Medical treatments for the maintenance therapy of reflux oesophagitis and endoscopic negative reflux disease
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effectiveness of PPIs, H2Ras, prokinetic therapy, sucralfate and combinations compared to each other and placebo in the continuous maintenance therapy of ENRD and reflux oesophagitis.
To compare the incidence of adverse effects associated with the different treatments.
Background
Gastro‐oesophageal reflux disease (GORD) is a common disease with an estimated prevalence of 20% in the adult American population (Sonnenberg 1999) and similar rates in Europe. It has a significant impact on morbidity and quality of life.
GORD is primarily attributable to acid and bile refluxing through the lower oesophageal sphincter (Armstrong 1999). The main treatments available concentrate on reducing acid secretion by proton pump inhibitors (PPIs) and H2 receptor antagonists (H2RAs), increasing the pressure at the lower oesophageal sphincter, enhancing gastric emptying with prokinetics and protecting mucosa from acid damage with sucralfate.
Endoscopic examination is the investigation of choice for GORD (Navaratham 1998). When endoscopy is undertaken a majority of patients have normal findings (endoscopy negative reflux disease or ENRD) with the remainder having oesophageal inflammation (reflux oesophagitis).
The efficacy of medical therapy in acute management of oesophagitis is the subject of another Cochrane review (Donellan 2001) and ENRD acute management has been evaluated in a previous Cochrane Review (van Pinxteren 2000). GORD is a chronic relapsing condition with significant impact on quality of life (Scott 1999). GORD symptoms recur rapidly on discontinuation of therapy therefore maintenance therapy is central to management of the condition (Williams 1997). There are currently no systematic reviews assessing maintenance therapy in the treatment of oesophagitis and ENRD.
GORD affects a significant number of patients who present for treatment and place a burden on healthcare budgets (Chiba 1997). Primary and secondary care physicians are faced with a variety of treatment options. Randomised controlled trials suggest that PPIs are the most effective treatment (Earnest 1999) and but the actual relative efficacy of each drug in the maintenance therapy for reflux oesophagitis and ENRD is uncertain. An accurate assessment of this would inform clinical decision making. Efficacy is not the only aspect of the decision making process as cost of therapy also needs to be considered (Dent 1999). Nevertheless, a more precise estimate of relative efficacy would help establish the most cost‐effective therapy for maintenance of reflux oesophagitis and ENRD patients.
This review will perform a systematic review of randomised controlled trials examining the efficacy of PPIs, H2RAs, prokinetic therapy and sucralfate in the maintenance therapy of reflux oesophagitis and endoscopy negative reflux disease.
Objectives
To assess the effectiveness of PPIs, H2Ras, prokinetic therapy, sucralfate and combinations compared to each other and placebo in the continuous maintenance therapy of ENRD and reflux oesophagitis.
To compare the incidence of adverse effects associated with the different treatments.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials assessing maintenance therapy of reflux oesophagitis and ENRD.
Types of participants
All patients must be adults who have had an endoscopy. In the case of ENRD, the main presenting symptoms should be heartburn and/or acid reflux. Patients with reflux oesophagitis at endoscopy should have a repeat endoscopy to demonstrate healing after a course of therapy before entering into the maintenance phase of the trial.
Types of interventions
The tested drug has to fall within the following drug classes a‐d, the comparison regimen must also be one of a‐e. (Combinations of these are admissible for either arm).
a) PPIs: lansoprazole, omeprazole, pantoprazole, rabeprazole.
b) H2RAs: cimetidine, famotidine, nizatidine, ranitidine.
c) Prokinetic therapy: cisapride, domperidone, metoclopramide.
d) Sucralfate
e) Placebo +/‐ antacid +/‐ no treatment
Patients must have had at least 12 weeks of continuous therapy.
Types of outcome measures
TTrials will be included if they report evidence of assessment at 12 to 52 weeks.
Primary outcomes will vary according to the group evaluated. The primary outcome in the reflux oesophagitis group is the proportion of patients in whom the oesophagitis has remained healed. The primary outcome in the ENRD is the proportion with no or minimal symptoms.
Secondary outcomes will assess quality of life (standard mean difference in scores) and adverse events/dropout rates (total number for each drug). The proportion of patients with no or minimal symptoms in the reflux oesophagitis group is a further secondary outcome measure.
Search methods for identification of studies
See: Collaborative Review Group search strategy
The principal electronic search will be undertaken according to the Cochrane Upper Gastrointestinal and Pancreatic Diseases Review Group module (published in the Cochrane Library).
Cochrane Controlled Trials Register (CCTR)
Relevant studies will be retrieved from the CCTR using the broad search terms used in the title of the paper.
Complementary Published Electronic Database Searches
Electronic searches of MEDLINE (1966‐2000), EMBASE (1988‐2000) and CINAHL ((1982‐2000) will be undertaken using a combination of subject headings and text words related to the title words. Standard methodological filters will be applied to identify randomised controlled trials.
Correspondence
Experts in the filed registered with the CC UGPD review group will be contacted for leads on unpublished studies.
Abstracts
We will hand search DDW and UEGW abstract books between 1994 and 2000. Authors of trial reports published only as abstracts will be contacted and asked to contribute full datasets or completed papers.
Data collection and analysis
Selection of studies
The lead reviewer will screen titles and trial abstracts that have been identified by the search strategy. A sample of 200 of these will then be assessed independently. Two reviewers will then screen the full article of selected trials to confirm eligibility, using pre‐designed eligibility forms, and assess quality. An adjudicator will assess any discrepancies.
Data extraction
Data will be extracted by the lead reviewer. There will be an unblinded check on this by a second reviewer.
The following features will be recorded:
‐ Setting: primary or secondary care
‐ country of origin
‐ method of randomisation: true vs. pseudo, stated vs. not stated
‐ adequacy of allocation concealment: stated vs. not stated
‐ details of blinding of patients and outcome assessors: stated vs. not stated, masked vs. not masked
‐ inclusion and exclusion criteria used
‐ baseline comparability between treatment groups
‐ treatments compared and number of patients in each arm
‐ drop‐outs reported and their reasons
‐ dose of drugs
‐ grading system for oesophagitis (e.g. Savary‐Miller, Los Angeles)
‐ validated GORD questionnaires
‐ adverse events: the total number reported
Data analysis
All analysis will be on intention to treat data and reflux oesophagitis and ENRD patients will be considered separately. The main outcomes being assessed will be oesophagitis healing (reflux oesophagitis patients), symptom control (reflux oesophagitis and ENRD) and quality of life (reflux oesophagitis and ENRD). These will be performed at 3, 6 and 12 months. We will compare interventions to themselves, placebo and combinations as described previously. The impact of interventions will be expressed as relative risks together with 95% confidence intervals. Meta‐analysis will only be attempted if there are sufficient trials of similar comparisons reporting the same outcomes. Relative risks will be combined for binary outcomes. Change in quality of life will be compared in individual studies using standard mean differences. Where significant heterogeneity is detected (p>0.15), possible explanations will be investigated informally and the data summarised using a random effects model.
The following features will be prospectively evaluated as a cause for any heterogeneity in the study outcomes:
a) Multi‐centre versus single centre
b) Country of origin
c) Mean age of patients included in the study
d) Method of randomisation
e) Method of concealment of allocation
f) Masking versus no masking
g) Dose of drug
h) Different drugs in a specific class (e.g. omeprazole versus lansoprazole)
i) Duration of treatment
j) Severity of reflux oesophagitis included at study entry in the reflux oesophagitis group. The influence of the proportions of mild/ moderate and severe reflux oesophagitis in each study on the outcome will be assessed. Mild/moderate is defined as Savary‐Miller grade 1‐2 or Los Angeles grade A‐B, whilst severe is equivalent to Savary‐Miller grade 3‐5 or Los Angeles grade C‐D.
k) Proportion Helicobacter pylori positive patients included in study (if known).
l) Patients allowed to have acid suppression or prokinetic therapy within 4 weeks of initial endoscopy (permitted versus not permitted).
m) Symptom severity at entry into the study.
