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Ip S, Chung M, Moorthy D, et al. Comparative Effectiveness of Management Strategies for Gastroesophageal Reflux Disease: Update [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 Sep. (Comparative Effectiveness Reviews, No. 29.)
This publication is provided for historical reference only and the information may be out of date.
Comparative Effectiveness of Management Strategies for Gastroesophageal Reflux Disease: Update [Internet].
Show detailsThe present report is an update of the 2005 AHRQ Comparative Effectiveness Review (CER) of management strategies for GERD.1 The Tufts EPC held teleconferences with a Technical Expert Panel (TEP) formed for this project. The TEP served in an advisory capacity, helping to refine key questions, identify important issues, and define parameters for the review.
Analytic Framework and Key Questions
The analytic framework depicted in Figure 1 was applied to answer the Key Questions in the evaluation of the treatment modalities for GERD. This framework addressed relevant clinical and intermediate outcomes, as well as examined clinical factors that affected treatment outcomes. While evidence from high quality randomized controlled trials (RCTs) was preferred, where there was a paucity of data or such studies were unavailable, non-randomized and uncontrolled studies were also included.
Figure 1
Analytic framework of the comparative effectiveness of management strategies for GERD.
Key Question 1. What is the evidence of the comparative effectiveness of medical, surgical and other newer forms of treatments for improving objective and subjective outcomes in patients with chronic gastroesophageal reflux disease (GERD)? Is there evidence that effectiveness varies by specific technique, procedure, or medication? Objective outcomes addressed include esophagitis healing, ambulatory pH, other indicators of reflux, need for medication, healthcare utilization, and incidence of esophageal stricture, Barrett's esophagus or esophageal adenocarcinoma. Subjective outcomes include symptom frequency and severity, sleep/productivity, and overall quality of life.
Key Question 2. Is there evidence that effectiveness of medical, surgical and newer forms of treatments vary for specific patient subgroups? What are the characteristics of patients who have undergone these therapies, including the nature of previous medical therapy, severity of symptoms, age, sex, weight, and other demographic and medical factors? What are the provider characteristics for procedures including provider volume and setting (e.g., academic vs. community)?
Key Question 3. What are the short-term and long-term adverse events associated with specific medical, surgical, and other, newer forms of therapies for GERD? Does the incidence of adverse events vary with duration of follow-up, specific surgical intervention, or patient characteristics?
Search Strategy
To identify relevant studies published since the compilation of the 2005 GERD CER,1 we conducted a comprehensive search of the literature. We began by searching MEDLINE (2004-August 2010) for English language studies of adult humans and articles pertinent to each key question identified. Reference lists of all review articles were also inspected for additional relevant studies.
For the current update, the scope of the CER was expanded to include patients with extraesophageal GERD (i.e., patients with chronic cough, laryngitis or hoarseness, or asthma believed to be related to GERD). For extraesophageal GERD topics, results from previously conducted meta-analyses and systematic reviews were also sought and included where appropriate, and updated when necessary. Specifically, our search was expanded to include previously conducted meta-analyses and systematic reviews of management strategies for patients with extraesophageal GERD listed in MEDLINE, the Cochrane Database of Systematic Reviews, the American College of Physicians Journal Club, the Database of Abstracts of Reviews of Effects, and the Centre for Reviews and Dissemination's Health Technology Assessments (up to October, 2009). Terms for gastroesophageal reflux disease and relevant research designs were combined in the electronic searches. For the search of meta-analyses and systematic reviews, the same terms for gastroesophageal reflux disease were combined with those for systematic reviews or meta-analyses and major extraesophageal GERD symptoms such as chronic cough, reflux laryngitis, and asthma (see Appendix A for complete search strategy). TEP members were also invited to provide additional references. Upon completion of our search, we compiled evidence tables of the characteristics and results of included studies, and appraised their methodological quality.
The Scientific Resource Center at Oregon Health & Science University conducted the grey literature search that provided information related to GERD from regulatory agencies, trial registries, conference proceedings, and miscellaneous sources. This was supplemented with an internal search of the FDA MAUDE database. We did not search systematically for unpublished data.
As the adverse events related to PPI use (GERD and non-GERD indications) are of particular interest, the decision was made to further explore this topic by searching for the latest systematic review on this subject. A Medline targeted search (up to July, 2010) related specifically to fracture risk associated with the use of PPIs was also conducted upon recommendation of a domain expert (see Appendix A for complete search strategy).
Study Selection
Titles and/or abstracts of citations identified from literature searches were assessed for inclusion using the criteria described below. Full-text articles of potentially relevant abstracts were retrieved and a second review for inclusion was conducted by applying the same criteria. Results published only in abstract form were generally not included in the review due to lack of adequate information with which to assess the validity of data.
Population and Condition of Interest
Patients With Chronic GERD
GERD is considered a chronic and recurrent disease. The coincidence of one or more of several potential complications related to GERD including esophageal strictures, Barrett's esophagus and esophageal adenocarcinoma, is considered “complicated” GERD.
GERD has been variously defined throughout the literature. To be as inclusive as possible, studies that based the diagnosis of GERD on any commonly used criteria were considered. Such criteria included an abnormal ambulatory pH study while off medications, endoscopy showing esophagitisa in patients with symptoms suggestive of GERD, typical symptoms of GERD (heartburn or regurgitation), a response to a therapeutic trial of a proton pump inhibitor, and other definitions (e.g., ICD-9 codes). The stringency of the diagnosis was recorded for each study.
Comparative, randomized, non-randomized, and cohort studies of adults (≥18 years) with chronic GERD using the above definitions were included. Studies which did not explicitly state whether only adult patients were recruited were included provided that the median age of the population was at least 40. Comparative and cohort studies that specifically examined the incidence of Barrett's esophagus or esophageal adenocarcinoma in patients with complicated GERD were also included.
Studies that focused exclusively on patients with post-surgical GERD, pregnancy induced GERD, duodenal or peptic ulcer, gastritis, primary esophageal motility disorder, scleroderma, diabetic gastroparesis, radiation esophagitis, Zollinger-Ellison syndrome, Zenker's diverticulum, previous antireflux surgery, infectious, pill, or chemical burn esophagitis were excluded.
Patients With Extraesophageal Manifestations of GERD
In addition to heartburn and regurgitation, multiple studies have suggested that GERD may have extraesophageal manifestations like chronic cough, laryngitis or hoarseness, asthma, or other non-gastrointestinal symptoms. Diagnosis of extraesophageal GERD is difficult as patients may not have concomitant complaints of heartburn or regurgitation. Studies that focused exclusively on patients with extraesophageal manifestations of GERD were excluded in the previous CER;1 However, the topic is considered in the present update upon recommendation of the TEP.
In the interests of efficiency, for the review of extraesophageal GERD, rather than relying on data from primary studies, we instead capitalized on synthesized data from existing systematic reviews. We included systematic reviews or meta-analyses that aggregated studies focusing exclusively on patients with extraesophageal GERD symptoms (e.g., chronic cough, laryngitis or hoarseness, asthma). At minimum, systematic reviews had to incorporate the following three elements for inclusion: (1) a statement of the research question (aims or objectives), (2) a description of the literature search; and (3) a listing of the study eligibility criteria (methods used for evaluating published systematic reviews are listed in the “Study designs of interest” section). If an update of a qualifying systematic review was deemed necessary, we searched for primary studies published after the systematic review using the same inclusion and exclusion criteria.
Intervention of Interest
For studies on medical treatment, we included RCTs using a proton pump inhibitor (PPI) or histamine-2 receptor antagonist (H2RA) for the treatment of acute symptoms or as maintenance therapy. Acute treatment was defined as short-term therapy—up to 8 or, in some trials, 12 weeks—until symptom resolution or esophagitis healing. Maintenance treatment was defined as long-term treatment—at least 6 months—for the prevention of symptoms or esophagitis relapse. Only studies using a PPI or H2RA, given at any dose, and approved for use by the United States Food and Drug Administration (FDA), were included. We excluded reports that combined a PPI or H2RA with antibiotic treatment for H. pylori.
For studies with surgical procedures, we accepted only studies examining total (Nissen and Nissen-Rossetti) or partial (Toupet) fundoplication, either as an open or as a laparoscopic procedure. These techniques represent the most commonly used surgical approaches for the treatment of GERD. Studies on surgical treatment of achalasia, esophageal strictures or rings, esophageal adenocarcinoma, hiatal hernia repair (unless the indication was for reflux), and colon interposition were excluded.
In the previous CER, all endoscopic procedures, such as endoscopic suturing, radiofrequency energy delivery to the gastroesophageal junction, or implantation of inert polymers were included; however, reviewed studies were limited to those examining products approved in the United States (eg, Stretta™, EndoCinch™ Suturing System, NDO Plicator™, and Enteryx™).1 In the present update, Enteryx and NDO Plicator were excluded as they are no longer being marketed in the United States. Another device, EsophyX™, commercialized since the 2005 CER, was also included in the present update.
Comparators of Interest
For studies comparing one medical treatment with another, we included only those comparing a PPI with another PPI or an H2RA, irrespective of type or dose. Trials including other medical treatments (e.g., prokinetic agents, antacids, sucralfate), combinations of an alternate medical treatment with a PPI or an H2RA, or placebo as the only comparative group were excluded. Trials comparing different doses of H2RAs or different H2RA drugs were also excluded. These options are not considered to represent major current research interest.
For studies comparing a surgical or endoscopic procedure with a medical treatment, no restrictions were set as to the medication used in the control arm. Sham procedures were also considered as an acceptable control group.
For studies comparing one surgical procedure with another, the control arm was considered to be eligible if it included a total (Nissen) or partial (Toupet) fundoplication, either as an open or as a laparoscopic procedure.
No restrictions were set for control groups in studies that compared different endoscopic procedures.
Outcomes of Interest
To evaluate the comparative efficacy of different therapies (Key Question 1), we analyzed the subjective and objective outcomes generally considered to represent clinically important endpoints in the management of GERD.
Subjective outcomes included:
- Change in symptoms based on the clinical methods and scales that were described in each study.
- Quality of life (QoL) when it was based on a validated quality of life-instrument such as the Medical Outcomes Study Short-Form-36 or the GERD-Health Related Quality of Life Instrument.
- Any systematic assessment of patient satisfaction.
Objective outcomes included:
- Esophageal pH exposure, either as change from baseline exposure or, when provided, as the proportion of patients achieving “normal” acid exposure (as techniques for performing and interpreting esophageal pH studies, we accepted each study's definition of “normal”).
- Lower esophageal sphincter (LES) competence as described in each study.
- Esophagitis healing rate based on the proportion of patients without esophagitis after treatment as assessed by endoscopy (to evaluate the medical maintenance treatment, we used esophagitis relapse rate, which was defined as the proportion of patients who developed esophagitis again after healing as assessed by endoscopy).
- Continued need for antisecretory medications, reported as the proportion of patients who continued to require medication after treatment (we sought reporting of the proportion of patients who no longer required any antisecretory medications and also recorded the proportion in whom the daily requirement for PPIs or H2RAs had been reduced).
- Development of Barrett's esophagus or esophageal carcinoma.
We focused on the results with the longest followup when an endpoint was measured more than once and the trial in question reported results from different time points. Cost-effectiveness and cost-benefit outcomes were excluded.
For Key Question 2, we focused on the following baseline patient characteristics that may have influenced treatment efficacy: age, sex, smoking status, obesity status, severity of GERD symptoms (as gauged in each study), type and response to previous medication, presence and severity of esophagitis, presence and size of hiatal hernia, presence of esophageal motility abnormality (as determined in each study), and presence of abnormal esophageal acidification (abnormal pH study) among patients off medication.
To evaluate adverse events and complications (Key Question 3), the rate for each adverse event of medical treatment and the rate for every reported complication of surgical and endoscopic procedures were extracted. In addition, we looked at the length of in-hospital stay and assessed the rate for re-operation after a surgical procedure and, specifically for laparoscopic operations, the conversion rate to an open procedure. We attempted to differentiate complications for surgical and endoscopic procedures that happened intra-operatively, or resolved within 30 days from the procedure and long-term complications presenting, or persisting after the first 30 days, whenever possible.
Study Designs of Interest
Primary Studies
To address Key Question 1, we focused on evidence from randomized controlled trials. Where there was a paucity of data or RCTs were unavailable, non-randomized and uncontrolled studies were also included. For the comparisons of efficacy between medical and a surgical treatments, we retrieved all comparative studies, randomized and non-randomized. For the comparisons of surgical techniques, we retrieved all RCTs that recruited at least 50 participants and had a mean or median followup duration of at least 5 years, as well as non-randomized comparative studies that had at least 100 participants and a mean or median follow-up of at least 5 years. To supplement data on the long-term efficacy of surgery, we also included surgical cohort studies—prospective and retrospective—that recruited at least 100 participants and had a mean or median followup of at least 5 years. To assess the efficacy of endoscopic procedures, we collected all endoscopic publications, including comparative and cohort studies that recruited at least 10 participants and had a mean or median followup of 3 months or more. For comparisons of medical treatments, we included all RCTs in adult outpatients with symptoms of gastroesophageal reflux, peptic ulcer, or NSAID induced ulcer, with at least a 4-week treatment duration.
To address Key Question 2, we compiled data on patient characteristics of interest from the studies collected to address Key Question 1. In addition, we retrieved comparative and cohort studies that expressly investigated the relationship between selected patient characteristics and the efficacy of treatment modality. We also supplemented our review with data previously extracted for a manuscript on patient characteristics as modifiers of surgical outcomes in patients with GERD.5
To address Key Question 3, we examined all the studies already marked for inclusion in addressing Key Questions 1 and 2. We also collected all studies, including cohorts, comparative studies, and reviews, in which the focus was adverse events and complications after medical, surgical, or endoscopic interventions for GERD, with a minimum sample size of 100. For surgical procedures, we also retrieved papers that were designed to compare the complication rates at institutions with varying volumes of patients. In addition, data on adverse events related to endoscopic procedures (EndoCinch®, EsophyX®, and Stretta®) were collected from the Manufacturer and User Facility Device Experience (MAUDE) database of the U.S. Food and Drug Administration's (FDA) Center for Devices and Radiological Health Web site.6 The search was performed on July 12, 2010 using the search terms “Endocinch”, “Stretta”, and “Esophyx” individually (N.B., search terms like company names and types of procedure like Bard, Curon, Davol, Endogastric, endoluminal, suture, radio frequency, etc. were also tried; the results were sensitive but not very specific). Given that the data were reported voluntarily, no judgment was made on the causal link between devices and adverse events.
Systematic Reviews of Management for Extraesophageal Manifestations of GERD
To warrant inclusion, systematic reviews were required, at minimum, to incorporate the following three elements: (1) a statement of the research question (aims or objectives), (2) a description of the literature search; (3) a listing of the study eligibility criteria. Only systematic reviews or meta-analyses that synthesized studies focusing exclusively on patients with extraesophageal GERD symptoms (e.g., chronic cough, laryngitis, asthma) were included. Definitions and diagnoses of these symptoms and diseases varied across studies. All definitions and diagnoses of chronic cough, laryngitis, and asthma were accepted as reported. As the present review is concerned with the management of GERD in adults, selected systematic reviews were required to include primary studies in adults or provide separate analyses in adults.
If a qualifying systematic review was deemed to be out of date (e.g., search years earlier than 2005), we updated the systematic review by searching for primary studies published after the original review using the same inclusion and exclusion criteria. MEDLINE (2002–November August 2010) and the Cochrane database of Controlled trials (until August 2010) were searched for English language studies of adult humans to identify articles relevant to the treatment of asthma in patients with GERD and asthma (see Appendix A for complete search strategy).
Data Extraction
Data extracted included first author, year, country, setting, funding source, study design, and inclusion and exclusion criteria. For RCTs, we recorded the method of randomization, allocation concealment, blinding, and whether results were reported on an intention-to-treat basis. Specific population characteristics noted included age, sex, and smoking and obesity status (as assessed by BMI). For studies that reported short-term and long-term data in separate publications, we used the short-term publication to extract baseline data if the baseline data were not reported in the long-term publication.
To help interpret the results, we also extracted the following factors related to the diagnosis of GERD and disease severity (if reported at study entry): presenting symptoms and quality of life for patients on medication; whether patients had undergone endoscopy; whether patients with a hiatal hernia, esophagitis, esophageal stricture, or Barrett's esophagus were included. For hiatal hernia, the size used to exclude patients from participation was also noted. We also recorded whether pH or esophageal motility tests were performed as well as their results as described in the study. For pH studies, if possible, it was noted whether patients were receiving or abstaining from PPIs during the study. Finally, we recorded whether patients had tried any medical treatment (and what type) or lifestyle modifications prior to the study, and their response to these therapies. For all population-related factors that were extracted, baseline values were analyzed for significant differences among comparison groups.
Data on treatment modality, comparators, and primary and secondary outcomes were also extracted. For each outcome of interest, we reported the number of patients enrolled and analyzed, and the results (including baseline, final value, and within-treatment or between-treatment change with variability estimate) as provided by the study. Duration of in-hospital stay after a surgical or an endoscopic procedure was also recorded. The duration of followup, as well as the number and reasons for dropouts during the followup period were also noted.
For systematic reviews, items extracted were: design, population, intervention (exposure), comparator, and results. Please see Appendix C for the data extraction form templates.
Quality Assessment
We assessed the methodological quality of studies based on predefined criteria. We used a three-category grading system (A, B, or C) to denote the methodological quality of each study as described in the AHRQ methods guide.7 This grading system has been used in most of the previous evidence reports generated by the Tufts EPC. This system defines a generic grading scheme that is applicable to varying study designs including RCTs, nonrandomized comparative trials, cohort, and case-control studies. For the assessment of RCTs, the criteria were based on the CONSORT statement for reporting RCTs.8,9 We primarily considered the methods used for randomization, allocation concealment, and blinding as well as the use of intention-to-treat analysis, the report of dropout rate, and the extent to which valid primary outcomes were described. We also considered the presence (or absence) of washout periods in crossover studies, as well as any significant differential loss to follow-up between the comparative groups. For non-randomized trials, we used the report of eligibility criteria and the similarity of the comparative groups in terms of baseline characteristics and prognostic factors.
The validity and adequacy of the description of outcomes and results were also assessed. For the assessment of prospective and retrospective cohorts as well as case-control studies, we used the Newcastle-Ottawa Quality Assessment scales. Items assessed included selection of cases or cohorts and controls, comparability, and exposure or outcome.
Based on the aforementioned criteria, each study was assigned one of three grades (A, B, or C). This grading scheme was applied to all included RCTs, cohorts, and case-control studies; however, it should be noted that our grading system did not attempt to assess the comparative validity of studies across different design strata and studies of different design receiving similar grades should not be considered of equivalent rigor (e.g., an RCT rated “B” is not necessarily of the same methodological strength as a “B” case-control study). Thus, both design and quality should be weighed when interpreting the methodological rigor of a study.
- Category A studies have the least bias and their results are considered valid. A study that adheres mostly to the commonly held concepts of high quality including the following: a rigorously conducted meta-analysis; a formal randomized study; clear description of the population, setting, interventions and comparison groups; appropriate measurement of outcomes; appropriate statistical and analytic methods and reporting; no reporting errors; less than 20 percent dropout; clear reporting of dropouts; and no obvious bias.
- Category B studies are susceptible to some bias and do not meet all the criteria of category A. While deficient in some respects, they are not sufficiently such so as to invalidate results.
- Category C studies have significant bias that may invalidate results. These studies have serious errors in design, analysis, or reporting, and may be missing substantial portions of critical information.
Critical Appraisal of Systematic Reviews
The systematic reviews utilized in this report were also critically appraised; however, a summary quality grade was not assigned due to possible ambiguities in interpretation. While it may be straightforward to assign an A to a rigorously carried out systematic review of high quality primary studies, a rigorously conducted systematic review finding only poor quality primary studies to summarize has uncertain value. Similarly, a poorly conducted systematic review of high quality studies may also result in misleading conclusions.
Rather, to help readers appreciate the methodological quality of a systematic review, we applied the AMSTAR checklist.10 Instead of assigning a composite grade, the AMSTAR checklist evaluates individual elements explicitly for the reader. In addition to using AMSTAR, we made comments on special considerations, issues, or limitations concerning design, conduct, and analyses of the systematic review.
For the assessment of meta-analyses, the criteria for methodological quality were based on the QUOROM Guidelines for Meta-analyses and Systematic Reviews of RCTs.11
Data Synthesis
Evidence Tables
Evidence tables are provided as a condensed reference of study descriptions arranged by Key Question. The tables contain detailed information concerning design, sample size, intervention and comparison group treatments, patient characteristics, followup, major outcomes, and methodological quality. In addition, for systematic reviews and meta-analyses, we reported the databases searched and for which time period, the number and the type of primary studies included, and the category of comparison addressed (medical vs. medical, medical vs. surgery, or endoscopic vs. sham procedure). Medication usage data were reported as described by the study authors without attempting to standardize the definitions. Some authors reported medication usage as the proportion of patients off PPIs, while others reported the proportion of patients on PPIs or the number of days that patients regularly used antisecretory medications. These tables were designed to facilitate comparisons and synthesis across studies. Where a P-value was reported, P<0.05 was considered statistically significant.
Adverse Events Reporting
We reported the main adverse events associated with medical, surgical, and endoscopic treatments in the tables. For medical treatment, studies were grouped according to the type of comparison (PPI vs. H2RA or placebo, and PPI maintenance dose vs. healing dose). For the adverse events in each comparison, the total number of patients included, the number of studies, and the total percent adverse event rate for each of the comparative arms were reported when the data were available.
For surgical treatment, we considered studies examining Nissen and Nissen-Rossetti fundoplication within the same category. In the evidence tables, studies reporting complications according to the type of procedure and the complication reported were grouped together. For each study, we reported the absolute number and percentage of subjects with the complication. In other tables, we reported the number of studies and event rate for each complication and procedure. The mean event rate was calculated for two or more studies. Separate tables were created for studies that reported complications occurring within 30 days from the procedure, after 30 days, and for studies that were unclear on the time period between the procedure and a complication. Case reports were not included in the tables.
Results from the Manufacturer and User Facility Device Experience (MAUDE) database were summarized in narrative form.
Overall Comparative Synthesis Table
To aid discussion, comparative data were summarized across treatment modalities (medical, surgical, and endoscopic) in one table and grouped according to Key Question (see the section on conclusions/discussion/future research). Important comparative findings for each Key Question were summarized whenever data were available.
Grading a Body of Evidence for Each Key Question
We graded the strength of the body of evidence for each outcome within each Key Question as per the AHRQ methods guide.7 Ratings were defined as follows:
- High—There is a high level of assurance that the findings of the literature are valid with respect to the relevant Key Question. No important scientific disagreement exists across studies. At least two A-quality studies are required for this rating.
- Moderate—There is a moderate level of assurance that the findings of the literature are valid with respect to the relevant Key Question. Little disagreement exists across studies. Moderately rated bodies of evidence contain fewer than two A quality studies or A quality studies that lack long-term outcomes of relevant populations.
- Low—There is a low level of assurance that the findings of the literature are valid with respect to the relevant Key Question. Underlying studies may report conflicting results. Low rated bodies of evidence contain either B or C quality studies or examinations of populations that may have little direct relevance to the key question.
- Insufficient—Evidence is either unavailable or does not permit estimation of an effect due to a lack of data.
The ratings provide a concise summation of the strength of evidence supporting the outcome that each of the major questions addressed. However, a number of complex issues involved in appraising a body of evidence are necessarily left unexplored. The studies incorporated in the formulation of the composite rating differed in their design, reporting, and quality; the strengths and weaknesses of these reports ought to be considered individually and in-depth.
Peer Review
A draft version of this report was reviewed by a panel of expert reviewers, including representatives from professional organizations, pharmaceutical companies and manufacturers. Revisions of the draft were made based on their comments where appropriate. However, the findings and conclusions are those of the authors, who are solely responsible for the contents of this report.
Footnotes
- a
Several grading systems have been proposed to evaluate the severity of GERD; the most common of which are the Savary-Miller Classification and the Los Angeles Grade. Patients were considered to have mild to moderate esophagitis if they were categorized as Savary-Miller class I-II or Los Angeles grade A-B, while they were considered to have severe esophagitis if it was categorized as Savary-Miller class III-IV or Los Angeles grade C-D.
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