Sander Veldhuyzen van Zanten

The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus.

OBJECTIVES:A globally acceptable definition and classification of gastroesophageal reflux disease (GERD) is desirable for research and clinical practice. The aim of this initiative was to develop a consensus definition and classification that would be useful for patients, physicians, and regulatory agencies.METHODS:A modified Delphi process was employed to reach consensus using repeated iterative voting. A series of statements was developed by a working group of five experts after a systematic review of the literature in three databases (Embase, Cochrane trials register, Medline). Over a period of 2 yr, the statements were developed, modified, and approved through four rounds of voting. The voting group consisted of 44 experts from 18 countries. The final vote was conducted on a 6-point scale and consensus was defined a priori as agreement by two-thirds of the participants.RESULTS:The level of agreement strengthened throughout the process with two-thirds of the participants agreeing with 86%, 88%, 94%, and 100% of statements at each vote, respectively. At the final vote, 94% of the final 51 statements were approved by 90% of the Consensus Group, and 90% of statements were accepted with strong agreement or minor reservation. GERD was defined as a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications. The disease was subclassified into esophageal and extraesophageal syndromes. Novel aspects of the new definition include a patient-centered approach that is independent of endoscopic findings, subclassification of the disease into discrete syndromes, and the recognition of laryngitis, cough, asthma, and dental erosions as possible GERD syndromes. It also proposes a new definition for suspected and proven Barretts esophagus.CONCLUSIONS:Evidence-based global consensus definitions are possible despite differences in terminology and language, prevalence, and manifestations of the disease in different countries. A global consensus definition for GERD may simplify disease management, allow collaborative research, and make studies more generalizable, assisting patients, physicians, and regulatory agencies.

Eradication of Helicobacter pylori using one-week triple therapies combining omeprazole with two antimicrobials: the MACH I Study.

Background.Eradication of Helicobacter pylori provides potential cure in the majority of patients with peptic ulcer disease, and eradication rates of more than 90% have been reported, using omeprazole in combination with two antimicrobials. The choice of antimicrobials, dose regimen and duration of treatment have varied between studies, however, and an optimal treatment still has to be established.

Lack of Effect of Treating Helicobacter pylori Infection in Patients with Nonulcer Dyspepsia

BACKGROUND It is uncertain whether treatment of Helicobacter pylori infection relieves symptoms in patients with nonulcer, or functional, dyspepsia. METHODS We conducted a double-blind, multicenter trial of patients with H. pylori infection and dyspeptic symptoms (moderate-to-very-severe pain and discomfort centered in the upper abdomen). Patients were excluded if they had a history of peptic ulcer disease or gastroesophageal reflux disease and had abnormal findings on upper endoscopy. Patients were randomly assigned to seven days of treatment with 20 mg of omeprazole twice daily, 1000 mg of amoxicillin twice daily, and 500 mg of clarithromycin twice daily or with omeprazole alone and then followed up for one year. Treatment success was defined as the absence of dyspeptic symptoms or the presence of minimal symptoms on any of the 7 days preceding the 12-month visit. RESULTS Twenty of the 348 patients were excluded after randomization because they were not infected with H. pylori, were not treated, or had no data available. For the remaining 328 patients (164 in each group), treatment was successful for 27.4 percent of those assigned to receive omeprazole and antibiotics and 20.7 percent of those assigned to receive omeprazole alone (P=0.17; absolute difference between groups, 6.7 percent; 95 percent confidence interval, -2.6 to 16.0). After 12 months, gastritis had healed in 75.0 percent of the patients in the group given omeprazole and antibiotics and in 3.0 percent of the patients in the omeprazole group (P<0.001); the respective rates of H. pylori eradication were 79 percent and 2 percent. In the group given omeprazole and antibiotics, the rate of treatment success among patients with persistent H. pylori infection was similar to that among patients in whom the infection was eradicated (26 percent vs. 31 percent). There were no significant differences between the groups in the quality of life after treatment. CONCLUSIONS In patients with nonulcer dyspepsia, the eradication of H. pylori infection is not likely to relieve symptoms.

The MACH2 study: Role of omeprazole in eradication of Helicobacter pylori with 1-week triple therapies

BACKGROUND & AIMS The role of omeprazole in triple therapy and the impact of Helicobacter pylori resistance on treatment outcome are not established. This study investigated the role of omeprazole and influence of primary H. pylori resistance on eradication and development of secondary resistance. METHODS Patients (n = 539) with a history of duodenal ulcer and a positive H. pylori screening test result were randomized into 4 groups. OAC group received 20 mg omeprazole, 1000 mg amoxicillin, and 500 mg clarithromycin; OMC group received 20 mg omeprazole, 400 mg metronidazole, and 250 mg clarithromycin; and AC (amoxicillin, 1000 mg, and clarithromycin, 500 mg) and MC (metronidazole, 400 mg, and clarithromycin, 250 mg) groups received no omeprazole. All doses were administered twice daily for 1 week. H. pylori status was assessed before and after therapy by 13C-urea breath test. Susceptibility testing was performed at entry and in patients with persistent infection after therapy. RESULTS Eradication (intention to treat [n = 514]/per protocol [n = 449]) was 94%/95% for OAC, 26%/25% for AC (P < 0.001), 87%/91% for OMC, and 69%/72% for MC (P < 0.001). Primary resistance was 27% for metronidazole, 3% for clarithromycin, and 0% for amoxicillin. Eradication in primary metronidazole-susceptible/-resistant strains was 95%/76% for OMC and 86%/43% for MC. Secondary metronidazole and clarithromycin resistance each developed in 12 patients: 8 treated with omeprazole and 16 without omeprazole. CONCLUSIONS Addition of omeprazole achieves high eradication rates, reduces the impact of primary resistance, and may decrease the risk of secondary resistance compared with regimens containing only two antibiotics.

Metronidazole resistance in Helicobacter pylori is due to null mutations in a gene (rdxA) that encodes an oxygen‐insensitive NADPH nitroreductase

Metronidazole (Mtz) is a critical component of combination therapies that are used against Helicobacter pylori, the major cause of peptic ulcer disease. Many H. pylori strains are Mtz resistant (MtzR), however, and here we show that MtzR results from loss of oxygen‐insensitive NADPH nitroreductase activity. The underlying gene (called ‘rdxA’) was identified in several steps: transformation of Mtz‐susceptible (MtzS) H. pylori with cosmids from a MtzR strain, subcloning, polymerase chain reaction (PCR) and DNA sequencing. We also found that (i) E. coli (normally MtzR) was rendered MtzS by a functional H. pylori rdxA gene; (ii) introduction of rdxA on a shuttle vector plasmid into formerly MtzRH. pylori rendered it MtzS; and (iii) replacement of rdxA in MtzSH. pylori with an rdxA::camR null insertion allele resulted in a MtzR phenotype. The 630 bp rdxA genes of five pairs of H. pylori isolates from infections that were mixed (MtzR/MtzS), but uniform in overall genotype, were sequenced. In each case, the paired rdxA genes differed from one another by one to three base substitutions. Typical rdxA genes from unrelated isolates differ by ≈ 5% in DNA sequence. Therefore, the near identity of rdxA genes from paired MtzR and MtzS isolates implicates de novo mutation, rather than horizontal gene transfer in the development of MtzR. Horizontal gene transfer could readily be demonstrated under laboratory conditions with mutant rdxA alleles. RdxA is a homologue of the classical nitroreductases (CNRs) of the enteric bacteria, but differs in cysteine content (6 vs. 1 or 2 in CNRs) and isoelectric point (pI = 7.99 vs. 5.4–5.6), which might account for its reduction of low redox drugs such as Mtz. We suggest that many rdxA (MtzR) mutations may have been selected by prior use of Mtz against other infections. H. pylori itself is an early risk factor for gastric cancer; the possibility that its carcinogenic effects are exacerbated by Mtz use, which is frequent in many societies, or the reduction of nitroaromatic compounds to toxic, mutagenic and carcinogenic products, may be of significant concern in public health.

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.

Abstract Objective: To determine whether a “test for Helicobacter pylori and treat” strategy improves symptoms in patients with uninvestigated dyspepsia in primary care. Design: Randomised placebo controlled trial. Setting: 36 family practices in Canada. Participants: 294 patients positive for H pylori (13C- urea breath test) with symptoms of dyspepsia of at least moderate severity in the preceding month. Intervention: Participants were randomised to twice daily treatment for 7 days with omeprazole 20 mg, metronidazole 500 mg, and clarithromycin 250 mg or omeprazole 20 mg, placebo metronidazole, and placebo clarithromycin. Patients were then managed by their family physicians according to their usual care. Main outcome measures: Treatment success defined as no symptoms or minimal symptoms of dyspepsia at the end of one year. Societal healthcare costs collected prospectively for a secondary evaluation of actual mean costs. Results: In the intention to treat population (n=294), eradication treatment was significantly more effective than placebo in achieving treatment success (50% v 36%; P=0.02; absolute risk reduction=14%; number needed to treat=7, 95% confidence interval 4 to 63). Eradication treatment cured H pylori infection in 80% of evaluable patients. Treatment success at one year was greater in patients negative for H pylori than in those positive for H pylori (54% v 39%; P=0.02). Eradication treatment reduced mean annual cost by

Canadian Consensus Conference on the management of gastroesophageal reflux disease in adults - Update 2004

C53 (86 to 180) per patient. Conclusions: A “test for H pylori with 13C-urea breath test and eradicate” strategy shows significant symptomatic benefit at 12 months in the management of primary care patients with uninvestigated dyspepsia. What is already known on this topic Dyspepsia is a common problem in primary health care, although controversy exists about its definition Studies of H pylori eradication in patients with uninvestigated dyspepsia have shown reduced need for endoscopy and thus significant cost savings compared with a strategy of prompt endoscopy The “test for H pylori and treat” strategy has been recommended for uninvestigated dyspepsia, but there have been no randomised controlled trials showing improvement in symptoms What this study adds When given eradication treatment in primary care, H pylori positive patients with uninvestigated dyspepsia show improvement in overall dyspepsia symptoms at 12 months This supports the “test for H pylori and treat” strategy

Canadian Helicobacter Study Group Consensus Conference: Update on the Approach to Helicobacter Pylori Infection in Children and Adolescents – an Evidence-Based Evaluation

BACKGROUND Gastroesophageal reflux disease (GERD) is the most prevalent acid-related disorder in Canada and is associated with significant impairment of health-related quality of life. Since the last Canadian Consensus Conference in 1996, GERD management has evolved substantially. OBJECTIVE To develop up-to-date evidence-based recommendations relevant to the needs of Canadian health care providers for the management of the esophageal manifestations of GERD. CONSENSUS PROCESS A multidisciplinary group of 23 voting participants developed recommendation statements using a Delphi approach; after presentation of relevant data at the meeting, the quality of the evidence, strength of recommendation and level of consensus were graded by participants according to accepted principles. OUTCOMES GERD applies to individuals who reflux gastric contents into the esophagus causing symptoms sufficient to reduce quality of life, injury or both; endoscopy-negative reflux disease applies to individuals who have GERD and a normal endoscopy. Uninvestigated heartburn-dominant dyspepsia - characterised by heartburn or acid regurgitation - includes erosive esophagitis or endoscopy-negative reflux disease, and may be treated empirically as GERD without further investigation provided there are no alarm features. Lifestyle modifications are ineffective for frequent or severe GERD symptoms; over-the-counter antacids or histamine H2-receptor antagonists are effective for some patients with mild or infrequent GERD symptoms. Proton pump inhibitors are more effective for healing and symptom relief than histamine H2-receptor antagonists; their efficacy is proportional to their ability to reduce intragastric acidity. Response to initial therapy - a once-daily proton pump inhibitor unless symptoms are mild and infrequent (fewer than three times per week) - should be assessed at four to eight weeks. Maintenance medical therapy should be at the lowest dose and frequency necessary to maintain symptom relief; antireflux surgery is an alternative for a small proportion of selected patients. Routine testing for Helicobacter pylori infection is unnecessary before starting GERD therapy. GERD is associated with Barretts epithelium and esophageal adenocarcinoma but the risk of malignancy is very low. Endoscopic screening for Barretts epithelium may be considered in adults with GERD symptoms for more than 10 years; Barretts epithelium and low-grade dysplasia generally warrant surveillance; endoscopic or surgical management should be considered for confirmed high-grade dysplasia or malignancy. CONCLUSION Prospective studies are needed to investigate clinically relevant risk factors for the development of GERD and its complications; GERD progression, on and off therapy; optimal management strategies for typical GERD symptoms in primary care patients; and optimal management strategies for atypical GERD symptoms, Barretts epithelium and esophageal adenocarcinoma.

Efficacy of cisapride and domperidone in functional (nonulcer) dyspepsia: a meta-analysis

As an update to previously published recommendations for the management of Helicobacter pylori infection, an evidence-based appraisal of 14 topics was undertaken in a consensus conference sponsored by the Canadian Helicobacter Study Group. The goal was to update guidelines based on the best available evidence using an established and uniform methodology to address and formulate recommendations for each topic. The degree of consensus for each recommendation is also presented. The clinical issues addressed and recommendations made were: population-based screening for H. pylori in asymptomatic children to prevent gastric cancer is not warranted; testing for H. pylori in children should be considered if there is a family history of gastric cancer; the goal of diagnostic interventions should be to determine the cause of presenting gastrointestinal symptoms and not the presence of H. pylori infection; recurrent abdominal pain of childhood is not an indication to test for H. pylori infection; H. pylori testing is not required in patients with newly diagnosed gastroesophageal reflux disease; H. pylori testing may be considered before the use of long-term proton pump inhibitor therapy; testing for H. pylori infection should be considered in children with refractory iron deficiency anemia when no other cause has been found; when investigation of pediatric patients with persistent or severe upper abdominal symptoms is indicated, upper endoscopy with biopsy is the investigation of choice; the 13C-urea breath test is currently the best noninvasive diagnostic test for H. pylori infection in children; there is currently insufficient evidence to recommend stool antigen tests as acceptable diagnostic tools for H. pylori infection; serological antibody tests are not recommended as diagnostic tools for H. pylori infection in children; first-line therapy for H. pylori infection in children is a twice-daily, triple-drug regimen comprised of a proton pump inhibitor plus two antibiotics (clarithromycin plus amoxicillin or metronidazole); the optimal treatment period for H. pylori infection in children is 14 days; and H. pylori culture and antibiotic sensitivity testing should be made available to monitor population antibiotic resistance and manage treatment failures.

Double balloon enteroscopy and capsule endoscopy for obscure gastrointestinal bleeding: An updated meta-analysis

Background:The efficacy of prokinetic agents in functional (nonulcer) dyspepsia has been questioned based on recent trial results. We performed a meta-analysis to determine the efficacy of cisapride and domperidone in functional dyspepsia.METHODS:Computer and manual searching was used to identify placebo-controlled studies that included >20 patients. The statistical analysis focused on: global assessment by the investigator, epigastric pain, early satiety, abdominal distension and nausea (all rated on four-point scales). Results are reported as odds ratios (OR) in favor of treatment. Regression analysis was performed to evaluate possible effect modifiers. The relationship between improvement in gastric emptying and symptoms was also evaluated.RESULTS:For cisapride, 17 studies met the inclusion criteria, but varying numbers of studies had to be used for the different outcome measures. For all outcome measures, there was a statiscally significant benefit in favor of cisapride: global assessment of improvement by the investigator or patient (OR 2.9, 95% CI 1.5–5.8), epigastric pain (OR 0.19, 95% CI 0.05–0.7), early satiety (OR 0.18, 95% CI 0.9–0.4), abdominal distension (OR 0.32, 95% CI 0.1–0.7), and nausea (OR 0.26, 95% CI 0.1–0.5). Age of patient, year of publication, and country where study was performed had only small modifying effects. There were insufficient data to determine whether there is a relationship between improvement in gastric emptying and response to treatment. For domperidone, four of eight studies could be used for the analysis of global assessment of improvement by the investigator. This showed an OR of 7.0 (95% CI 3.6–16) in favor of domperidone.CONCLUSIONS:Both cisapride and domperidone seem to be efficacious in functional dyspepsia, although this conclusion is largely based on global assessment by the investigator, which may not be an optimal outcome measure.