improvement in symptoms of functional dyspepsia after 12 months of follow-up is clinically relevant to both patients and physicians. However, there are some limitations of the study. First, efficacy was only judged at a single time point during follow-up, rather than at several points throughout the study. Second, the investigators used a questionnaire that has not been well-validated outside of Brazil to determine response to therapy. Third, patients were recruited via a single center, which may limit generalizability. Finally, the authors did not conduct a true intention-to-treat analysis. If this is performed, then 47% of PPI triple therapy patients achieved the primary end point, compared with 35.5% of those randomized to PPI and placebo antibiotics, yielding an absolute difference of 11.5%, and a number needed to treat of 9, rather than 8. Despite these minor criticisms, this trial adds further evidence to support the efficacy of eradication therapy in H pylori-positive patients with functional dyspepsia. The benefit has remained more or less the same as more studies have accumulated. However, it is more modest than the effect of eradication therapy in the setting of duodenal or gastric ulcer (Am J Gastroenterol 2004;99: 1833–1855) in terms of the number needed to treat, suggesting the causative role of H pylori in functional dyspepsia is less clear cut than in peptic ulcer disease. Nevertheless, the benefit of H pylori eradication in functional dyspepsia has now been demonstrated in primary, secondary, and tertiary care settings for periods of up to

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12 months. Current guidelines provide conflicting recommendations concerning testing individuals with functional dyspepsia for H pylori, with the American College of Gastroenterology taking no definite stance (Am J Gastroenterol 2007;102:1808 –1825), whereas the European H pylori Study Group’s latest guidelines recommend this approach (Gut 2007;56:772–781). This disparity in guidelines exists despite evidence published ⬎10 years ago suggesting that treating H pylori in functional dyspepsia improves symptoms and is cost effective (Br Med J 2000; 321:659 – 664). In addition, the American College of Gastroenterology guideline has not been updated in ⬎5 years. Given the current data from meta-analyses and large RCTs, it is clear that testing for H pylori and treating it, if present, in functional dyspepsia is beneficial and appropriate. In summary, this study has shown that eradicating H pylori in primary care patients with functional dyspepsia using PPI triple therapy is more effective than PPI and placebo antibiotics. Given that the benefit appeared to last up to 12 months after treatment, this will have significant cost implications for the management of functional dyspepsia in this setting; therefore, a course of eradication therapy should now be the accepted standard of care for all H pylori-positive patients with functional dyspepsia. Guidelines for the management of functional dyspepsia need to be updated and standardized, in terms of recommending this approach ALEXANDER C. FORD Leeds Gastroenterology Institute St. James’s University Hospital Leeds, United Kingdom

OVERUTILIZATION OF ENDOSCOPIC SURVEILLANCE IN NONDYSPLASTIC BARRETT’S: TOO MUCH OF A GOOD THING? Crockett SD, Lipkus IM, Bright ST, et al. Overutilization of endoscopic surveillance in nondysplastic Barrett’s esophagus: a multicenter study. Gastrointest Endosc 2012;75:23–31. Endoscopic surveillance for Barrett’s esophagus is currently accepted as an appropriate and indicated medical intervention. A number of prior studies have demonstrated a clear association between Barrett’s esophagus and esophageal adenocarcinoma (Gastroenterology 2000; 119:333–338). Surveillance is therefore recommended, with the understanding that the development of dysplasia represents an intermediate stage in the evolution from nondysplastic Barrett’s to esophageal adenocarcinoma. Although no prospective studies to date exist demonstrating that surveillance does indeed result in a reduction in esophageal cancer-related mortality (Gastroenterology 2004; 127:310 –330), surveillance is currently recommended given the strength of available evidence and strong biologic plausibility. Current guidelines put forth by the American Gas-