Peter A Bonis

Short-Term Treatment with Proton-Pump Inhibitors as a Test for Gastroesophageal Reflux Disease: A Meta-Analysis of Diagnostic Test Characteristics

Context Does symptomatic response to a proton-pump inhibitor (PPI) diagnose gastroesophageal reflux disease (GERD)? Contribution This meta-analysis included 15 studies that compared clinical response to a short course of a PPI with an objective measure of GERD, such as 24-hour pH monitoring. The positive likelihood of a symptomatic response detecting GERD ranged from 1.63 to 1.87. Sensitivity was 0.78 (95% CI, 0.66 to 0.86) and specificity was 0.54 (CI, 0.44 to 0.65). Implications Symptomatic response to short-term treatment with a PPI does not confidently diagnose GERD. The Editors Patients with symptoms suggestive of uncomplicated gastroesophageal reflux disease (GERD) are frequently treated empirically with lifestyle modifications and acid suppressive medications (1, 2), a strategy endorsed by several major medical societies (3, 4). Proton-pump inhibitors (PPIs) are often selected as first-line therapy because they are more effective than other available treatments for GERD (5). Furthermore, a rapid symptomatic response to normal-dose PPIs in patients with a presumptive diagnosis of GERD is commonly considered to validate the diagnosis (the PPI test) (6). However, the accuracy of a symptomatic response to PPIs compared with objective measures of GERD (such as ambulatory pH monitoring) is unclear. Studies addressing this issue have produced variable estimates of test accuracy (7-11). The differences may be due in part to several factors, such as the dose of the PPI used, population-specific features, specific end points, and the reference standard measures used to define GERD. A more thorough understanding of the characteristics of the PPI test is needed, especially from a primary care perspective, because the diagnosis of GERD can have significant clinical and economic implications. False-positive results on the PPI test, for example, may result in long-term administration of PPIs in patients who do not have GERD. In contrast, false-negative results may lead to undertreatment or incorrect diagnosis in patients with GERD. Our study sought to better define sensitivity, specificity, and predictive values of the PPI test for GERD while delineating factors that have a bearing on test accuracy. We performed a systematic review and meta-analysis of diagnostic test characteristics by using responses to PPI treatment as a test to compare with several objective measures of GERD. Methods Search Strategy Many symptoms have been attributed to gastroesophageal reflux. As a general rule, the term GERD is applied to patients with symptoms suggestive of reflux or complications of reflux but not necessarily with esophageal inflammation (12). We sought studies that enrolled patients on the basis of symptoms that were suggestive of GERD. Studies were identified by searching the MEDLINE database (1 January 1980 through 1 July 2003) and the Cochrane Controlled Trial Register. Search terms were omeprazole, lansoprazole, pantoprazole, rabeprazole, and esomeprazole, expanded to randomized, controlled trials, random allocation, double blind, single blind, comparative studies, esophageal motility disorders, or esophagitis. Additional search terms were GERD or GORD, expanded to diagnosis, reproducibility of results, false negative reactions, false positive reactions, logistic models, regression analysis, predictive value, sensitivity and specificity, accuracy, screening, and likelihood ratio (13). The searches were limited to English-language studies performed in adults (age 18 years). We reviewed the bibliographies of relevant studies to search for additional eligible studies. Only data accessible in peer-reviewed journals were included to minimize potential sources of bias and inaccuracy (14). Inclusion Criteria We included studies that assessed a symptomatic response in adults with a presumptive diagnosis of GERD (on the basis of presenting symptoms and history) who were treated with a PPI and who also underwent objective testing for GERD with 24-hour pH monitoring or endoscopy or both. We also evaluated studies that used a structured symptom scoring system as the reference standard, a method that has been proposed to be useful for discriminating patients with GERD from those with other causes of symptoms (15-17). These studies focused mostly on patients with dyspepsia, in whom the symptom scores were used to distinguish patients with reflux-like symptoms from those with other symptom characteristics. Such studies were included if the outcomes after PPI treatment in patients with GERD-like symptoms could be compared with the outcomes of patients with other symptom characteristics and if patients had been included irrespective of their symptom characteristics. Exclusion Criteria Studies were excluded if they focused only on children (age <18 years), if they included only patients with complications caused by GERD (such as esophageal strictures, severe esophagitis, Barrett esophagus), patients with alarm symptoms (such as anemia or dysphagia), patients with extraesophageal symptoms of GERD (such as asthma or laryngitis), patients suspected of having cardiovascular disease, or patients in whom a symptomatic response to the PPI could not be correlated with any of the objective tests for GERD (24-hour pH monitoring, upper endoscopy, or a symptom score). Data Extraction Studies were screened for inclusion by one author. Final decisions on exclusion were made by consensus with 2 of the other authors. Two investigators independently extracted the data. Information extracted included patient characteristics, study design, setting, specific type and dose of medication, duration of treatment, and definitions of outcomes. Numbers were extracted directly from the tables or derived from percentages if only the total number of patients was available. Data were recorded separately for the appropriate treatment group in studies with a randomized or crossover design. Discrepancies were resolved by discussion until consensus was achieved for all data. Quality Assessment of Studies Studies included in the meta-analysis were assessed for quality, as suggested by a previously reported standard (18). We particularly focused on whether the authors clearly defined normal and abnormal results according to the reference standard, whether the study sample included those with and without GERD according to the reference standard, whether the authors adequately described how the reference tests were performed, whether test results were interpreted appropriately, whether the report presented the results with sufficient detail so that the study could be replicated, and whether the outcome measures and objective measure of GERD were consistent with accepted standards for the evaluation of GERD (12). Our study selection criteria required fulfillment of most of the quality standards. Definition of PPI Treatment Success as a Diagnostic Test The definition of a symptomatic response to a PPI was based on criteria defined in the individual reports. Whenever possible, we chose definitions that would reasonably be interpreted as representing success in clinical practice (Table 1). As a general rule, we considered complete relief of heartburn as representing success because it represents a reasonable end point in clinical practice. Table 1. Studies of Patients with Symptoms Suggestive of Gastroesophageal Reflux Disease in Whom the Study Outcome Is Symptom Relief with Short-Term Normal- or High-Dose Proton-Pump Inhibitor Treatment Reference Standards for GERD The following reference standards for GERD were used in this study, all of which were based on commonly accepted measures (12). Ambulatory Monitoring Ambulatory esophageal pH monitoring is generally considered to provide the most objective measurement of pathologic reflux. Results were considered to be abnormal if an esophageal pH less than 4.0 was recorded during more than 4% of the time during a 24-hour period. This definition of esophageal pH is consistent with widely accepted standards (32). Some investigators have used a symptom index in which symptoms are correlated to episodes of esophageal acidification (pH < 4.0) while patients are in the erect or supine position. A symptom index greater than 50% is considered to be abnormal (10, 23). A related measure (symptom associated probability) has also been described (33, 34). Some patients may have increased sensitivity to esophageal acid exposure, thereby developing typical symptoms of GERD without abnormal esophageal acid exposure, as assessed by ambulatory pH monitoring. The clinical response to acid suppression in such patients is similar to that in patients without esophageal hypersensitivity (5). As a result, reference values and interpretation of ambulatory esophageal pH monitoring continue to undergo evaluation. Upper Endoscopy Gastroesophageal reflux disease is also suggested by findings on upper endoscopy (esophagogastroduodeno-scopy [EGD]). Esophageal erosions, ulcers, Barrett esophagus, or strictures suggest the presence of GERD. However, results are frequently normal in patients with symptoms of GERD and abnormal esophageal acid exposure (32). Gastroesophageal reflux disease was considered to be present in studies reporting esophagitis according to one of the commonly used classification systems, such as the Savary, Los Angeles, Berstad, or Hetzel-Dent grading systems (30, 31, 35, 36). Endoscopy was considered to be diagnostic of GERD in patients with supporting clinical features who had at least grade I esophagitis in one of the scoring systems. Because our study focused on the diagnosis of GERD that might safely be treated empirically, studies that focused exclusively on patients with severe or complicated esophagitis (such as Savary III or IV or Los Angeles C or D) after selection with endoscopy were excluded. Once recognized, this group of patients not only needs further investigation but might also be most likely to respond clinically to PPI treatmen

Variation in prevalence, diagnostic criteria, and initial management options for eosinophilic gastrointestinal diseases in the United States

Objectives: Variation in the prevalence of eosinophilic gastrointestinal diseases in different geographical regions has not been extensively studied. The aim of the present study was to define the regional and national prevalence of eosinophilic gastrointestinal diseases, and differences in practice approaches. Patients and Methods: We administered a survey electronically to members of the American College of Gastroenterology, the American Academy of Allergy, Asthma, and Immunology, and the North American Society Pediatric Gastroenterology, Hepatology, and Nutrition. Questions pertained to the number and proportion of patients seen with eosinophilic gastroenteritis or colitis and eosinophilic esophagitis (EoE), and methods used to diagnose and treat these conditions. Results: A total of 1836 physicians responded from 10,874 requests (17% response). Extrapolating responses from our US sample, we estimated an overall prevalence of 52 and 28/100,000 for EoE and eosinophilic gastroenteritis or colitis. The patient burden of EoE is higher in urban (0.58) and suburban (0.44) compared with rural settings (0.36, P < 0.0065), observations consistent with other allergic disorders. There was also increased prevalence in northeast region when calculated by prevalence per 100,000. There was considerable variability in criteria and initial treatment options used to diagnose EoE. Only one-third of respondents reported using diagnostic criteria proposed in a 2007 consensus document. Seventy-one and 35% of respondents reported treating some patients with EoE with a food elimination or elemental diet, respectively. Conclusions: EoE is diagnosed more often in northeastern states and urban areas. There is considerable variability in diagnostic criteria and initial treatment approach supporting the need for additional clinical trials and consensus development.

Abscesses in Crohn's disease. Outcome of medical versus surgical treatment

Goals: To compare the long-term outcome of medical, percutaneous, and surgical treatment of abdominal and pelvic abscesses complicating Crohns disease. Study: All patients with Crohns disease and an abdominal abscess treated at one institution during a 10-year period were retrospectively identified. We reviewed hospital and outpatient records and contacted patients for telephone interviews. Outcome measures included abscess recurrence, subsequent surgery for Crohns disease, and medications used at the time of most recent follow-up. Results: Fifty-one subjects were identified, with a mean follow-up of 3.75 years. Fewer patients developed recurrent abscesses after initial surgical drainage and bowel resection (12%) than patients treated with medical therapy only or percutaneous drainage (56%) (p = 0.016), One half of the patients treated nonoperatively ultimately required surgery, whereas only 12% of those treated with initial surgery required reoperation during the follow-up period (p = 0.010). Most failures of nonoperative therapy occurred within 3 months. Medication use was similar between the treatment groups at the time of most recent follow-up. Conclusions: In this series, surgical management of abscesses in Crohns disease was more effective than medical treatment or percutaneous drainage for prevention of abscess recurrence. However, nonoperative therapy prevented subsequent surgery in half of the patients and may be a reasonable treatment option for some patients.

A randomized controlled trial of colchicine plus ursodiol versus methotrexate plus ursodiol in primary biliary cirrhosis: Ten‐year results

Primary biliary cirrhosis frequently progresses despite treatment with ursodeoxycholic acid (UDCA), the only approved therapy. Previous studies suggested that colchicine and methotrexate may improve biochemical tests of liver function, symptoms, and liver histology. The aim of the present study was to determine if the addition of colchicine or methotrexate to UDCA would improve survival free of liver transplantation. Eighty‐five patients with histologically confirmed primary biliary cirrhosis whose serum alkaline phosphatase levels were at least twice the normal level and who were not yet candidates for liver transplantation were randomly assigned to receive colchicine or methotrexate in a double‐blind study. UDCA was administered to all patients after 2 years. The primary end point was survival free of liver transplantation. Patients were followed up for a total of up to 10 years or until treatment failure. Data were analyzed on an intention‐to‐treat basis. Transplant‐free survival was similar in both groups: 0.57 for colchicine plus UDCA and 0.44 for methotrexate plus UDCA, results that are similar to those predicted by the Mayo prognostic model. Significant improvement in liver biochemical tests and liver histology was observed in a subset of patients in both treatment groups who remained in the study for all 10 years. In conclusion, neither colchcine plus UDCA nor methotrexate plus UDCA improved survival beyond that predicted by the Mayo prognostic model. However, clinical, histologic, and biochemical improvement observed among those who remained in the study for 10 years suggests a possible benefit of these drugs in a subset of patients. (HEPATOLOGY 2004;39:915–923.)

Short-term treatment of gastroesophageal reflux disease.

OBJECTIVE: To investigate the efficacy of acid suppressant drugs in the empirical treatment of gastroesophageal reflux disease (GERD) and in the treatment of endoscopy-negative reflux disease (ENRD).DESIGN: MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched. Bibliographies were reviewed.SETTING: Studies were eligible that compared the short-term use of proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) with each other or with placebo in adults with GERD who were enrolled irrespective of endoscopic findings (empirical cases) or in whom endoscopy showed no signs of esophagitis (endoscopy-negative cases).MEASUREMENTS: Of 1,408 studies, only 13 could be included for meta-analysis. Data on 3,433 patients empirically treated for GERD and 2,520 patients treated for ENRD were extracted. The primary endpoint was relief of heartburn.MAIN RESULTS: In the empirical treatment of GERD, the summary relative risk (sRR) for symptom relief from H2RAs versus placebo was 0.77 (95% confidence interval [95% CI], 0.60 to 0.99). RR in the only placebo-controlled PPI trial was 0.35 (95% CI, 0.26 to 0.46). The sRR for standard dose PPIs versus H2RAs was 0.55 (95% CI, 0.44 to 0.68). In treatment of ENRD, both PPis (sRR, 0.64; 95% CI, 0.52 to 0.79) and H2RAs (sRR, 0.78; 95% CI, 0.62 to 0.97) were superior to placebo, and PPis were superior to H2RAs (sRR, 0.81; 95% CI, 0.70 to 0.95).CONCLUSIONS: Acid suppressant therapy (with a PPI or an H2RA) is more effective than placebo for short-term relief of heartburn in patients with persistent symptoms who are treated empirically for GERD and in those in whom esophagitis was excluded after endoscopy. The benefit of PPIs compared with H2RAs is more pronounced in patients treated empirically.

Association of a clinical knowledge support system with improved patient safety, reduced complications and shorter length of stay among Medicare beneficiaries in acute care hospitals in the United States

BACKGROUND Electronic clinical knowledge support systems have decreased barriers to answering clinical questions but there is little evidence as to whether they have an impact on health outcomes. METHODS We compared hospitals with online access to UpToDate with other acute care hospitals included in the Thomson 100 Top Hospitals Database (Thomson database). Metrics used in the Thomson database differentiate hospitals on a variety of performance dimensions such as quality and efficiency. Prespecified outcomes were risk-adjusted mortality, complications, the Agency of Healthcare Research and Quality Patient Safety Indicators, and hospital length of stay among Medicare beneficiaries. Linear regression models were developed that included adjustment for hospital region, teaching status, and discharge volume. RESULTS Hospitals with access to UpToDate (n=424) were associated with significantly better performance than other hospitals in the Thomson database (n=3091) on risk-adjusted measures of patient safety (P=0.0163) and complications (P=0.0012) and had significantly shorter length of stay (by on average 0.167 days per discharge, 95% confidence interval 0.081-0.252 days, P<0.0001). All of these associations correlated significantly with how much UpToDate was used at each hospital. Mortality was not significantly different between UpToDate and non-UpToDate hospitals. LIMITATIONS The study was retrospective and observational and could not fully account for additional features at the included hospitals that may also have been associated with better health outcomes. CONCLUSIONS An electronic clinical knowledge support system (UpToDate was associated with improved health outcomes and shorter length of stay among Medicare beneficiaries in acute care hospitals in the United States. Additional studies are needed to clarify whether use of UpToDate is a marker for the better performance, an independent cause of it, or a synergistic part of other quality improvement characteristics at better-performing hospitals.

Working with the US Food and Drug Administration: Progress and timelines in understanding and treating patients with eosinophilic esophagitis

The article by Fiorentino et al. (1) summarizes recent progress in the development of therapeutics for the emerging allergic disorder eosinophilic esophagitis (EoE) (2). The authors present an encouraging picture of an ongoing partnership between the Food and Drug Administration (FDA) and a number of stakeholders, including patients, families, advocacy organizations, a network of physician investigators (The International Group of Eosinophilic Disease Researchers [TIGERS]), academicians, researchers and the pharmaceutical industry who all focus on EoE. A basic premise of the article is the urgent need to develop validated and meaningful Clinical Outcome Assessment (COA) tools such as Patient Related Outcomes (PRO)(3). The lack of these questionnaires are described as currently hindering key progress in understanding and effectively treating this emerging disease. We agree that such tools would likely advance the field. The authors suggest that we are in the early stages of understanding EoE disease pathogenesis and clinical description, but we would like to touch on the tremendous progress that has actually been made over the past decade, including effective clinical trials that have been carried out despite the limitations in currently available COA and PRO tools. We present the concern that the search for a COA tool and its eventual employment have the potential to slow drug development; thus, caution is warranted so as not to become solely focused on COA tools for regulatory product approval.

A predictive model for the development of hepatocellular carcinoma, liver failure, or liver transplantation for patients presenting to clinic with chronic hepatitis C.

ObjectiveChronic infection with hepatitis C may lead to the development of cirrhosis, liver failure, and hepatocellular carcinoma. However, not all patients progress to these endpoints. Ideally, clinicians could improve their capability of stratifying the risk and the time frame within which their patients will progress to these endpoints. The purpose of the present study was to construct statistical models predicting disease progression for individual patients.MethodsStudy endpoints were the development of hepatocellular carcinoma, liver transplantation, or death due to liver disease. The study cohort was 256 patients with hepatitis C acquired from either blood transfusion or use of intravenous drugs. During follow-up, 17 patients developed hepatocellular carcinoma, seven received liver transplantation, and 12 died from liver disease.ResultsOn multivariate analysis a history of decompensation (relative risk [RR] 4.321, 95% confidence interval [CI] 1.777–10.511) and the serum albumin (RR 0.253, 95% CI 0.136–0.474) were independently associated with the study endpoints. Patients without a history of decompensation and with a serum albumin ≥4.1 mg/dl had a 3.2% chance of developing the study endpoints within 5 yr. Patients with a history of decompensation and a serum albumin <4.1 mg/dl had a 40% chance of developing a study endpoint within 5 yr. Baseline genotype and quantitative RNA were not associated with development of the clinical endpoints, with the exception of patients coinfected with two or more genotypes.ConclusionsThus, the serum albumin and a history of decompensation are useful for predicting the development of hepatocellular carcinoma, liver transplantation, and death due to liver disease among patients with hepatitis C.

Putting the puzzle together: epidemiological and clinical clues in the etiology of eosinophilic esophagitis.

The cause of eosinophilic esophagitis remains unknown, but its epidemiology and clinical features provide pieces to the puzzle. Eosinophilic esophagitis probably emerged in the 1950s or early 1960s, has an increasing incidence, occurs in most developed countries, is related to food allergies, affects adults and children, has a strong male predominance, clusters in families, and is commonly associated with other allergic and atopic disorders. Several theories have been proposed to explain its evolution, but none has been convincingly demonstrated.

Summary of the First International Gastrointestinal Eosinophil Research Symposium

Received April 24, 200 Authors’ affiliations ap Address correspondence MD, University of Penn Gastroenterology, Hepato of Philadelphia, 34th and The FIGER Symposiu Society of Pediatric Gast Academy of Allergy, Asth ship for Eosinophilic Di Institutes of Health; a phil and educational grants fro cia, TAP, Ception, Glaxo upta, James J. Lee, Simon P. Hoga Barry K. Wershil, Marc E. Rothenberg, Steven J. Ackerman, Ignatius Gomes, Simon Murch, Anil Mishra, and Glenn T. Furuta