Abstract
This article comes from Clinical Evidence (1999 ; 1 : 145-153), anew resource for clinicians produced jointly by the BMJ Publishing Group and the American College of Physicians-American Society of Internal Medicine.Clinical Evidence is an extensively peer-reviewed publication that summarizes the best available evidence on the effects of common clinical interventions gleaned from thorough searches and appraisal of the world literature. It became available in the United States late last year. Please see advertisement for more information or, alternatively, visit the web site atwww.evidence.org.
QUESTIONS
What are the effects of treatment of erosive esophagitis ? What are the effects of treatment of non erosive esophagitis ? What are the effects of treatment of gastroesophageal reflux disease on the progression of Barrett's esophagus ? What are the effects of treatment in people with extra esophageal manifestations of gastroesophageal reflux ?
INTERVENTIONS
In descending order of effectiveness
Proton pump inhibitors
Histamine-2 antagonists (less effective than proton pump inhibitors)
Fundoplication
Medical and surgical treatment of gastroesophageal reflux in selected people with extra esophageal manifestations
Different surgical therapies for erosive and nonerosive esophagitis
Medical and surgical treatment of gastroesophageal reflux in people with Barrett's esophagus
Surgical treatment of nonerosive esophagitis
Medical and surgical treatment of erosive and nonerosive esophagitis
Diet and lifestyle changes
DEFINITION
Gastroesophageal reflux occurs when gastric contents enter the esophagus because of transient or chronic relaxation of the lower esophageal sphincter.Excessive reflux causes symptoms of gastroesophageal reflux disease (heartburn, acid taste in the mouth). It can be divided into nonerosive esophagitis and erosive esophagitis in which endoscopy shows inflammation and erosions.
Summary points
One systematic review of randomized controlled trials (RCTs) found that proton pump inhibitors were more effective than H2 antagonists in both erosive and nonerosive esophagitis, and 1 RCT found no significant difference in the effectiveness of different proton pump inhibitors
We found inadequate evidence from RCTs on surgical treatment versus place boor versus medical treatment
We found no RCTs evaluating whether people with Barrett's esophagus benefit from medical or surgical treatment of gastroesophageal reflux
We found limited and conflicting evidence on the effects of treating gastroesophageal reflux in people with extra esophageal manifestations of gastro esophageal reflux disease
INCIDENCE/PREVALENCE
Gastroesophagel reflux disease is common. Weekly heartburn occurs in about20% of people questioned in population surveys. As much as 10% of these will have erosive disease.
ETIOLOGY
There are no clear predictive factors for gastroesophageal reflux disease.
PROGNOSIS
Gastroesophageal reflux disease is generally benign, with little mortality.Persistent symptoms, however, can interfere with normal activities and cause considerable morbidity. Long-term retrospective data (about 22 years) suggest that, in people with initially normal findings on endoscopy, endoscopic appearance tends to remain normal.1 In a small subset of people, strictures, Barrett's esophagus, adenocarcinoma, or extra esophageal manifestations develop (table).2
Table.
Extraesophageal manifestations of gastroesophageal reflux disease*
| Pulmonary | Ear, nose, and throat | Other |
|---|---|---|
| Asthma, chronic bronchitis, aspiration pneumonia, sleep apnea, atelectasis, interstitial pulmonary fibrosis | Chronic cough, hoarseness, enamel erosion, halitosis, pharyngitis, subglotticstenosis, vocal cord inflammation, granuloma, possible cancer | Noncardiac chest pain, chronic hiccups, nausea |
From Richter.2
AIMS
To relieve symptoms, prevent complications in patients with severe esophagitis, control extra esophageal manifestations, minimize adverse effects of treatment, and improve quality of life.
OUTCOMES
Frequency and severity of symptoms ; degree of esophagitis ; esophageal pH(assessed by ambulatory monitoring) ; prevalence and severity of extra esophageal manifestations ; and incidence of stricture, Barrett's esophagus, and adenocarcinoma. Symptoms do not correlate well with the extent of esophagitis. People with Barrett's esophagus may have minimal symptoms, and those with severe symptoms may have no evidence of esophagitis.
METHODS
Clinical Evidence issues were searched and appraised through May1999. Primary sources were searched on MEDLINE, and a manual search was done of earlier issues of European Journal of Gastroenterology andHepatology. Reference lists of retrieved articles were searched.
QUESTION :
What are the effects of treatment of erosive esophagitis ?
OPTION : PROTON PUMP INHIBITORS VS H2 ANTAGONISTS
One systematic review of randomized controlled trials (RCTs) found that proton pump inhibitors were more effective than histamine-2 (H2)antagonists at healing erosive esophagitis and preventing recurrence. No significant difference was found in rates of short-term adverse events. No good data were found on the long-term risks of treatment or on possible long-term benefits.
Benefits
One systematic review published in 1997 identified 43 single- and double-blind RCTs involving 7,635 participants that compared the use of proton pump inhibitors versus that of H2 antagonists.3 Proton pump inhibitors were more effective at healing by 12 weeks on endoscopic examination (84%, 95% confidence interval [CI] 79%-88%, vs 52%, 95% CI47%-57%), irrespective of drug dose or treatment duration. Proton pump inhibitors provided the fastest overall healing rate, with 11.7% of cases of esophagitis healed per week (95% CI 10.7%-12.6%), twice as fast asH2 antagonists (5.9% healed per week, 95% CI 5.5%-6.3%) and 4 times faster than placebo (2.9% healed per week, 95% CI 2.4%-3.4%). Two of the RCTsadded a prokinetic agent to the H2 antagonist, but results still strongly favored the proton pump inhibitor.4,5Doses of proton pump inhibitors varied, not routinely exceeding 40 mg of omeprazole or 30 mg of lansoprazole. In a cohort study of people with esophagitis treated with omeprazole, higher doses achieved even higher healing rates. 6
Preventing recurrence
Three of the RCTs looked at recurrence rates. Two RCTs (1 double- and 1single-blind) compared the use of omeprazole versus ranitidine (with or without cisapride) in people with endoscopically confirmed esophagitis who had already received a regimen of omeprazole for 4 to 8 weeks.8,8At 1 year, people treated with daily omeprazole were significantly less likely to relapse than those treated with ranitidine hydrochloride. In the first RCT,159 participants were randomly assigned to treatment with omeprazole, 20 mg daily ; omeprazole, 20 mg on 3 consecutive days a week (weekend omeprazole) ;or ranitidine, 150 mg twice a day. At 12 months, a significantly greater proportion of people treated with omeprazole daily remained in remission than those treated with either weekend omeprazole (absolute risk reduction [ARR]57%, 95% CI 42%-71%) or ranitidine daily (ARR 64%, 95% CI 50%-78%). There was no significant difference between weekend omeprazole and daily ranitidine treatments (ARR 7%, 95% CI -11% to +25%).7 In the second RCT,175 participants were randomly allocated to receive omeprazole, ranitidine, or cisapride alone and in various combinations. After 12 months, people receiving omeprazole were significantly more likely to be in remission than those receiving either ranitidine or cisapride alone (80% still in remission vs 50%; CIs not reported).8
Preventing complications
No RCTs that examined possible longer term benefits of medical treatment were found.
Harms
Complications of incomplete treatment
No RCTs were found that examined the course of incompletely treated gastroesophageal reflux disease, nor any good data on the natural history of inflammatory esophageal disease.1 Also, no data were found on the level of gastric acid suppression needed to ensure adequate esophageal healing.
Short-term adverse effects
In placebo-controlled RCTs, proton pump inhibitors and H2antagonists have similar rates of adverse effects. Most data on significant adverse effects come from case reports or uncontrolled trials. H2antagonists have been associated rarely with cytopenia, gynecomastia, abnormal liver function test results, and hypersensitivity reactions. Rare adverse effects of proton pump inhibitors in people with gastroesophageal reflux disease include abnormal results of liver function tests, increased small bowel bacterial counts, cytopenias, hypersensitivity reactions, and decreased (but not clinically important) vitamin B12 levels.
Long-term adverse effects
No controlled trials were found with long-term follow-up on the safety of the long-term use of H2 antagonists. The long-term use of proton pump inhibitors in the presence of Helicobacter pylori infection has been linked in 2 uncontrolled trials to atrophic gastritis after 3 to 5 years.9,10Among people treated with omeprazole, none of whom had atrophic gastritis at baseline, atrophic gastritis developed in 18 of the 59 people infected withH pylori and 2 of the 46 people who were not infected.9 Of 14 people with persistent H pylori infection, 6 developed mild to severe atrophy in5 years. 10
OPTION : DIFFERENT PROTON PUMP INHIBITORS
Randomized controlled trials have found no evidence of a difference between different proton pump inhibitors in healing esophagitis.
Benefits
No systematic review was found, but 1 good multicenter, double-blind RCT(225 people) was found.11 No significant difference was found in the proportion of people healed at 8 weeks by lansoprazole, 30 mg, versus omeprazole, 20 mg, in people with erosive esophagitis (absolute risk healing at 8 weeks : 85% with lansoprazole and 87%with omeprazole ; ARR 2%, 95% CI -6% to +14% ; relative risk reduction [RRR]2%, 95% CI -7% to +16%). Relapse rates were not evaluated. Another double-blind RCT (202 people) compared the use of rabeprazole, 20 mg, with that of omeprazole, 20 mg, and found no significant differences in efficacy in healing of erosive and ulcerative esophagitis at 4 weeks (81% for both) and at 8 weeks (92% for rabeprazole vs 94% for omeprazole ; ARR 2%, 95% CI-3% to +15%).12
Harms
No differences in adverse effects were reported, but the data are limited.
OPTION : MEDICAL VS SURGICAL TREATMENT
Medical and surgical treatment have not been adequately compared in RCTs.Preliminary data suggest that proton pump inhibitors and fundoplication are about equally effective at healing. No good comparative data on preventing relapse or complications were found.
Benefits Healing
One RCT (243 men and 4 women) compare medical versus surgical treatment in people with complicated gastroesophageal reflux disease (erosive esophagitis,Barrett's esophagus, stricture, or esophageal ulcer).13 It compared continuous medical treatment (antacids, ranitidine, metoclopramide, or sucralfate), medical treatment of symptoms only, or open fundoplication.Evaluation was performed at 6 weeks (201 people), 1 year (176 people), and 2years (106 people). Those receiving fundoplication had significantly better results, measured by a symptom score (78 vs 88 vs 90), and grade of esophagitis (1.5 vs 1.9 vs 2.2 ; P <0.03).
Preventing relapse
The trial did not evaluate relapse rates. Uncontrolled trials on the long-term results of open fundoplication found that as much as 90% of people continue to benefit 6 to 20 years after surgery in relief of symptoms, reduced acid exposure on pH monitoring, and absence of inflammation on endoscopy.14,15,16
Preventing complications
No good data relating to this outcome were found.
Harms
The RCT found no operative deaths, but operative complications occurred in15% and postoperative complications in 18% of people.13 Uncontrolled studies found that intraoperative complications included splenic trauma(0%-4%), viscus perforation (1%-2%), and less commonly, abscess or inadvertent vagotomy. Immediate postoperative complications included pleural effusion, pulmonary embolism, or late abscess formation. Although morbidity was substantial, mortality related to the surgery was usually less than 1%. Late adverse effects related to fundoplication included bloating, dysphagia, gastric herniation, or breakdown of the fundoplication. Reoperation was required in up to 15% of people for either complications or failure.
Comment
Erosive esophagitis, stricture, and Barrett's esophagus are now known to require at least a proton pump inhibitor for healing and maintenance of remission.6,7,8,17The use of only an H2 antagonist in the RCT13 may have biased the results in favor of fundoplication. Preliminary data from 1 RCT suggest approximately equal treatment efficacy when comparing fundoplication with omeprazole for people with erosive esophagitis at 3-year follow-up.18 Individual patient characteristics may direct the physician toward medical or surgical treatment. Some people are refractory to proton pump inhibitors19 or have severe“mechanical” reflux requiring surgery. Some people may be high-risk surgical candidates or have relative contraindications to refluxsurgery (such as scleroderma, multiple prior laparotomies, or previous gastric surgery). Younger people may prefer surgery to lifelong drug treatment. No studies addressing these issues were found.
OPTION : DIFFERENT SURGICAL TECHNIQUES
No RCTs were found that compared Nissen, Tope, or Dor fundoplication orHill gastroplasty, nor were RCTs found that compared open versus laparoscopic approaches.
QUESTIONS :
What are the effects of treatment in nonerosive esophagitis ?
OPTION : PROTON PUMP INHIBITORS VS H2 ANTAGONISTS
Proton pump inhibitors have been found in RCTs to be more effective at relieving symptoms than H2 antagonists, with or without prokinetic agents.
Benefits Symptom relief
No systematic review was found, but there were 3 good double-blind RCTs.One RCT compared the use of omeprazole, 10 mg, versus cimetidine, 800 mg daily(149 people), and found that after 24 weeks, considerably more people taking omeprazole were free of symptoms (ARs 45% vs 15% ; ARR 31%, 95% CI 13%-50% ;RRR 205%, 95% CI 85%-334% ; number needed to treat : 3, 95% CI 2-8).20 Another RCTcompared the use of omeprazole, 20 mg, versus that of cimetidine, 400 mg (108people), and found significantly greater symptom relief in those taking omeprazole (66% free of heartburn with omeprazole vs 31% with cimetidine ; ARR34%, 95% CI 21%-46%).21 Similar results were found when treatment with omeprazole, 20 or 10 mg, was compared with that of cisapride, 40 mg (10 mg 4 times a day).22 In most trials, symptom relief was about twice as good with omeprazole. Omeprazole has also been found to be superior to ranitidine when measured by symptom scores and scores of psychological well-being.23,24
Recurrence
No good data were found on recurrence rates.
OPTION : SURGICAL TREATMENT
No RCTs were found that compared medical with surgical treatment in people with non erosive esophagitis, and none were found that compared different surgical techniques.
Comment
Good long-term trials are needed that compare laparoscopic fundoplication with proton pump inhibitors, taking into account symptom relief, adherence, prevention of complications, and adverse effects of treatment.
QUESTIONS :
Does treatment of gastroesophageal reflux disease reduce the risk of progression of Barrett's esophagus ?
No good evidence was found of the effects of treatment of gastroesophageal reflux in people with Barrett's esophagus.
Benefits
No RCTs were found. Uncontrolled studies that looked at the long-term effect of either cimetidine, ranitidine, or fundoplication in people with Barrett's esophagus found no significant effect.25,26One uncontrolled study of proton pump inhibitors found evidence of regression of Barrett's esophagus,27 but other uncontrolled studies found no evidence of regression.28,29None of these studies observed more than 27 people. Small long-term studies of the effects of fundoplication on Barrett's esophagus found that effective fundoplication (defined by ambulatory pH monitoring, symptoms, and endoscopy) may lead to regression.30,31
Harms
Weak evidence was found of the harms of treatment of gastroesophageal reflux in people with Barrett's esophagus. Small long-term studies of fundoplication suggest that after failed procedures, there may be progression to dysplasia and carcinoma.30,31
Comment
Few centers see enough people with Barrett's esophagus to perform long-termRCTs. In addition, our poor understanding of the pathophysiologic characteristics of Barrett's esophagus means that what end point of treatment of gastroesophageal reflux—symptom relief, healing, elimination of acidreflux—that may change the course of Barrett's metaplasia is not known.Whether progression can be measured endoscopically is also not clear.32,33Only a long-term, multicenter trial will be able to answer these questions.
QUESTIONS :
Does the treatment of gastroesophageal reflux alter outcome in people with extra esophageal manifestations of gastroesophageal reflux disease?
Limited and conflicting evidence was found from RCTs in people with asthma and symptoms of reflux. No RCTs were found that looked at the effects of treatment on other extra esophageal manifestations (seetable).
Asthma
One RCT (double-blind, placebo-controlled crossover design, 25 people with adult-onset asthma and symptoms of reflux) compared treatment with omeprazole,40 mg per day, with that of placebo.34 The design included a washout and a crossover period. Symptoms and results of pulmonary function tests were monitored. Omeprazole improved evening peak expiratory flow rates and lessened reflux symptoms, but there was no significant difference in asthmatic symptoms or treatment requirements or in lung function (forced expiratory volume in 1 second, forced vital capacity, histamine bronchial responsiveness, and daytime peak expiratory flow rate), although the confidence intervals were wide. One prospective open-label cohort study evaluated the use of omeprazole in people with nonallergic asthma and reflux symptoms 35 The mean asthma score improved in people receiving omeprazole but not as significantly as pulmonary function study results. Abnormal proximal acid exposure on pH monitoring and a history of frequent regurgitation were good predictors of clinical response.
Two RCTs compared the use of H2 antagonists with placebo (1induced a surgical treatment arm). The first was a double-blind crossover RCTof ranitidine, 150 mg twice a day, versus placebo in 48 people with asthma with abnormal findings on pH monitoring.36 It found no significant improvement in bronchial reactivity, lung function, or peak flow.The second (90 people with adult-onset asthma and reflux) compared placebo, cimetidine, and fundoplication. It found significant improvement in the results of pulmonary function tests and the need for asthmatic medication with active treatment (surgery more so than cimetidine), whereas the placebo group worsened. 37 Both active treatments achieved long-term benefit (nearly 6 years), the greatest being in the surgically treated group (after a mean of 77 months, 11 of 22[50%] receiving surgery still had respiratory symptoms vs 19 of 20 [95%]receiving placebo ; ARR 45%, 95% CI 5%-85% ; NNT 2, 95% CI 1-19). One RCT (247people with gastroesophageal reflux disease but without obvious lung disease) found no improvement in pulmonary function after 1 year of either medical treatment or fundoplication.38
Other extra esophageal manifestations
No RCTs were found. One prospective open-label cohort study of the use of omeprazole in 182 people with chronic laryngitis and reflux found improvement.39
Harms
No good data were found on the harms of treatment of gastroesophageal reflux specifically in people with extra esophageal symptoms.
Comment
The link between extra esophageal symptoms and gastro-esophageal reflux is by association ; symptoms are multi-factorial, making it hard to prove that gastroesophageal reflux is the primary cause. There was little standardizationin these trials with regard to treatments used or patient characteristics.Before good RCTs can be performed, further research must first identify clear criteria for reflux as the cause of these syndromes.
Competing interests : Dr Katzka has received lecture fees from AstraZeneca and TAP-Abbott.
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