White Paper AGA: Functional Dyspepsia.

Functional dyspepsia remains a major challenge for clinicians with no approved drugs available in the Western World. In October 2016, a meeting was held in Washington, DC, sponsored by the American Gastroenterological Association's Center for Diagnostics and Therapeutics, which included members of the Food and Drug Administration (FDA) and the pharmaceutical industry, experts in FD, and representatives of patient organizations. This white paper summarizes our current status, progress with a validated patient reported outcome instrument in functional dyspepsia, future directions and needs.

Arbaclofen placarbil in GERD: a randomized, double-blind, placebo-controlled study.

OBJECTIVES: It has been shown that arbaclofen placarbil (AP) inhibits reflux in gastroesophageal reflux disease (GERD) following single oral dosing. This study evaluated the efficacy and safety of AP over 4 weeks in subjects with symptomatic GERD. METHODS: One hundred fifty-six subjects with heartburn and/or regurgitation ≥3 days/week and either no history of taking proton pump inhibitors (PPIs naive, n=58) or at least partial symptom response to PPI therapy (PPI responsive, n=98) were enrolled in this randomized, double-blind, placebo-controlled trial. All GERD therapies including PPIs were discontinued 2 weeks before randomization to AP 20, 40, or 60 mg daily, 30 mg twice daily, or placebo for 4 weeks. Randomization was stratified by prior PPI use. RESULTS: In the primary analysis, change from baseline in weekly heartburn events between AP and placebo for the entire study group was not statistically significant. However, a significant interaction was observed between prior PPI use and response to AP treatment. In pre-planned secondary analyses of the PPI-responsive subgroup, percent reductions from baseline in weekly heartburn events were greater for each AP dose vs. placebo (P<0.05) and the percentage of subjects who reported complete resolution of heartburn during week 4 was higher in each AP treatment group (21, 28, 30, and 50% for AP 20, 40, 60 mg daily, and 30 mg twice daily, respectively) compared with placebo (6%) (P<0.05 for 30 mg twice daily). Corresponding analyses of the PPI-naive subgroup showed no significant differences. AP was well tolerated; withdrawals due to adverse events were infrequent. CONCLUSIONS: AP was not superior to placebo in reducing the number of weekly heartburn events over 4 weeks in the primary analysis of the entire study population. Exploratory subgroup analyses suggest that response to PPI treatment before the study was associated with a response to AP treatment.

A second-order simulation model of the cost-effectiveness of managing dyspepsia in the United States.

BACKGROUND: The "gold-standard'' evidence of effectiveness for a clinical practice guideline is the randomized controlled trial (RCT), although RCTs have a limited ability to explore potential management strategies for a chronic disease where these interact over time. Modeling can be used to fill this gap, and models have become increasingly complex, with both dynamic sampling and representation of second-order uncertainty to provide more precise estimates. However, both simulation modeling and probabilistic sensitivity analysis are rarely used together. The objective of this study was to explore uncertainty in controversial areas of the 2005 American Gastroenterology Association position statement on the management of dyspepsia. METHODS: Individual sampling model, incorporating a second-order probabilistic sensitivity analysis. POPULATION: US adult patients presenting in primary care with dyspepsia. Interventions compared: empirical acid suppression, test and treat for Helicobacter pylori, initial endoscopy, acid suppression then endoscopy, test and treat then proton pump inhibitor (PPI) then endoscopy. OUTCOMES: Cost-effectiveness, quality-adjusted life years, and costs in US dollars from a societal perspective, measured over a 5-year period. DATA SOURCES: mainly Cochrane meta-analyses. RESULTS: Endoscopy was dominated at all ages by other strategies. PPI therapy was the most cost-effective strategy in 30-year-olds with a low prevalence of H. pylori. In 60-year-olds, H. pylori test and treat was the most cost-effective option. CONCLUSIONS: Acid suppression alone was more cost-effective than either endoscopy or H. pylori test and treat in younger dyspepsia patients with a low prevalence of infection.

Will the history and physical examination help establish that irritable bowel syndrome is causing this patient's lower gastrointestinal tract symptoms?

CONTEXT: Many individuals experience lower gastrointestinal tract symptoms, most commonly attributable to functional conditions. These individuals are frequently diagnosed with irritable bowel syndrome (IBS) based on their symptoms; however, some may require additional testing or referral to specialists before this diagnosis is made. OBJECTIVE: To systematically review the literature of the accuracy of individual symptoms and combinations of findings in diagnosing IBS. DATA SOURCES: Search of MEDLINE and EMBASE (up to June 2008) for prospective studies reporting on unselected cohorts of adult patients with lower gastrointestinal tract symptoms recorded before investigation. STUDY SELECTION: Studies prospectively evaluating accuracy of individual symptoms or combinations of findings compared with results from investigations of the lower gastrointestinal tract. DATA EXTRACTION: Two authors independently assessed studies and extracted data to estimate likelihood ratios (LRs) of individual symptoms and combinations of findings in diagnosing IBS. RESULTS: Ten studies evaluating 2355 patients were identified, with a summary prevalence of IBS following investigation of 57%. Individual symptom items yielded positive LRs from 1.2 (95% confidence interval [CI], 0.93-1.6) for passage of mucus per rectum to 2.1 (95% CI, 1.4-3.0) for looser stools at onset of abdominal pain and negative LRs from 0.29 (95% CI, 0.12-0.72) for no lower abdominal pain to 0.88 (95% CI, 0.72-1.1) for no passage of mucus per rectum in diagnosing IBS. The Manning criteria had a summary positive LR of 2.9 (95% CI, 1.3-6.4) and a summary negative LR of 0.29 (95% CI, 0.12-0.71). The Rome I criteria had a positive LR of 4.8 (95% CI, 3.6-6.5) and a negative LR of 0.34 (95% CI, 0.29-0.41). The Kruis scoring system provided a summary positive LR of 8.6 (95% CI, 2.9-26.0) and a summary negative LR of 0.26 (95% CI, 0.17-0.41). The Rome II and III criteria have not been studied. CONCLUSIONS: Individual symptoms have limited accuracy for diagnosing IBS in patients referred with lower gastrointestinal tract symptoms. The accuracy of the Manning criteria and Kruis scoring system were only modest. Despite strong advocacy for use of the Rome criteria, only the Rome I classification has been validated. Future research should concentrate on validating existing diagnostic criteria or developing more accurate ways of predicting a diagnosis of IBS without the need for investigation of the lower gastrointestinal tract.

Clinical Rationale for Confirmation Testing After Treatment of Helicobacter pylori Infection: Implications of Rising Antibiotic Resistance.

Helicobacter pylori (H pylori) infection is one of the most common chronic bacterial infections worldwide. International guidelines recommend H pylori eradication in several scenarios: patients with peptic ulcer disease, patients who have had endoscopic resection of early gastric cancer, and patients with a gastric mucosa-associated lymphoid tissue lymphoma (MALToma). There is variability among the guidelines for other conditions. Treatment options for H pylori infection include triple, quadruple, and sequential therapy. Ideally, patients in whom previous eradication attempts failed and those suspected to have resistant strains should be considered for antimicrobial sensitivity testing, which requires culture of gastric mucosal biopsies; such testing, however, has limited availability in the United States. Resistance rates vary by location depending on local antibiotic usage rates. As such, the success rates associated with different regimens vary throughout the world. Many patients with H pylori infection are asymptomatic, whereas others are diagnosed with the infection during evaluation of dyspeptic symptoms or following a diagnosis of peptic ulcer. Symptoms may not be an accurate indicator of treatment success. The American College of Gastroenterology (ACG) endorses the carbon 13-labeled urea breath test ((13)C-UBT) as the most reliable test to confirm H pylori eradication. This clinical roundtable monograph begins with an overview of H pylori infection and then discusses treatment, antibiotic resistance, management of patients with antibiotic resistance, and posttreatment testing, with a focus on the ACG guidelines.

Systematic review of patient-reported outcome instruments for gastroesophageal reflux disease symptoms.

Gastroesophageal reflux disease (GERD) symptoms are best assessed using patient-reported outcome (PRO) instruments. Guidance on developing well-defined and reliable instruments that capture optimal information from the patient's perspective was recently published by the US Food and Drug Administration and the European Medicines Agency. The aim of this systematic review was to identify and evaluate existing PRO instruments for GERD symptoms with regard to regulatory requirements. Systematic literature searches were conducted in PubMed and Embase to identify PRO instruments for GERD symptoms that have undergone psychometric evaluation. Content, construct and test-retest reliability, internal consistency, and responsiveness were evaluated in relation to regulatory recommendations. Supplementary searches were conducted to assess whether identified instruments had been used as clinical trial endpoint measures. The systematic literature searches identified 15 PRO instruments for GERD symptoms that have undergone psychometric evaluation. Eight were designed to evaluate GERD symptoms, two were to diagnose GERD, four were designed for both evaluative and diagnostic purposes, and one was designed for screening purposes. Five instruments were developed and reported to include most steps recommended by the Food and Drug Administration and European Medicines Agency, and have also been used as endpoint measures in clinical trials: the GERD Symptom Assessment Scale, the Nocturnal Gastro-oesophageal Reflux Disease Symptom Severity and Impact Questionnaire, the Reflux Questionnaire, the Reflux Disease Questionnaire, and the Proton pump inhibitor Acid Suppression Symptom test. Existing PRO instruments for GERD do not meet all the regulatory requirements for an outcome instrument in reflux trials and may need further validation.

Dysphagia in patients with erosive esophagitis: prevalence, severity, and response to proton pump inhibitor treatment.

BACKGROUND & AIMS: Dysphagia is considered an alarm symptom, raising the question of stricture or malignancy. We sought to determine the prevalence and severity of dysphagia in patients with uncomplicated erosive esophagitis and its response to therapy. METHODS: A total of 11,945 patients with endoscopically confirmed erosive esophagitis (Los Angeles grades A-D) participated in 5 double-blind, randomized, clinical trials evaluating the efficacy of up to 8 weeks of treatment with either once-daily esomeprazole 40 mg (n = 5068), esomeprazole 20 mg (n = 1243), omeprazole 20 mg (n = 3018), or lansoprazole 30 mg (n = 2616). The severity of dysphagia (4-point scale) was rated at baseline and at week 4. Esophagitis was classified as mild (grade A or B) or severe (grade C or D). RESULTS: At baseline, 4449 of 11,945 patients (37%) had dysphagia-43% of patients with severe esophagitis, and 35% of patients with mild esophagitis (odds ratio, 1.39; 95% confidence interval, 1.27-1.51, P < 0.001). Dysphagia resolved in 83% of patients after 4 weeks of proton pump inhibitor (PPI) treatment. Resolution of dysphagia was associated with a mean healing rate of 90% across all treatments. Seventeen percent of patients reported persistent dysphagia, and in these patients the healing rates were decreased significantly (mean 72%; P < 0.0001). CONCLUSIONS: Dysphagia is common in patients with erosive esophagitis but is not a reliable clinical predictor of severe erosive esophagitis. Dysphagia resolved with PPI therapy in most cases, but persistent dysphagia may indicate failed healing.

Symptom response and healing of erosive esophagitis with proton-pump inhibitors in patients with Helicobacter pylori infection.

OBJECTIVES: The aim of this article is to determine the severity of esophagitis and the response to treatment with proton-pump inhibitors in patients with and without evidence of Helicobacter pylori infection. METHODS: This retrospective analysis evaluated data collected in a randomized, double-blind clinical trial that assessed the efficacy and safety of once-daily esomeprazole 40 mg (n = 2,624) versus lansoprazole 30 mg (n = 2,617) for up to 8 wk in the treatment of reflux-associated erosive esophagitis. At baseline, erosive esophagitis was graded using the Los Angeles (LA) classification; serologic testing for H. pylori was performed using a FlexSure HP serum test. RESULTS: There were 14.7% of patients who were seropositive for H. pylori. The percentages of seropositive and seronegative patients with each grade of esophagitis were: LA grade A, 38%, 36%; LA grade B, 41%, 39%; LA grade C, 16%, 19%; and LA grade D, 5%, 6%, respectively. Severe heartburn was present at baseline in 42% of H. pylori-positive and 42% of H. pylori-negative patients. Life-table healing rates with esomeprazole were not influenced by H. pylori status (seropositive 92.6% (95% confidence interval: 89.8-95.4); seronegative 92.6% (95% confidence interval: 91.4-93.7)). The rates with esomeprazole were significantly higher than those with lansoprazole (seropositive 90.5% (95% confidence interval: 87.5-93.5); seronegative 88.5% (95% confidence interval: 87.1-89.8)) after adjusting for baseline H. pylori status (p = 0.001). CONCLUSIONS: The severity of erosive esophagitis at baseline was similar regardless of H. pylori seropositivity. Healing rates were not influenced by H. pylori status.

Comparison of inter- and intraobserver consistency for grading of esophagitis by expert and trainee endoscopists.

BACKGROUND: This study evaluated intra- and interobserver variability in the endoscopic scoring of esophagitis by using two grading schemes, the Los Angeles and Hetzel-Dent scales. METHODS: Three hundred twenty-five endoscopic photographs of esophagitis or healed esophagitis were randomly displayed twice to 9 endoscopist evaluators (4 experts, 5 trainees) by means of a CD-ROM. Evaluators scored each photograph by using both classification schemes. The analysis was based on the kappa (kappa) statistic as a measure of consistency. RESULTS: For trainees, intraobserver reproducibility was good (kappa = 0.436) when using the Los Angeles classification and marginal (kappa = 0.395) by using the Hetzel-Dent classification. For experts, intraobserver reproducibility was better by using both the Los Angeles (kappa = 0.545) and Hetzel-Dent classification (kappa = 0.552). Interobserver consistency for trainees was good when using both classifications (Los Angeles, kappa = 0.459; Hetzel-Dent, kappa = 0.427). Again, intraobserver reproducibility was better for experts when using both classifications (Los Angeles, kappa = 0.556, Hetzel-Dent, kappa = 0.571). By using the Los Angeles classification, only 5.1% and 7.5% of the photographs were interpreted to be more than 1 grade different from the mean grade for, respectively, experts and trainees. This same consistency was found by using the Hetzel-Dent classification scheme (experts 5.1%, trainees 10.2%). CONCLUSIONS: Reproducibility in grading esophagitis was good for both expert endoscopists and fellows, although there was greater consistency among the experts. Both the Los Angeles and Hetzel-Dent scoring systems are reproducible.

Minimizing recurrent peptic ulcer hemorrhage after endoscopic hemostasis: the cost-effectiveness of competing strategies.

OBJECTIVES: Controversy exists regarding the optimal strategy to minimize recurrent ulcer hemorrhage after successful endoscopic hemostasis. Our objective was to evaluate the cost-effectiveness of competing strategies for the posthemostasis management of patients with high risk ulcer stigmata. METHODS: Through decision analysis, we calculated the cost-effectiveness of four strategies: 1) follow patients clinically after hemostasis and repeat endoscopy only in patients with evidence of rebleeding (usual care); 2) administer intravenous proton pump inhibitors (i.v. PPIs) after hemostasis and repeat endoscopy only in patients with clinical signs of rebleeding; 3) perform second look endoscopy at 24 h in all patients with successful endoscopic hemostasis; and 4) perform selective second look endoscopy at 24 h only in patients at high risk for rebleeding as identified by the prospectively validated Baylor Bleeding Score. Probability estimates were derived from a systematic review of the medical literature. Cost estimates were based on Medicare reimbursement. Effectiveness was defined as the proportion of patients with rebleeding, surgery, or death prevented. RESULTS: The selective second look endoscopy strategy was the most effective and least expensive of the four competing strategies, and therefore dominated the analysis. The i.v. PPI strategy required 50% fewer endoscopies than the competing strategies, and became the dominant strategy when the rebleed rate with i.v. PPIs fell below 9% and when the cost of i.v. PPIs fell below 10 dollars/day. CONCLUSIONS: Compared with the usual practice of "watchful waiting," performing selective second look endoscopy in high risk patients may prevent more cases of rebleeding, surgery, or death at a lower overall cost. However, i.v. PPIs are likely to reduce the need for second look endoscopy and may be preferred overall if the rebleed rate and cost of i.v. PPIs remains low.

Esomeprazole (40 mg) compared with lansoprazole (30 mg) in the treatment of erosive esophagitis.

OBJECTIVES: Esomeprazole, the S isomer of omeprazole, has been shown to have higher healing rates of erosive esophagitis than omeprazole. This study compared esomeprazole with lansoprazole for the healing of erosive esophagitis and resolution of heartburn. METHODS: This United States multicenter, randomized, double blind, parallel group trial was performed in 5241 adult patients (intent-to-treat population) with endoscopically documented erosive esophagitis, which was graded by severity at baseline (Los Angeles classification). Patients received 40 mg of esomeprazole (n = 2624) or 30 mg of lansoprazole (n = 2617) once daily before breakfast for up to 8 wk. The primary efficacy endpoint was healing of erosive esophagitis at week 8. Secondary assessments included proportion of patients healed at week 4, resolution of investigator-recorded heartburn, time to first and time to sustained resolution of patient diary-recorded heartburn, and proportion of heartburn-free days and nights. RESULTS: Esomeprazole (40 mg) demonstrated significantly higher healing rates (92.6%, 95% CI = 91.5-93.6%) than lansoprazole (30 mg) (88.8%, 95% CI = 87.5-90.0%) at week 8 (p = 0.0001, life-table estimates, intent-to-treat analysis). A significant difference in healing rates favoring esomeprazole was also observed at week 4. The difference in healing rates between esomeprazole and lansoprazole increased as baseline severity of erosive esophagitis increased. Sustained resolution of heartburn occurred faster and in more patients treated with esomeprazole. Sustained resolution of nocturnal heartburn also occurred faster with esomeprazole. Both treatments were well tolerated. CONCLUSIONS: Esomeprazole (40 mg) is more effective than lansoprazole (30 mg) in healing erosive esophagitis and resolving heartburn. Healing rates are consistently high with esomeprazole, irrespective of baseline disease severity.