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BMJ Clinical Evidence logoLink to BMJ Clinical Evidence
. 2008 Jun 13;2008:0403.

GORD in adults

Brendan Delaney 1,#, Paul Moayyedi 2,#
PMCID: PMC2907949  PMID: 19450297

Abstract

Introduction

Up to 25% of people have symptoms of gastro-oesophageal reflux disease (GORD), but only 25-40% of these have oesophagitis visible on endoscopy. About 80% of people with GORD will have recurrent symptoms if treatment is stopped, and severe oesophagitis may result in oesophageal stricture or Barrett's oesophagus.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of initial treatment of GORD associated with oesophagitis? What are the effects of maintenance treatment of GORD associated with oesophagitis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2007 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations, such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 29 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review, we present information relating to the effectiveness and safety of the following interventions: antacids/alginates, H2 receptor antagonists, laparoscopic surgery, lifestyle advice/modification, motility stimulants, open surgery, and proton pump inhibitors.

Key Points

Up to 25% of people have symptoms of GORD, but only 25-40% of these people have oesophagitis visible on endoscopy.

  • Although obesity, smoking, alcohol, or certain foods are considered risk factors, we don't know that they are actually implicated in GORD.

  • About 80% of people with GORD will have recurrent symptoms if they stop treatment, and severe oesophagitis may result in oesophageal stricture or Barrett's oesophagus.

Proton pump inhibitors (PPIs) increase healing in oesophagitis compared with placebo and H2 receptor antagonists, but we don't know whether one specific PPI is more effective than the others.

  • H2 receptor antagonists increase oesophagitis healing rate compared with placebo, and may improve symptoms more than antacids.

We don't know whether antacids/alginates, motility stimulants, or lifestyle advice to either lose weight or to raise the head of the bed are effective in either improving symptoms of GORD or in preventing recurrence.

  • The motility stimulant cisapride has been associated with heart rhythm problems.

Both standard- and low-dose proton pump inhibitors reduce relapse of oesophagitis and reflux symptoms compared with placebo or H2 receptor antagonists, but we don't know which is the optimum drug regimen.

  • H2 receptor antagonists may reduce the risk of relapse of reflux symptoms compared with placebo, although they have not been shown to prevent recurrence of oesophagitis.

Laparoscopic or open surgery (Nissen fundoplication) may improve endoscopic oesophagitis compared with medical treatment, although studies have given conflicting results.

  • Laparoscopic surgery seems as effective as open surgery, with lower risks of operative morbidity and shorter duration of admission, but both types of surgery may have serious complications.

About this condition

Definition

Gastro-oesophageal reflux disease (GORD) is defined as reflux of gastroduodenal contents into the oesophagus, causing symptoms sufficient to interfere with quality of life. People with GORD often have symptoms of heartburn and acid regurgitation. GORD can be classified according to the results of upper gastrointestinal endoscopy. Currently, the most validated method is the Los Angeles classification, in which an endoscopy showing mucosal breaks in the distal oesophagus indicate the presence of oesophagitis, which is graded in severity from grade A (mucosal breaks of less than 5 mm in the oesophagus) to grade D (circumferential breaks in the oesophageal mucosa). Alternatively, severity may be graded according to the Savary-Miller classification (grade I: linear, non-confluent erosions, to grade IV: severe ulceration or stricture).

Incidence/ Prevalence

Surveys from Europe and the USA suggest that 20-25% of people have symptoms of GORD, and 7% have heartburn daily. In primary-care settings, about 25-40% of people with GORD have oesophagitis on endoscopy, but most have endoscopy-negative reflux disease.

Aetiology/ Risk factors

We found no evidence of clear predictive factors for GORD. Obesity is reported to be a risk factor, but epidemiological data are conflicting. Smoking and alcohol are also thought to predispose to GORD, but observational data are limited. It has been suggested that some foods, such as coffee, mints, dietary fat, onions, citrus fruits, and tomatoes, may predispose to GORD. However, we found insufficient data on these factors. We found limited evidence that drugs that relax the lower oesophageal sphincter, such as calcium channel blockers, may promote GORD. Twin studies suggest that there may be a genetic predisposition to GORD.

Prognosis

GORD is a chronic condition, with about 80% of people relapsing once medication is discontinued. Therefore, many people require long-term medical treatment or surgery. Endoscopy-negative reflux disease remains stable, with a minority of people developing oesophagitis over time. However, people with severe oesophagitis may develop complications, such as oesophageal stricture or Barrett's oesophagus.

Aims of intervention

To relieve reflux symptoms, increase healing rates, and reduce the complications of GORD, such as stricture formation; to improve quality of life; to minimise adverse effects of treatment.

Outcomes

Frequency and severity of symptoms; quality of life. Healing rates (assessed endoscopically in people with oesophagitis), which have been shown to be closely associated with clinical outcomes. pH Measurement of reflux is an intermediate outcome often used in RCTs, but it is difficult to interpret clinically. We excluded RCTs based solely on this outcome.

Methods

BMJ Clinical Evidence search and appraisal July 2007. The following databases were used to identify studies for this systematic review: Medline 1966 to July 2007, Embase 1980 to July 2007, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2007, Issue 2. Additional searches used these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE. We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, at least single blinded, and containing more than 20 individuals of whom more than 80% were followed up. A minimum of 4 weeks' follow-up was required for inclusion. We excluded all studies described as "open", "open label", or not blinded, unless blinding was impossible. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).

Table.

GRADE evaluation of interventions for GORD in adults

Important outcomes Symptom severity, relapse rates, quality of life, adverse effects
Number of studies (participants) Outcome Comparison Type of evidence Quality Consistency Directness Effect size GRADE Comment
What are the effects of initial treatment of GORD associated with oesophagitis?
1 (71) Symptom severity Raising the head of the bed v not raising the head of the bed 4 –2 0 –1 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for unclear measurement of outcomes
1 (19) Symptom severity Low-calorie diet plus advice and support v standard instructions on reflux and general advice to loose weight 4 –3 0 0 0 Very low Quality points deducted for sparse data, no intention-to-treat analysis, and incomplete reporting of results
2 (123) Symptom severity Antacids/alginates v placebo 4 –3 0 0 0 Very low Quality points deducted for sparse data, incomplete reporting of results, and no intention-to-treat analysis
2 (211) Symptom severity Antacids/alginates v H2RAs 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting of results. Directness point deducted for no long-term results in one RCT
At least 9 (at least 1847) Symptom severity H2RAs v placebo 4 0 –1 0 0 Moderate Consistency point deducted for heterogeneity between RCTs
26 ( 4032) Symptom severity H2RAs v PPIs 4 0 –1 0 +1 High Consistency point deducted for heterogeneity between RCTs. Effect-size point added for RR less than 0.5
5 (645) Symptom severity PPIs v placebo 4 0 –1 0 +1 High Consistency point deducted for heterogeneity between RCTs. Effect-size point added for RR less than 0.5
At least 29 (21,436) Symptom severity PPIs v each other 4 –1 –1 0 0 Low Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results
What are the effects of maintenance treatment of GORD associated with oesophagitis?
5 (716) Relapse rates H2RAs v placebo 4 –1 –1 0 0 Low Quality point deducted for incomplete reporting. Consistency point deducted for different results for different outcomes
1 (72) Relapse rates H2RAs v each other 4 –1 0 –2 0 Very low Quality point deducted for sparse data. Directness points deducted for narrow range of comparators and incomplete definition of outcome
11 (1933) Relapse rates H2RAs v PPIs 4 –1 +1 0 0 High Quality point deducted for incomplete reporting. Consistency point added for evidence of dose effect
At least 10 (at least 1465) Relapse rates PPIs v placebo 4 0 0 0 0 High
At least 25 (at least 13772) Relapse rates PPIs v each other 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting
4 (518) Symptom severity Open surgery v medical treatment 4 –2 0 –2 0 Very low Quality points deducted for incomplete reporting and heterogeneity between RCTs. Directness points deducted for uncertainty about relevance of one outcome and unclear measurement of outcomes
6 (449) Relapse rates Open surgery v laparoscopic surgery 4 –1 0 –1 0 Low Quality points deducted for incomplete reporting. Directness point deducted for unclear measurement of outcome
4 (474) Symptom severity Open surgery v laparoscopic surgery 4 –1 0 –2 0 Very low Quality points deducted for incomplete reporting. Directness points deducted for unclear outcome measurement and use of subjective outcomes
6 (449) Adverse effects Open surgery v laparoscopic surgery 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting of results. Directness point deducted for unclear outcome measurement
1 (104) Symptom severity Laparoscopic surgery v medical treatment 4 –1 0 –1 0 Low Quality point deducted for sparse data. Directness point deducted for restricted population
2 (321) Quality of life Laparoscopic surgery v medical treatment 4 –1 –1 –1 0 Very low Quality point deducted for high loss to follow-up. Consistency point deducted for conflicting results. Directness point deducted for restricted population
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Type of evidence: 4 = RCT; 2 = Observational; Consistency: similarity of results across studies; PPI, proton pump inhibitors; H2RA, H2 receptor antagonistsDirectness: generalisability of population or outcomes Effect size: based on relative risk or odds ratio

Glossary

BMI

A measure of body composition defined as weight (kg) divided by the square of the height (m2).

Fundoplication

A surgical process involving plication (folding) of the fundus region of the stomach around the lower end of the oesophagus.

High-quality evidence

Further research is very unlikely to change our confidence in the estimate of effect.

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Very low-quality evidence

Any estimate of effect is very uncertain.

GORD in children

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Contributor Information

Brendan Delaney, Department of Primary Care and General Practice, University of Birmingham Medical School, Birmingham, UK.

Paul Moayyedi, Department of Medicine, Division of Gastroenterology, McMaster University, Hamilton, Canada.

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BMJ Clin Evid. 2008 Jun 13;2008:0403.

Lifestyle advice/modification

Summary

SYMPTOM SEVERITY Raising the head of the bed compared with not raising the head of the bed: We don't know whether raising the head of the bed (to produce a 10 ° slope) is more effective at increasing self-reported improvement or endoscopic appearance in people with endoscopically diagnosed GORD (grade C) ( very low-quality evidence ). Low-calorie diet plus advice and support compared with standard instructions about reflux disease plus general advice to lose weight: We don't know whether a low-calorie diet plus advice and support is more effective at improving symptoms or at reducing the number of episodes of reflux in people with GORD confirmed by 24-hour pH measurement (very low-quality evidence). NOTE We found no direct evidence about the effects of reducing coffee intake, stopping smoking, reducing alcohol intake, or reducing fatty food intake in the initial treatment of people with GORD associated with oesophagitis.

Benefits

Raising the head of the bed:

We found one systematic review (search date 2004), which identified no RCTs evaluating clinical outcomes of interest.We found one additional RCT (71 people aged 22–77 years with endoscopically diagnosed gastro-oesophageal reflux [grade C]), comparing raising the head of the bed (to produce a 10 ° slope) versus not raising the head of the bed in people additionally randomised to ranitidine 150 mg twice daily versus placebo for 6 weeks. It found that, in people taking placebo, raising the head of the bed increased self-reported improvement at 6 weeks compared with not raising the head of the bed (grading of improvement not specified; 10/17 [59%] with bed raised v 4/14 [29%] without bed raised; P value not reported). The benefit of raising the head of the bed was increased in people taking ranitidine (13/15 [87%] with ranitidine plus raised head of bed v 10/17 [59%] with placebo plus raised head of bed; P value not reported). Endoscopic appearances were not significantly different among any of the four groups.

Weight loss:

We found one systematic review, which identified one RCT evaluating clinical outcomes of interest. The RCT (20 people with GORD confirmed by 24-hour pH measurement, mean BMI 31.4 kg/m2) compared a low-calorie diet (430 kcal/day for the first 6 weeks) plus advice and support for 6 months versus standard instructions about GORD and general advice to lose weight. It found no significant difference between groups in change in symptoms or in the number of episodes of reflux (analysis not by intention to treat; 19 people in analysis; no further data reported), but the study may have lacked power to detect a clinically significant difference.

Reducing coffee intake; stopping smoking; reducing alcohol intake; reducing fatty food intake:

We found one systematic review, which found no RCTs evaluating clinical outcomes of interest for these lifestyle measures.

Harms

Raising the head of the bed:

The systematic review gave no information on adverse effects. The additional RCT gave no information on adverse effects.

Weight loss:

The systematic review gave no information on adverse effects. The RCT identified by the review gave no information on adverse effects.

Reducing coffee intake; stopping smoking; reducing alcohol intake; reducing fatty food intake:

The review found no RCTs on these lifestyle measures.

Comment

None.

Substantive changes

Lifestyle advice/modification (treatment) One systematic review added; benefits and harms data enhanced; categorisation unchanged (Unknown effectiveness). The review identified no RCTs evaluating clinical outcomes.

BMJ Clin Evid. 2008 Jun 13;2008:0403.

Antacids/alginates

Summary

SYMPTOM SEVERITY Compared with placebo: Antacids/alginates may be more effective at reducing the number of days with reflux symptoms at 8 weeks, but not in reducing the frequency or severity of reflux at 4 weeks, or endoscopic healing at 4–8 weeks in people with GORD and oesophagitis ( very low-quality evidence ). Compared with H2 receptor antagonists: We don't know whether antacids are more effective than cimetidine at improving endoscopic healing at 8 weeks. Calcium carbonate may be less effective than ranitidine at reducing the frequency and severity of heartburn at 1 week ( low-quality evidence ).

Benefits

Antacids/alginates versus placebo:

We found no systematic review. We found two RCTs. The first RCT (91 people with GORD and endoscopically confirmed oesophagitis grade A–C) compared antacids (1 tablet of aluminium hydroxide/magnesium carbonate 1 hour after meals and at bedtime) versus cimetidine 400 mg twice daily versus placebo for 8 weeks. It found that antacids significantly reduced the number of days with reflux symptoms compared with placebo, and reduced the median symptom score (days with reflux: 5 days with antacids v 13 days with placebo; P less than 0.05; symptom score, measured on a 100 mm visual analogue scale [100 mm = worst score]: 8 mm with antacids v 33 mm with placebo). However, it found no significant difference in endoscopic healing at 8 weeks (8/27 [30%] with antacids v 6/29 [21%] with placebo). The second, smaller RCT (32 people with GORD and oesophagitis confirmed by pH monitoring and an acid perfusion test) compared antacids (15 mL doses of aluminium and magnesium hydroxide 7 times daily) versus placebo for 4 weeks. The results of this RCT may be biased in favour of antacids because 11 people who had no heartburn symptoms after taking placebo for 1 week were eliminated from the analysis. It found no significant difference at 4 weeks between antacids and placebo in the frequency or severity of reflux or in endoscopic healing (reported as not significant; P value not reported), although it may have lacked power to exclude a clinically significant effect.

Antacids/alginates versus H2 receptor antagonists:

We found no systematic review. We found two RCTs. The first RCT (3-arm RCT, 91 people, described above) found no significant difference in endoscopic healing at 8 weeks between antacids and cimetidine (8/27 [30%] people taking antacids v 11/29 [38%] people taking cimetidine). The second RCT (155 people with oesophagitis up to grade D) found that calcium carbonate (750 mg as needed) was significantly less effective after 1 week than ranitidine 150 mg twice daily for reducing the frequency and severity of heartburn (results presented graphically; P less than 0.05). Subgroup analysis in people with erosive oesophagitis of grade A or greater (73 people) found that calcium carbonate significantly reduced the proportion of people with endoscopic healing at 12 weeks compared with ranitidine (10/35 [29%] with calcium carbonate v 21/38 [55%] with ranitidine; RR 0.52, 95% CI 0.28 to 0.94).

Harms

Antacids/alginates versus placebo:

The first RCT (91 people) found that six people in the antacid group reported transient constipation after 4 weeks of treatment. The second RCT gave no information on adverse effects.

Antacids/alginates versus H2 receptor antagonists:

The second RCT (155 people) found that antacids were associated with a higher rate of gastrointestinal adverse effects, including diarrhoea, nausea, vomiting, occult blood in the stool, gas, constipation, and duodenal ulcer, compared with ranitidine (12% with antacids v 3% with ranitidine; P = 0.056). One person taking antacids developed a duodenal ulcer. The RCT also found that a smaller proportion of people had headache, dizziness, insomnia, malaise, fatigue, weakness, chills, and nervousness with antacids than with ranitidine, but the difference was not significant (1% with antacids v 4% with ranitidine; P = 0.37).

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Jun 13;2008:0403.

Motility stimulants

Summary

We found no direct evidence about motility stimulants in the initial treatment of people with GORD associated with oesophagitis. NOTE The use of cisapride has been restricted because of concerns about heart rhythm abnormalities. This review does not search for, or include, cisapride.

Benefits

We found one systematic review (search date 2004; 4 RCTs, 520 people) assessing the effects of motility stimulants.All trials identified in the review evaluated the effectiveness of cisapride. We do not include cisapride in our search, and so these results are not discussed further. The review identified no RCTs comparing metoclopramide or domperidone versus placebo or other prokinetic drugs. We found no RCTs comparing metoclopramide or domperidone versus placebo or other prokinetic drugs.

Harms

The review gave no information on adverse effects of motility stimulants other than cisapride.

Drug safety alert

FDA highlights the risk of tardive dyskinesia associated with long-term or high-dose use of metoclopramide (26 February 2009).

The risk of tardive dyskinesia associated with long-term or high-dose use of metoclopramide has been highlighted by the FDA (http://www.fda.gov).

Comment

In some countries, use of cisapride has been restricted because of concerns about heart rhythm abnormalities associated with sudden death.

Substantive changes

Motility stimulants (treatment) One systematic review added;benefits and harms data amended; categorisation changed (from Likely to be ineffective or harmful to Unknown effectiveness). We no longer search for cisapride, as its use has been restricted in some countries because of potential heart-rhythm abnormalities associated with sudden death. The review added in this update identified no RCTs comparing metoclopramide or domperidone versus placebo or other prokinetic drugs.

BMJ Clin Evid. 2008 Jun 13;2008:0403.

H2 receptor antagonists

Summary

SYMPTOM SEVERITY Compared with placebo: H 2 receptor antagonists seem more effective at decreasing the proportion of people with persistent oesophagitis at 4 and 12 weeks, and at decreasing the proportion of people with reflux symptoms at 12 weeks ( moderate-quality evidence ). Compared with proton pump inhibitors: H 2 receptor antagonists are less effective at decreasing the proportion of people with persistent oesophagitis at 4 and 12 weeks ( high-quality evidence ). Compared with antacids/alginates: We don't know whether cimetidine is more effective than antacids at improving endoscopic healing at 8 weeks. Ranitidine may be more effective than calcium carbonate at reducing the frequency and severity of heartburn at 1 week ( low-quality evidence ).

Benefits

H2 receptor antagonists versus placebo:

We found one systematic review (search date 2004, 10 RCTs, 1241 people) comparing H2 receptor antagonists (H2RAs) versus placebo in people with oesophagitis. It found that H2RAs significantly decreased the proportion of people with persistent oesophagitis at 4 and 12 weeks compared with placebo (4 weeks, 3 RCTs, 763 people: 259/384 [67%] with H2RA v 305/379 [80%] with placebo; RR 0.79, 95% CI 0.63 to 0.98; 12 weeks, 9 RCTs, 1847 people; 415/997 [42%] with H2RA v 534/850 [63%] with placebo; RR 0.64, 95% CI 0.57 to 0.72).The review also found that H2RAs significantly reduced the risk of persistence of reflux symptoms at 12 weeks compared with placebo (1 RCT, 191 people; 90/125 [72%] with H2RA v 60/66 [91%] with placebo; RR 0.79, 95% CI 0.69 to 0.90). The difference between groups at 4 weeks was not significant (1 RCT, 30 people; 8/15 [53%] with H2RA v 10/15 [67%] with placebo; RR 0.80, 95% CI 0.44 to 1.45). However, this analysis was based on one small RCT that did not meet BMJ Clinical Evidence inclusion criteria. The review found significant heterogeneity between the studies for all time frames (P = 0.006). Predefined subgroup analyses did not reveal any explanation for the observed heterogeneity.

H2 receptor antagonists versus proton pump inhibitors:

See benefits of proton pump inhibitors for initial treatment of GORD.

H2 receptor antagonists versus antacids:

See benefits of antacids/alginates for initial treatment of GORD.

Harms

H2 receptor antagonists versus placebo:

The review found no significant difference between H2RAs and placebo in the proportion of people reporting at least one adverse effect (2 RCTs, 488 people; 98/246 [40%] with H2RA v 88/242 [36%] with placebo; RR 1.10, 95% CI 0.88 to 1.38).

H2 receptor antagonists versus proton pump inhibitors:

See harms of proton pump inhibitors for initial treatment of GORD.

H2 receptor antagonists versus antacids:

See harms of antacids/alginates for initial treatment of GORD.

Comment

None.

Substantive changes

H2 receptor antagonists (treatment) One systematic review added; benefits and harms data enhanced; categorisation unchanged (Beneficial); systematic review added at this update supersedes a review with an earlier search date. The review with the later search date reaches the same conclusions as the earlier review: H2 receptor antagonists are effective in the treatment of oesophagitis.

BMJ Clin Evid. 2008 Jun 13;2008:0403.

Proton pump inhibitors

Summary

SYMPTOM SEVERITY Compared with placebo: Standard-dose proton pump inhibitors are more effective at decreasing the proportion of people with persistent oesophagitis at 4 and 8 weeks ( high-quality evidence ). Compared with H2 receptor antagonists: Proton pump inhibitors are more effective at decreasing the proportion of people with persistent oesophagitis at 4 and 12 weeks (high-quality evidence). Proton pump inhibitors compared with each other: We don't know whether one proton pump inhibitor is any more effective than the others at improving clinical benefit in people with reflux oesophagitis ( low-quality evidence ).

Benefits

Proton pump inhibitors versus placebo:

We found one systematic review (search date 2004, 5 RCTs, 645 people with oesophagitis comparing proton pump inhibitors (PPIs) versus placebo.The review found that, at 4 and 8 weeks, standard-dose PPIs significantly decreased the proportion of people with persistent oesophagitis compared with placebo (4 weeks: 4 RCTs, 595 people; 131/369 [36%] with PPI v 190/226 [84%] with placebo; RR 0.38, 95% CI 0.23 to 0.65; 8 weeks: 5 RCTs, 645 people; 66/394 [17%] with PPI v 180/251 [72%] with placebo; RR 0.24, 95% CI 0.19 to 0.31; NNT 1.7, 95% CI 1.5 to 2.1). It also found that, compared with placebo, PPIs significantly reduced the proportion of people with persistence of reflux symptoms after 8 weeks' treatment (1 RCT, 50 people; 15/25 [60%] with PPI v 24/25 [96%] with placebo; RR 0.63, 95% CI 0.45 to 0.87). There was significant heterogeneity between the trial results at 4 weeks (P less than 0.0001), but not at 8 weeks (P = 0.34): predefined subgroup analyses did not reveal any explanation for the observed heterogeneity at 4 weeks.

Proton pump inhibitors versus H2 receptor antagonists:

We found one systematic review (search date 2004; 34 RCTs, 5887 people).The meta-analysis carried out by the review compared PPIs versus H2 receptor antagonists (H2RAs) and H2RAs plus prokinetics (motility stimulant). Of the 34 RCTs included in the review, 27 compared proton pump inhibitor (PPI) versus H2RA alone. The review did not carry out a subgroup analysis of PPIs versus H2RAs alone. At 4 and 12 weeks, the review found that PPIs significantly decreased the proportion of people with persistent oesophagitis compared with H2RA (4 weeks; 26 RCTs, 4032 people; 655/2079 [32%] with PPI v 1201/1953 [62%] with H2RA; RR 0.50, 95% CI 0.45 to 0.56; NNT 4, 95% CI 3 to 4: 12 weeks: 3 RCTs, 393 people; 45/199 [23%] with PPI v 105/194 [54%] with H2RA; RR 0.44, 95% CI 0.26 to 0.73).It also found a significantly lower rate of persistence of global symptoms at 4 and 8 weeks in the PPI group compared with the H2RA group (4 weeks; 15 RCTs, 2941 people; 524/1486 [35%] with PPI v 850/1455 [58%] with H2RA; RR 0.57, 95% CI 0.48 to 0.68; 8 weeks: 3 RCTs, 898 people; 145/451 [32%] with PPI v 247/447 [55%] with H2RA; RR 0.56, 95% CI 0.40 to 0.77). The review found significant heterogeneity between the trial results (P less than 0.0007).

Proton pump inhibitors versus each other:

We found two systematic reviews (search dates 2004 and 2005) and five subsequent RCTs comparing different proton pump inhibitors in people with reflux oesophagitis.

Esomeprazole versus omeprazole:

The first review found that a significantly lower proportion of people had persistent oesophagitis after 4 weeks' treatment with esomeprazole 20 mg compared with omeprazole 20 mg (see table 1 ).However, at 8 weeks, there was no significant difference between treatments (see table 1 ). One subsequent RCT found no significant difference in healed oesophagitis after 8 weeks' treatment between esomeprazole 20 mg and omeprazole 20 mg, although the difference between groups was of borderline significance (see table 1 ). The reviewand subsequent RCT assessed esomeprazole 20 mg. However, esomeprazole is marketed at a standard dose of 40 mg. A subsequent RCT compared healing rates of esomeprazole 40 mg versus omeprazole 20 mg after 8 weeks' treatment. The RCT, which carried out an intention-to-treat analysis (defined as all patients randomised to treatment), found no significant difference in healing rates at 8 weeks between esomeprazole and omeprazole (see table 1 ). However, a subgroup analysis of people with moderate or severe disease (LA grade C–D) found a significantly higher rate of healing at 8 weeks with esomeprazole compared with omeprazole (167/189 [88%] with esomeprazole v 131/169 [78%] with omeprazole; P = 0.007). The RCT found no significant difference between treatments in the proportion of people with investigator-assessed resolution of heartburn (see table 1 ). Another subsequent RCT (48 people with endoscopically confirmed oesophagitis) found a trend towards increased healing rates at 8 weeks with esomeprazole 40 mg compared with omeprazole 20 mg, but this trend did not reach significance (see table 1 ).

Table 1.

Summary of RCTs for the comparison of proton pump inhibitors versus each other

Ref Number of people Duration Proportion of people in remission or with persistence of symptoms Effect size for remission or symptom persistence
Esomeprazole versus omeprazole
1 RCT, 1306 people 4 weeks Persistence of oesophagitis: 229/650 (35%) with omeprazole v 194/656 (30%) with esomeprazole RR 1.19, 95% CI 1.02 to 1.39
1 RCT, 1306 people 8 weeks Persistence of oesophagitis: 85/650 (13%) with omeprazole v 66/656 (10%) with esomeprazole RR 1.30, 95% CI 0.96 to 1.76
1 RCT, 1250 people 4 weeks Persistence of heartburn: 267/624 (43%) with omeprazole v 244/626 (39%) with esomeprazole RR 1.10, 95% CI 0.96 to 1.25
1176 people with endoscopically confirmed LA grade A to D oesophagitis 8 weeks Healed oesophagitis: 508/587 (87%) with esomeprazole v 484/588 (82%) with omeprazole P = 0.052
1148 people with endoscopically confirmed LA grade A to D oesophagitis 8 weeks Healed oesophagitis: 501/576 (90%) with esomeprazole v 491/572 (86%) with omeprazole P = 0.552
Investigator-assessed resolution of heartburn: 65% with esomeprazole v 63% with omeprazole; absolute numbers not reported P = 0.48
48 people with endoscopically confirmed oesophagitis 8 weeks Healed oesophagitis: intention-to-treat analysis: 16/25 (64%) with esomeprazole v 10/22 (46%) with omeprazole P = 0.25
Esomeprazole versus pantoprazole
563 people with endoscopically confirmed oesophagitis 4 weeks Mean number of episodes: 0.7 with esomeprazole v 0.7 with pantoprazole Significance not assessed
Esomeprazole versus other proton pump inhibitors
10 RCTs, 15,316 people 4 weeks Healed oesophagitis: absolute numbers not reported Random effects model; RR 1.10, 95% CI 1.05 to 1.15
8 weeks Healed oesophagitis: absolute numbers not reported Random effects model; RR 1.05, 95% CI 1.02 to 1.08
4 weeks Relief from GORD symptoms: absolute numbers not reported Fixed effects model: RR 1.08, 95% CI 1.05 to 1.11
Omeprazole versus rabeprazole
2 RCTs, 409 people 4 weeks Persistence of oesophagitis: 30/205 (15%) with omeprazole v 34/204 (17%) with rabeprazole RR 0.88, 95% CI 0.56 to 1.37
3 RCTs, 469 people 8 weeks Persistence of oesophagitis: 21/235 (9%) with omeprazole v 23/234 (10%) with rabeprazole RR 0.92, 95% CI 0.52 to 1.62
1 RCT, 200 people 4 weeks Persistence of global symptoms: 75/102 (75%) with omeprazole v 69/98 (70%) with rabeprazole RR 1.04, 95% CI 0.88 to 1.24
1 RCT, 200 people 8 weeks Persistence of global symptoms: 70/102 (70%) with omeprazole v 61/98 (62%) with rabeprazole RR 1.10, 95% CI 0.90 to 1.35
1 RCT, 207 people 8 weeks Overall adverse effects: 24/103 (23%) with omeprazole v 21/104 (20%) with rabeprazole RR 1.15, 95% CI 0.69 to 1.94
560 people with Savary–Miller grade I–III oesophagitis 8 weeks Proportion of people with healed oesophagitis: 228/233 (98%) with rabeprazole v 231/237 (98%) with omeprazole P less than 0.0001
Incidence of headache: 13/272 (5%) with omeprazole v 4/277 (1%) with rabeprazole P = 0.024
Mean time to first day with satisfactory heartburn relief: 2.8 days with rabeprazole v 4.7 days with omeprazole P = 0.0045
Omeprazole versus lansoprazole
4 RCTs, 969 people 4 weeks Persistence of oesophagitis: 192/488 (39%) with omeprazole v 170/481 (35%) with lansoprazole RR 1.11, 95% CI 0.95 to 1.31
4 RCTs, 1004 people 8 weeks Persistence of oesophagitis: 124/508 (24%) with omeprazole v 110/496 (22%) with lansoprazole RR 1.10, 95% CI 0.88 to 1.38
1 RCT, 307 people 4 weeks Persistence of heartburn: 24/151 (16%) with omeprazole v 34/156 (22%) with lansoprazole RR 0.73, 95% CI 0.45 to 1.17
1 RCT, 307 people 8 weeks Persistence of heartburn: 20/151 (13%) with omeprazole v 30/156 (19%) with lansoprazole RR 0.69, 95% CI 0.41 to 1.16
1 RCT, 228 people 8 weeks Overall adverse effects: 33/113 (29%) with omeprazole v 38/115 (33%) with lansoprazole RR 0.88, 95% CI 0.60 to 1.30
Omeprazole versus pantoprazole
4 RCTs, 881 people 4 weeks Persistence of oesophagitis: 105/396 (27%) with omeprazole v 134/485 (28%) with pantoprazole RR 1.00, 95% CI 0.80 to 1.25
4 RCTs, 890 people 8 weeks Persistence of oesophagitis: 59/399 (14.8%) with omeprazole v 75/491 (15.3%) with pantoprazole RR 1.02, 95% CI 0.73 to 1.41
1 RCT, 286 people 4 weeks Persistence of global symptoms: 21/95 (22%) with omeprazole v 50/191 (26%) with pantoprazole RR 0.84, 95% CI 0.54 to 1.32
2 RCTs, 527 people 8 weeks Overall adverse effects: 22/216 (10%) with omeprazole v 41/311 (13%) with pantoprazole RR 0.74, 95% CI 0.45 to 1.22
Pantoprazole versus lansoprazole
1 RCT, 461 people 4 weeks Persistence of oesophagitis: 42/226 (19%) with pantoprazole v 46/235 (20%) with lansoprazole RR 0.95, 95% CI 0.65 to 1.38
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Esomeprazole versus pantoprazole:

The first systematic review did not identify any RCTs for this comparison. One subsequent RCT compared esomeprazole 40 mg versus pantoprazole 40 mg. The RCT found similar numbers of symptom episodes at 4 weeks for the two treatments. The RCT did not assess significance for the between-group comparison, but reported that pantoprazole was non-inferior to esomeprazole during treatment (see table 1 ).

Esomeprazole versus other proton pump inhibitors:

The second systematic review (search date 2005; 10 RCTs; 15,316 people with oesophagitis) compared esomeprazole 40 mg versus proton pump inhibitors (PPIs).Of the 10 studies included in the meta-analysis carried out by the review, one study was reported in only abstract form, and one set of data was taken from packaging insert. The remaining 8 RCTs were identified by the first review. The review found a significant increase in rate of healing of oesophagitis at 4 and 8 weeks with esomeprazole 40 mg compared with other PPIs at standard doses (see table 1 ). The review also found that esomeprazole 40 mg significantly improved relief from symptoms of GORD at 4 weeks compared with other PPIs (see table 1 ).

Omeprazole versus lansoprazole, pantoprazole, or rabeprazole:

The first review (search date 2004) found no significant difference between omeprazole 20 mg and lansoprazole 30 mg, pantoprazole 40 mg, or rabeprazole 20 mg in proportion of people with persistent oesophagitis at 4 and 8 weeks (see table 1 ). The review also found no significant difference between omeprazole and lansoprazole and pantoprazole in persistence of global symptoms at 4 weeks, and no significant difference between omeprazole and lansoprazole in persistence of heartburn at 4 and 8 weeks (see table 1 ). One subsequent RCT (560 people with Savary–Miller grade I–III oesophagitis) found rabeprazole 20 mg and omeprazole 20 mg to be statistically equivalent in the proportion of people with healed oesophagitis at 8 weeks (see table 1 ).However, the RCT found that rabeprazole relieved symptoms of heartburn significantly faster compared with omeprazole (see table 1 ).

Pantoprazole versus lansoprazole:

The first review found no significant difference between pantoprazole and lansoprazole in proportion of people with persistent oesophagitis at 4 weeks (see table 1 ).

Proton pump inhibitors plus H2 receptor antagonists versus proton pump inhibitors alone:

We found no systematic review or RCTs comparing proton pump inhibitors plus H2 receptor antagonists versus proton pump inhibitors alone in adults with GORD.

Harms

Proton pump inhibitors versus placebo:

The first review found no significant difference between proton pump inhibitors (PPIs) and placebo in the rate of overall adverse effects (2 RCTs, 608 people: 69/383 [18%] with PPI v 21/225 [9%] with placebo; RR 1.01, 95% CI 0.67 to 1.52). It also found no significant difference between groups in rates of diarrhoea and headache (1 RCT, 256 people: diarrhoea: 14/174 [8%] with PPI v 4/82 [5%] with placebo; RR 1.65; 95% CI 0.56 to 4.86; headache: 14/174 [8%] with PPI v 10/82 [12%] with placebo; RR 0.66; 95% CI 0.31 to 1.42).

Proton pump inhibitors versus H2 receptor antagonists:

The review found no significant difference in rate of overall adverse effects between proton pump inhibitors (PPIs) and H2 receptor antagonists (H2RAs) (6 RCTs, 1359 people: 170/685 [25%] with PPI v 174/674 [26%] with H2RA; RR 0.92, 95% CI 0.63 to 1.36). It also found no significant difference between groups in incidence of diarrhoea and headache (diarrhoea: 13 RCTs, 3077 people: 92/1600 [6%] with PPI v 68/1477 [5%] with H2RA; RR 1.26, 95% CI 0.88 to 1.81: headache: 9 RCTs, 2208 people; 64/1159 [5.5%] with PPI v 65/1049 [6.2%] with H2RA: RR 0.98, 95% CI 0.62 to 1.53).

Proton pump inhibitors versus each other:

esomeprazole versus omeprazole:

The first review gave no information on adverse effects for this comparison. Two subsequent RCTs comparing esomeprazole and omeprazole found similar proportions of adverse effects reported for both groups (first RCT: 44% with esomeprazole v 43% with omeprazole; second RCT: 49% with esomeprazole v 45% with omeprazole: absolute numbers not reported in either RCT; significance not assessed in either RCT). The most common adverse effect in the two groups in both RCTs was headache (absolute numbers reported; significance not assessed). The third RCT comparing esomeprazole and omeprazole found no significant difference between groups in the proportion of people reporting at least one adverse effect (7/25 [28%] with esomeprazole v 6/23 [26%] with omeprazole; P = 1.00).

Esomeprazole versus pantoprazole:

The RCT found that both treatments were well tolerated, with only 7 people stopping treatment because of an adverse effect (4/277 [1.4%] with esomeprazole v 3/284 [1.1%] with pantoprazole; significance not assessed).

Esomeprazole versus other proton pump inhibitors:

The second review found no difference in total number of adverse effects, or in reported rates of diarrhoea, abdominal pain, or nausea, between the different proton pump inhibitors (data not reported; significance not assessed). However, it found a significant increase in the proportion of people reporting headache with esomeprazole compared with other proton pump inhibitors (RR 1.22, 95% CI 1.03 to 1.44; absolute numbers not reported).

Omeprazole versus lansoprazole, pantoprazole, or rabeprazole:

The first review found no significant difference in overall adverse effects between omeprazole and rabeprazole, lansoprazole, or pantoprazole (see table 1 ).One subsequent RCT found a significant increase in incidence of headache with omeprazole compared with rabeprazole (see table 1 ).

Pantoprazole versus lansoprazole:

The review gave no information on adverse effects for this comparison.

Proton pump inhibitors plus H2 receptor antagonists versus proton pump inhibitors alone:

We found no RCTs.

Drug safety alert

FDA issues drug safety alert on the possible increased risk of fractures of the hip, wrist, and spine, associated with the use of proton pump inhibitors. (25 May 2010)

A drug safety alert has been issued on the possible increased risk of fractures of the hip, wrist, and spine, associated with the use of proton pump inhibitors. (www.fda.gov)

Comment

We identified one RCT in Korean comparing proton pump inhibitors versus H2 receptor antagonists. We are awaiting translation of this RCT, and will assess the trial for potential inclusion after translation.

Substantive changes

Proton pump inhibitors (treatment) Two systematic reviews and 5 RCTs added; benefits and harms data enhanced; categorisation unchanged (Beneficial). The reviews and RCTs found proton pump inhibitors to be effective in the treatment of GORD. They seem more effective than H2 receptor antagonists. The reviews and RCTs added found similar effects with various proton pump inhibitors in treating symptoms of GORD and in incidence of adverse effects.

BMJ Clin Evid. 2008 Jun 13;2008:0403.

Lifestyle advice/modification

Summary

WE FOUND NO DIRECT EVIDENCE ABOUT LIFESTYLE ADVICE/MODIFICATION (REDUCING COFFEE INTAKE, STOPPING SMOKING, REDUCING ALCOHOL INTAKE, REDUCING FATTY FOOD INTAKE, OR RAISING THE HEAD OF THE BED) IN THE MAINTENANCE TREATMENT OF PEOPLE WITH GORD ASSOCIATED WITH OESOPHAGITIS.

Benefits

We found no systematic review or RCTs on lifestyle advice/modification (reducing coffee intake, stopping smoking, reducing alcohol intake, reducing fatty food intake, or raising the head of the bed) for the long-term management of reflux oesophagitis.

Harms

We found no RCTs.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Jun 13;2008:0403.

Antacids/alginates

Summary

WE FOUND NO DIRECT EVIDENCE ABOUT ANTACIDS/ALGINATES IN THE MAINTENANCE TREATMENT OF PEOPLE WITH GORD ASSOCIATED WITH OESOPHAGITIS.

Benefits

We found no systematic review or RCTs.

Harms

See harms of antacids/alginates for the initial treatment of GORD.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Jun 13;2008:0403.

Motility stimulants

Summary

We found no direct evidence about motility stimulants in the maintenance treatment of people with GORD associated with oesophagitis. NOTE The use of cisapride has been restricted because of concerns about heart rhythm abnormalities. This review does not search for, or include, cisapride.

Benefits

We found one systematic review comparing cisapride (up to 40 mg/day) versus placebo for 6–12 months in people with healed oesophagitis. We do not include cisapride in our search, and so these results are not discussed further. We found no RCTs comparing other prokinetic drugs versus placebo for maintenance treatment in people with GORD and healed oesophagitis.

Harms

See harms of motility stimulants for initial treatment of GORD.

Comment

None.

Substantive changes

Motility stimulants (maintenance) Categorisation changed (from Likely to be ineffective or harmful to Unknown effectiveness). We no longer search for cisapride as its use has been restricted in some countries because of potential heart-rhythm abnormalities associated with sudden death. We found no RCTs comparing other prokinetic drugs versus placebo for maintenance treatment in people with GORD and healed oesophagitis.

BMJ Clin Evid. 2008 Jun 13;2008:0403.

H2 receptor antagonists (reduce relapse of oesophagitis and reflux symptoms at 6–12 months compared with placebo, but not as effective as proton pump inhibitors)

Summary

RELAPSE RATES Compared with placebo: H 2 receptor antagonists may be more effective at reducing the proportion of people with symptomatic relapse of reflux symptoms in people with healed oesophagitis, but not in reducing the proportion of people with relapse of oesophagitis ( low-quality evidence ). H2 receptor antagonists compared with each other: Nizatidine may be marginally more effective than famotidine at maintaining remission (not further defined) in people with endoscopically healed oesophagitis ( very low-quality evidence ). Compared with proton pump inhibitors: H 2 receptor antagonists are less effective than standard- or low-dose proton pump inhibitors at reducing the proportion of people with relapse of oesophagitis or relapse of reflux symptoms at 6–12 months in people with healed oesophagitis ( high-quality evidence ).

Benefits

H2 receptor antagonists versus placebo:

We found one systematic review and one additional RCT. The review (search date 2003) found that H2 receptor antagonists (H2RAs) reduced relapse of oesophagitis compared with placebo, but the difference was not significant (oesophagitis relapse: 4 RCTs, 655 people with healed oesophagitis; AR: 124/467 [27%] with H2RAs v 89/188 [47%] with placebo; RR 0.57, 95% CI 0.32 to 1.01). It found that H2RAs significantly reduced relapse of reflux symptoms compared with placebo (symptomatic relapse: 2 RCTs, 451 people with healed oesophagitis; AR: 92/328 [28%] with H2RAs v 62/123 [50%] with placebo; RR 0.52, 95% CI 0.41 to 0.67). The additional RCT (69 people with endoscopically healed oesophagitis) compared ranitidine (150 mg at bedtime) versus placebo for 6 months. It found no significant difference in relapse rates at 6 months between ranitidine and placebo (8 people excluded from analysis: 14/33 [42%] with ranitidine v 10/28 [36%] with placebo; CI and P value not reported).

H2 receptor antagonists versus each other:

We found one RCT comparing nizatidine 150 mg twice daily versus famotidine 20 mg twice daily for 6 months. It found that nizatidine significantly increased maintenance of remission compared with famotidine (72 people with endoscopically healed oesophagitis; proportion of people with continued remission: 17/35 [49%] with nizatidine v 9/37 [24%] with famotidine; P = 0.049).

H2 receptor antagonists versus proton pump inhibitors:

See benefits of proton pump inhibitors for maintenance treatment in GORD.

Harms

H2 receptor antagonists versus placebo:

The systematic review found no significant difference in adverse effects between H2 receptor antagonists and placebo (3 RCTs, 524 people; proportion of people with at least one adverse effect: 13% with H2 receptor antagonists v 9% with placebo; RR 1.36, 95% CI 0.78 to 2.37). In the additional RCT (69 people), four people taking placebo reported adverse effects (rashes, transient headache, transient paraesthesia).

H2 receptor antagonists versus each other:

The RCT gave no information on adverse effects.

H2 receptor antagonists versus proton pump inhibitors:

See harms of proton pump inhibitors for maintenance treatment in GORD.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2008 Jun 13;2008:0403.

Proton pump inhibitors

Summary

RELAPSE RATES Compared with placebo: Standard- and low-dose proton pump inhibitors are more effective at reducing the proportion of people with relapse of oesophagitis or relapse of reflux symptoms at 6–12 months in people with healed oesophagitis ( high-quality evidence ). Compared with H2 receptor antagonists: Standard- or low-dose proton pump inhibitors are more effective at 6–12 months at reducing the proportion of people with relapse of oesophagitis or relapse of reflux symptoms in people with healed oesophagitis ( high-quality evidence ). Proton pump inhibitors compared with each other: Standard-dose proton pump inhibitors seem more effective than low-dose proton pump inhibitors at reducing the proportion of people with relapse of oesophagitis or relapse of reflux symptoms in people with healed oesophagitis. We don't know whether different dosage schedules or different proton pump inhibitors are more effective at preventing relapse compared with each other in people with healed oesophagitis ( moderate-quality evidence ).

Benefits

Proton pump inhibitors versus placebo:

We found one systematic review (search date 2003), which compared standard-dose proton pump inhibitors (PPIs) (omeprazole 20 mg, lansoprazole 30 mg, rabeprazole 20 mg, and pantoprazole 40 mg all once daily) or low-dose PPIs (omeprazole 10 mg, lansoprazole 15 mg, rabeprazole 10 mg, and pantoprazole 20 mg all once daily) versus placebo in people with healed oesophagitis. The review found that standard-dose PPIs significantly reduced relapse of oesophagitis at 6–12 months compared with placebo (oesophagitis relapse: 9 RCTs, 1385 people; 156/720 [22%] with PPI v 524/665 [79%] with placebo; RR 0.26, 95% CI 0.19 to 0.36) and reflux symptoms (symptom relapse: 9 RCTs, 1334 people; 189/680 [28%] with PPI v 489/641 [76%] with placebo; RR 0.34, 95% CI 0.25 to 0.46). The review found that low-dose PPIs significantly reduced relapse of oesophagitis (oesophagitis relapse: 10 RCTs, 1465 people; 268/742 [36%] with PPI v 545/723 [75%] with placebo; RR 0.46, 95% CI 0.38 to 0.57) and reflux symptoms (symptom relapse: 10 RCTs, 1426 people; 321/723 [44%] with PPI v 516/703 [73%] with placebo; RR 0.54, 95% CI 0.42 to 0.69) compared with placebo at 6–12 months.

Proton pump inhibitors versus H2 receptor antagonists:

We found one systematic review and one subsequent RCT. The review compared standard-dose proton pump inhibitors (PPIs) (omeprazole 20 mg, lansoprazole 30 mg, rabeprazole 20 mg, and pantoprazole 40 mg all once daily) or low-dose PPIs (omeprazole 10 mg, lansoprazole 15 mg, rabeprazole 10 mg, and pantoprazole 20 mg all once daily) versus H2 receptor antagonists (H2RAs) in people with healed oesophagitis. It found that, at 6–12 months, standard-dose PPIs significantly reduced relapse of oesophagitis and reflux symptoms compared with H2 receptor antagonists (oesophagitis relapse: 10 RCTs, 1583 people; 180/800 [22%] with PPI v 457/783 [58%] with H2RAs; RR 0.36, 95% CI 0.28 to 0.46; symptom relapse: 5 RCTs, 797 people; 87/402 [22%] with PPI v 175/395 [44%] with H2RAs; RR 0.48, 95% CI 0.39 to 0.60). The review found that low-dose PPIs also significantly reduced relapse of oesophagitis and reflux symptoms at 6–12 months compared with H2RAs (oesophagitis relapse: 6 RCTs, 1156 people; 226/581 [39%] with PPI v 380/575 [66%] with H2RAs; RR 0.57, 95% CI 0.47 to 0.69; symptom relapse: 4 RCTs, 831 people; 136/433 [31%] with PPI v 227/398 [57%] with H2RAs; RR 0.55, 95% CI 0.47 to 0.65). The subsequent RCT compared four treatments: pantoprazole 10 mg once daily, pantoprazole 20 mg once daily, pantoprazole 40 mg once daily, and ranitidine 150 mg twice daily. It found that pantoprazole 40 mg or 20 mg, but not pantoprazole 10 mg, significantly increased maintenance of remission at 12 months compared with ranitidine (350 people with healed oesophagitis; AR for continued remission at 12 months: 78% with 40 mg pantoprazole v 55% with 20 mg pantoprazole v 46% with 10 mg pantoprazole v 21% with ranitidine; P less than 0.001 for 40 mg or 20 mg pantoprazole v ranitidine; 10 mg pantoprazole v ranitidine reported as not significant, P value not reported).

Proton pump inhibitors versus each other:

We found one systematic review, and three subsequent RCTs. The review compared standard-dose proton pump inhibitors (PPIs) (omeprazole 20 mg, lansoprazole 30 mg, rabeprazole 20 mg, and pantoprazole 40 mg all once daily) versus low-dose PPIs (omeprazole 10 mg, lansoprazole 15 mg, rabeprazole 10 mg, and pantoprazole 20 mg all once daily).The review found that standard-dose PPIs significantly reduced relapse of oesophagitis and reflux symptoms compared with low-dose PPIs (oesophagitis relapse: 22 RCTs, 5964 people with healed oesophagitis; 555/3179 [17%] with standard-dose PPI v 810/2785 [29%] with low-dose PPI; RR 0.63, 95% CI 0.55 to 0.73; symptom relapse: 18 RCTs, 5116 people with healed oesophagitis; 844/2749 [31%] with standard-dose PPI v 848/2367 [36%] with low-dose PPI; RR 0.78, 95% CI 0.68 to 0.88). The review found no significant difference in oesophagitis relapse or reflux symptom relapse between lansoprazole 15 mg once daily and lansoprazole 30 mg on alternate days (oesophagitis relapse: 2 RCTs, 189 people; RR 0.77, 95% CI 0.46 to 1.30; reflux symptom relapse: 2 RCTs, 187 people: RR 0.74, 95% CI 0.46 to 1.19). It found no significant difference between high-dose esomeprazole (40 mg/day) and standard-dose esomeprazole (20 mg/day) in oesophagitis relapse or reflux symptom relapse (oesophagitis relapse: 2 RCTs, 354 people; RR 0.64, 95% CI 0.36 to 1.15; reflux symptom relapse: 2 RCTs, 334 people; RR 1.13, 95% CI 0.87 to 1.47). It found no significant difference in oesophagitis relapse between omeprazole and lansoprazole or rabeprazole (3 RCTs, 1020 people; RR 0.93, 95% CI 0.65 to 1.32). However, it found that omeprazole significantly increased relapse of reflux symptoms compared with lansoprazole or rabeprazole (3 RCTs, 1001 people; RR 1.19, 95% CI 1.02 to 1.38). The first subsequent RCT found that, at 12 months, pantoprazole 40 mg daily significantly increased maintenance of remission compared with pantoprazole 20 mg daily, and that both pantoprazole 40 mg and 20 mg daily significantly increased maintenance of remission compared with pantoprazole 10 mg daily (4-arm RCT [see PPIs versus H2 receptor antagonists, above, for details]; 350 people with healed oesophagitis; AR for continued remission at 12 months: 78% with pantoprazole 40 mg v 55% with pantoprazole 20 mg v 46% with 10 mg pantoprazole; P less than 0.01 for 40 mg v 20 mg pantoprazole; P less than or equal to 0.005 for 40 mg or 20 mg v 10 mg pantoprazole).The second subsequent RCT (1026 people with healed oesophagitis LA grade A–D) compared esomeprazole 20 mg once daily versus lansoprazole 15 mg once daily. The primary outcome was estimated endoscopic/symptomatic remission rate (Kaplan–Meier estimate). The RCT found that, at 6 months, esomeprazole 20 mg significantly increased maintenance of estimated endoscopic/symptomatic (P = 0.0007) and endoscopic remission (P = 0.0003) compared with lansoprazole 15 mg. The observed endoscopic/symptomatic remission rate at 3 months was significantly higher with esomeprazole 20 mg compared with lansoprazole 15 mg (465/501 [93%] with esomeprazole v 434/500 [87%] with lansoprazole; P less than 0.0001). The third subsequent RCT (1316 people with healed oesophagitis LA grade A–D) compared esomeprazole 20 mg once daily versus pantoprazole 20 mg once daily. The RCT carried out an intention-to treat-analysis (excluded people who had not received any dose of the study drug during an initial open label acute-treatment phase or during the maintenance phase). The RCT found no significant difference between treatments in maintenance of remission at 6 months (combined endoscopic and symptomatic remission rates) (ITT: 85% with esomeprazole v 84% with pantoprazole; absolute numbers not reported; reported as not significant; P value not reported).

Harms

Proton pump inhibitors versus placebo:

The review found that standard-dose proton pump inhibitors (PPIs) significantly increased adverse effects compared with placebo (proportion of people with at least one adverse effect: 5 RCTs, 806 people; 54% with PPI v 42% with placebo; RR 1.32, 95% CI 1.15 to 1.52). The review found that low-dose PPIs significantly increased adverse effects compared with placebo (proportion of people with at least one adverse effect: 6 RCTs, 1057 people; 42% with PPI v 34% with placebo; RR 1.25, 95% CI 1.09 to 1.43).

Proton pump inhibitors versus H2 receptor antagonists:

The review found no significant difference between standard-dose proton pump inhibitors (PPIs) and H2 receptor antagonists (H2RAs) (proportion of people with at least one adverse effect: 3 RCTs, 469 people; 19% with PPI v 15% with H2RAs; RR 1.26, 95% CI 0.89 to 1.80). The review found that low-dose PPIs significantly increased adverse effects compared with H2RAs (proportion of people with at least one adverse effect: 3 RCTs, 574 people; 44% with PPI v 31% with H2RAs; RR 1.38, 95% CI 1.11 to 1.72). The subsequent RCT found no significant difference between pantoprazole (10 mg, 20 mg, and 40 mg groups combined) and ranitidine in headache, serious adverse effects, or withdrawal caused by adverse effects (headache: 13% with pantoprazole v 6% with ranitidine; P = 0.09; serious adverse effects: 7% with pantoprazole v 3% with ranitidine; reported as non-significant; withdrawal: 5.4% with pantoprazole v 5.6% with ranitidine; P = 0.98).

Proton pump inhibitors versus each other:

The review found no significant difference in adverse effects between standard-dose proton pump inhibitors (PPIs) and low-dose PPIs (proportion of people with at least one adverse effect: 10 RCTs, 2812 people; 41.5% with standard-dose PPI v 41.4% with low-dose PPI; RR 1.01, 95% CI 0.93 to 1.09). It found no significant difference in adverse effects between lansoprazole 15 mg oral once daily and lansoprazole 30 mg on alternate days (1 RCT, 52 people; RR 0.62, 95% CI 0.11 to 3.39). The review did not report on harms for high-dose esomeprazole versus standard-dose esomeprazole, or for omeprazole versus rabeprazole or lansoprazole. The first subsequent RCT found similar rates of withdrawal caused by adverse effects with pantoprazole 10 mg, 20 mg, and 40 mg (5.7% with pantoprazole 10 mg v 4.5% with pantoprazole 20 mg v 5.9% with pantoprazole 40 mg; significance not reported).The second subsequent RCT found that esomeprazole and lansoprazole were well tolerated, with adverse effects occurring in a similar proportion of the two treatment groups (253/510 [50%] with esomeprazole v 234/514 [46%] with lansoprazole; significance not assessed; P value not reported). The third subsequent RCT found that esomeprazole and pantoprazole were well tolerated, with adverse effects occurring in a similar proportion of the two treatment groups (23% with esomeprazole v 22% with pantoprazole; significance not assessed; P value not reported).

Drug safety alert

FDA issues drug safety alert on the possible increased risk of fractures of the hip, wrist, and spine, associated with the use of proton pump inhibitors. (25 May 2010)

A drug safety alert has been issued on the possible increased risk of fractures of the hip, wrist, and spine, associated with the use of proton pump inhibitors. (www.fda.gov)

Comment

Limited evidence from cohort studies has suggested that long-term proton pump inhibitor (PPI) treatment may be associated with atrophic gastritis in people with Helicobacter pylori, but this has not yet been confirmed by RCT data. Gastric atrophy is a risk factor for gastric cancer. However, we found no reliable evidence of long-term clinical effects of PPIs on gastric cancer rates in people with GORD and oesophagitis. One crossover RCT (233 people with upper gastrointestinal disorders; 214 with GORD, whose symptoms were controlled with PPIs) compared 4 weeks of treatment with omeprazole versus rabeprazole. Post-crossover analysis revealed that a similar proportion of people preferred each of the treatments over the other (data and P value for overall comparison not reported). We identified one RCT in Korean that compared PPIs versus H2 receptor antagonists. We are awaiting translation of this RCT, and will assess the trial for potential inclusion after translation.

Substantive changes

Proton pump inhibitors (maintenance) Two RCTs added; benefits and harms data enhanced; categorisation unchanged (Beneficial); data added for comparison of proton pump inhibitors versus each other in maintenance of remission: insufficient evidence to compare effects of of different proton pump inhibitors in maintenance of remission: one RCT found esomeprazole to be more effective than lansoprazole in maintenance of remission at 6 months; however, the second RCT found no significant difference between esomeprazole and pantoprazole in maintenance of remission for the same time period.

BMJ Clin Evid. 2008 Jun 13;2008:0403.

Open surgery

Summary

SYMPTOM SEVERITY Compared with medical treatment: Open fundoplication may be more effective than medical treatment (antacids, H 2 receptor antagonists) at reducing reflux and at improving the endoscopic grade of oesophagitis (timescale not specified) in people with chronic GORD and oesophagitis, but not at improving endoscopic appearance after 10 years. Open antireflux surgery may be more effective than omeprazole at reducing the proportion of people with treatment failure at 5 years in people with chronic GORD and oesophagitis (treatment failure defined as one or more of: moderate or severe heartburn or acid regurgitation; oesophagitis higher than grade 2; moderate or severe dysphagia; and requiring or preferring alternative treatment) ( very low-quality evidence ). Compared with laparoscopic surgery: We don't know whether open surgery is more effective at improving relief of heartburn at 1, 3, or 5 years, the proportion of people satisfied with treatment at 3 and 5 years, or regurgitation or dysphagia for solids or liquids at 3 years (very low-quality evidence). RELAPSE RATES Compared with laparoscopic surgery: We don't know whether open fundoplication is more effective at preventing recurrence of chronic GORD ( low-quality evidence ). ADVERSE EFFECTS Compared with laparoscopic surgery: Open surgery may be less effective at reducing the risk of perioperative complications (not further defined) (low-quality evidence). NOTE The benefit of antireflux surgery in controlling symptoms must be balanced against the small risk of operative mortality (less than 1%) associated with this procedure.

Benefits

Open surgery versus medical treatment:

We found one systematic review (search date 1999, 4 RCTs, 518 people with chronic GORD and oesophagitis). Two of the included RCTs compared open antireflux surgery (fundoplication) versus antacids and H2 receptor antagonists in people with severe or complicated GORD. All RCTs reported that surgery significantly reduced reflux and improved the endoscopic grade of oesophagitis compared with medical treatment. One RCT compared open antireflux surgery (fundoplication) versus cimetidine (see comment below). The review did not perform a meta-analysis owing to heterogeneity between studies. Longer-term follow-up of one of the RCTs included in the review (239/247 [97%] people originally enrolled) found no significant difference in endoscopic appearance after 10 years between open surgery and medical treatment (mean endoscopic grade: 1.80 with surgery v 1.89 with medical treatment; P = 0.76; the authors converted grades on the Savary–Miller scale into continuous variables — which may not be a valid way to assess severity of oesophagitis). The fourth RCT in the review (298 people randomised, 255 analysed) compared open antireflux surgery versus omeprazole 20 mg daily over 5 years. It defined treatment failure as one or more of: moderate or severe heartburn or acid regurgitation; oesophagitis higher than grade 2; moderate or severe dysphagia; and requiring or preferring alternative treatment (omeprazole or surgery). It found that surgery significantly reduced treatment failure at 5 years compared with omeprazole (20/103 [19%] with surgery v 49/114 [43%] with omeprazole; P less than 0.001).

Open surgery versus laparoscopic surgery:

We found one systematic review (search date 2002, 6 RCTs, 449 people with chronic GORD and oesophagitis) and two subsequent RCTs. The review found no significant difference in recurrence of GORD between laparoscopic surgery and open fundoplication (OR 0.80, 95% CI 0.24 to 2.68). Five-year follow-up of one of the RCTs identified by the review (66 people with GORD) found no significant difference in relief of heartburn at 5 years between laparoscopic surgery and open fundoplication (complete heartburn relief: 15/17 [88%] with laparoscopic fundoplication v 19/23 [83%] with open surgery; P value not reported). Another five-year follow-up of an RCT identified by the review (177 people with GORD) found no significant difference between open fundoplication and laparoscopic surgery in the proportion of people satisfied with the outcome of surgery (62/69 [90%] with open surgery v 69/79 [87%] with laparoscopy; P = 0.32).The first subsequent RCT found no significant difference in relief of heartburn at 12 months between laparoscopic surgery and open fundoplication (AR for heartburn symptoms at 12 months: 1/42 [2%] with laparoscopic fundoplication v 3/39 [8%] with open surgery; difference reported as not significant; figures not reported).The second subsequent RCT (205 people with GORD) found no significant difference at 3 years' follow-up between open surgery and laparoscopic fundoplication in relief from heartburn (grade 2–3 scores), regurgitation, or dysphagia for solids and liquids (relief from heartburn: P = 0.37; regurgitation: P = 0.54; dysphagia for solids: P = 1.0; dysphagia for liquids: P = 1.0) (absolute numbers not reported for any comparison). It also found no significant difference between groups in patient-assessed satisfaction at 3 years' follow-up (94% with open surgery v 91% with laparoscopic fundoplication; absolute numbers not reported; P = 0.59).

Harms

Open surgery versus medical treatment:

One RCT included in the review found that surgery significantly reduced reflux compared with cimetidine, although width of confidence interval suggests that study results may not be reliable). Longer-term follow-up of one RCT included in the review reported significantly higher mortality with surgery compared with medical treatment, mainly because of CVD (RR 1.57, 95% CI 1.01 to 2.46). The systematic review reported that one included RCT found that open Nissen fundoplication significantly increased early satiety, inability to belch, and inability to vomit compared with medical treatment.

Open surgery versus laparoscopic surgery:

The systematic review found a significantly reduced risk of perioperative complications in laparoscopic compared with open surgery (OR 0.33, 95% CI 0.12 to 0.90; NNT to prevent a complication 8, 95% CI 3 to 16). The mean postoperative stay was significantly shorter with laparoscopic surgery than with open fundoplication (mean 3.1 days with laparoscopic surgery v 5.2 days with open fundoplication; P = 0.03).The first subsequent RCT found that mean postoperative stay was significantly shorter with laparoscopic surgery compared with open fundoplication (mean stay 3 days with laparoscopic surgery v 5 days with open fundoplication; P less than 0.001).The second subsequent RCT found that mean postoperative stay was significantly shorter and mean number of days taken as sick leave significantly lower with laparoscopic surgery compared with open fundoplication (mean postoperative stay: 5 days with open fundoplication v 3 days with laparoscopic surgery; P less than 0.001; mean number of days sick leave: 42 days with open fundoplication v 28 days with laparoscopic surgery; P less than 0.001).

Comment

The benefit of antireflux surgery in controlling symptoms must be balanced against the very small operative mortality (less than 1%) associated with this procedure.

Substantive changes

Open surgery One RCT and one 5-year follow-up study added;benefits and harms data enhanced; categorisation unchanged (Trade-off between benefits and harms). RCT added found no significant difference in relief from symptoms between open surgery and laparoscopic fundoplication.

BMJ Clin Evid. 2008 Jun 13;2008:0403.

Laparoscopic surgery

Summary

SYMPTOM SEVERITY Compared with medical treatment: Laparoscopic fundoplication may be more effective than continued proton pump inhibitor treatment in improving mean GORD score (measured by GERSS total scores) at 12 months in people with GORD symptoms controlled by proton pump inhibitor treatment ( low-quality evidence ). Compared with open surgery: We don't know whether laparoscopic surgery is more effective at improving relief of heartburn at 1, 3, or 5 years, or regurgitation or dysphagia for solids or liquids at 3 years, or at increasing the proportion of people satisfied with treatment at 3 and 5 years, ( very low-quality evidence ). RELAPSE RATES Compared with open surgery: We don't know whether laparoscopic surgery is more effective than open fundoplication at preventing recurrence of chronic GORD (low-quality evidence). ADVERSE EFFECTS Compared with open surgery: Laparoscopic surgery may be more effective at reducing the risk of perioperative complications (not further defined) (low-quality evidence). QUALITY OF LIFE Compared with medical treatment: We don't know whether laparoscopic fundoplication is more effective at 12 months than proton pump inhibitors at improving quality-of-life scores (very low-quality evidence). NOTE The benefit of antireflux surgery in controlling symptoms must be balanced against the small risk of operative mortality (less than 1%) associated with this procedure.

Benefits

Laparoscopic surgery versus medical treatment:

We found one systematic review (search date 1999) and two subsequent RCTs. The review identified no fully published RCTs comparing the effects of laparoscopic surgery versus medical treatment on symptoms or endoscopically defined healing. The first subsequent RCT (217 people with GORD for at least 6 months) compared laparoscopic Nissen fundoplication versus proton pump inhibitors (PPIs) (pantoprazole, rabeprazole, lansoprazole, omeprazole, and esomeprazole) at a dose that controlled symptoms. At 12 months, the mean gastrointestinal well-being and quality-of-life scores were significantly higher with laparoscopic fundoplication compared with medical treatment (changes in score from baseline: gastrointestinal well-being: from 31.7 to 37.0 with laparoscopic fundoplication v from 34.3 to 35.0 with medical treatment; P = 0.003; quality of life: from 95.4 to 106.2 with laparoscopic fundoplication v from 98.5 to 100.4 with medical treatment; P = 0.003). However, the follow-up at 12 months was 77%, and the RCT did not carry out an intention-to-treat analysis. Results should be interpreted with caution. After 12 months' treatment, all patients randomised to medical treatment were offered laparoscopic surgery. In a follow-up study (183 people included in the original trial based at one site), 54 people originally assigned to the PPI arm had undergone laparoscopic surgery. The follow-up study found that people who had undergone surgery had further symptomatic improvement, whereas those continuing on medical treatment had no change in symptom score after a median of 6.9 years' follow-up. The study reported similar symptom scores at 6.9 years for surgery alone (91 people), medical treatment plus surgery (54 people), and medical treatment alone (38 people); however, the RCT did not carry out a statistical analysis for the between-group comparisons (mean change in symptom score at 6.9 years: from 3.5 to 1.1 with laparoscopic surgery alone v from 3.3 to 0.8 with medical treatment plus laparoscopic surgery v from 2.4 to 0.9 with medical treatment alone; significance not assessed). The second subsequent RCT (104 people with GORD symptoms controlled with PPI treatment) compared laparoscopic fundoplication versus continued treatment with PPIs. At 12 months' follow-up, the RCT found a significant improvement in mean gastro-oesophageal reflux score (GERSS) with laparoscopic fundoplication compared with continued treatment with PPI (GERSS total scores at 12 months: 13.6 with PPI v 8.3 with laparoscopic fundoplication; mean difference between groups: 5.3, 95% CI 2.0 to 8.7 [in favour of laparoscopic surgery improving symptoms]; P = 0.002). However, the RCT found no significant difference between groups at 12 months in quality-of-life score (mean EQ5D score: 77.2 with PPI v 79.0 with surgery; mean difference between groups: –2.5, 95% CI –8.6 to +3.7; P = 0.43).

Laparoscopic surgery versus open surgery:

See benefits of open surgery.

Harms

Laparoscopic surgery versus medical treatment:

The first subsequent RCT reported six (6%) early postoperative complications with laparoscopic fundoplication, four of which required reoperations. In one case, gastric resection was required owing to necrosis. Five people (5%) in the laparoscopic fundoplication group developed dysphagia that persisted more than 3 months after surgery. There were no surgical deaths reported. The RCT reported no adverse effects in the proton pump inhibitor group. The second subsequent RCT reported seven (13%) minor postoperative complications (2 people had fever, 3 had delayed oral intake, and 2 had abdominal pain). Four people (8%) complained of dysphagia and seven (13%) people complained of bloating 3 months after surgery. The RCT reported no adverse effects in the medical-treatment arm of the trial.

Laparoscopic surgery versus open surgery:

See harms of open surgery.

Comment

Clinical guide:

The benefit of laparoscopic antireflux surgery compared with medical treatment in controlling symptoms must be balanced against the small operative mortality (less than 1%) associated with this procedure. Laparoscopic surgery is associated with a quicker recovery time compared with open surgery, but the decision about the type of surgery performed will depend on the surgical expertise and experience locally available, and on patient preference.

Substantive changes

Laparoscopic surgery Two RCTs and one follow-up study addedcomparing laparoscopic surgery versus medical treatment and one RCT added comparing laparoscopic surgery versus open surgery; benefits and harms data enhanced; categorisation unchanged (Trade-off between benefits and harms); two RCTs found that, compared with medical treatment, laparoscopic surgery improved GORD symptom scores at 12 months, but treatment associated with more adverse effects. One RCT found no significant difference in relief from symptoms between laparoscopic fundoplication and open surgery.

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