Intervention Protocol

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Proton pump inhibitor versus placebo in the short term management of gastro-esophageal reflux disease

  1. Nada Elmazariky1,*,
  2. Ignacio Neumann2,
  3. David Armstrong3,
  4. Grigorios I Leontiadis3,
  5. Paul Moayyedi3

Editorial Group: Cochrane Upper Gastrointestinal and Pancreatic Diseases Group

Published Online: 31 MAY 2013

DOI: 10.1002/14651858.CD010499


How to Cite

Elmazariky N, Neumann I, Armstrong D, Leontiadis GI, Moayyedi P. Proton pump inhibitor versus placebo in the short term management of gastro-esophageal reflux disease (Protocol). Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD010499. DOI: 10.1002/14651858.CD010499.

Author Information

  1. 1

    McMaster University, Department of Medicine, Hamilton, Canada

  2. 2

    Faculty of Medicine, Pontificia Universidad Católica de Chile, Department of Internal Medicine, Evidence Based Health Care Program, Santiago, Región metropolitana, Chile

  3. 3

    McMaster University, Department of Medicine, Division of Gastroenterology, Hamilton, Ontario, Canada

*Nada Elmazariky, Department of Medicine, McMaster University, Hamilton, Canada. nada.elmazariky@medportal.ca.

Publication History

  1. Publication Status: New
  2. Published Online: 31 MAY 2013

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Appendices
  6. Contributions of authors
  7. Declarations of interest
  8. Sources of support
 

Description of the condition

Gastro-esophageal reflux disease (GORD) is currently the most common disease of the gastrointestinal system. It is also the most frequently made diagnosis in gastroenterology outpatient practice (Shaheen 2006). Expenses are rising every year on its management (Hunt 2007).

The international Montreal consensus defined GORD as "a condition which develops when the reflux of stomach contents causes troublesome symptoms or complications" (Vakil 2006). Characteristic symptoms of substernal burning or acid regurgitation, or both, are considered troublesome when they affect a patient's well being. GORD often also leads to complications, inflammation leading to oesophagitis and oesophageal strictures, which may lead to Barrett's oesophagus or adenocarcinoma (Kahrilas 2008).

Patients with GORD can be further subdivided by endoscopy into two groups (Vakil 2006):

  1. reflux oesophagitis, which refers to visible erosions of the oesophagus associated with GORD symptoms;
  2. endoscopy negative reflux disease (NERD), which refers to normal oesophageal mucosa on endoscopy but is associated with GORD symptoms. It is often composed of several patient subgroups all leading up to a similar picture of symptoms via different underlying mechanisms (Chal 1995).

Both groups have similar presentations and recently studies have shown that NERD patients suffer from impairment of quality of life as do those patients with erosive oesophagitis (Tew 1997). In most cases, GORD Impacts on a patient's quality of life. GORD patients have been shown to score lower in quality of life assessment than patients with cardiac angina and heart failure (Dimenas 1993).

Proton pump inhibitors (PPIs) have been used for the management of all types of GORD. Erosive oesophagitis accounts for a more predictable response to PPIs. NERD however seems to respond quite differently (Fass 2002). Therefore, a review of the efficacy of PPIs and actual improvement in symptoms in all subgroups of GORD is needed.

 

Description of the intervention

The goal of treatment in patients is not only healing of oesophagitis but also adequate relief of GORD-related symptoms and thus an improvement in quality of life. Medical management of GORD primarily relies on reduction of gastric acid production and in turn healing of oesophagitis, if present, and relief of symptoms. Medical management includes PPIs, H₂-receptor antagonists (H₂RAs), prokinetics and antacids, either used alone or in combination. The medication analysed in this review will be PPIs, which are oral pharmacological agents prescribed to reduce gastric acid production.

 

How the intervention might work

PPIs act by binding to the cysteine molecule in the hydrogen pump located in the secreting membranes in the parietal cells, leading to inhibition of acid production in the final metabolic pathway of gastric parietal cells (Zamir 2005). This results in reduced gastric acid secretion and subsequent oesophageal acid exposure hence Improving GORD-related symptoms.

 

Why it is important to do this review

PPIs are the most commonly used medication for GORD. In 2006, expenditure on PPIs alone reached seven billion dollars globally (Mullin 2009). PPI short term management in non-erosive reflux disease (NERD) has been evaluated in a previous Cochrane review (van Pinxteren 2010) and the maintenance of NERD and reflux oesophagitis is also the subject of a previous Cochrane review (Donnellan 2010). This review will be based on a previous Cochrane review evaluating medical treatments in the short term management of reflux oesophagitis alone (Moayyedi 2011). The previous systematic review assessed the effectiveness of PPIs against other medications in healing of erosive oesophagitis; however, in general only 30% of patients with GORD have erosive disease while the remaining 70% have NERD (Savarino 2008).

Therefore, it is important to assess the overall effectiveness of PPIs not only on healing of mucosal lesions in erosive oesophagitis but actual symptom relief and quality of life in all subgroups of GORD. In addition, further randomised controlled trials have been published and the newer PPIs, specifically dexlansoprazole and esomeprazole, were not evaluated in the previous systematic review. Therefore the systematic review needs updating.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Appendices
  6. Contributions of authors
  7. Declarations of interest
  8. Sources of support

Meta-analysis of randomised controlled trials to assess the efficacy of short term use of proton pump inhibitors (PPIs) against placebo in the management of GORD and GORD-associated symptoms.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Appendices
  6. Contributions of authors
  7. Declarations of interest
  8. Sources of support
 

Criteria for considering studies for this review

 

Types of studies

Parallel group randomised controlled trials (RCTs)

 

Types of participants

Patients recruited in the trials and analysed must have been adults with an adequate diagnosis of GORD (either a clinical diagnosis of presumed GORD, or a post-endoscopic diagnosis of erosive oesophagitis or NERD).

 

Types of interventions

The active intervention must have been a PPI (either lansoprazole, omeprazole, pantoprazole, dexlansoprazole, esomeprazole, or rabeprazole). Participants must have had at least four weeks of therapy.

 

Types of outcome measures

Outcomes assessed at four to 12 weeks. We will conduct an intention-to-treat analysis (as randomised) whenever possible.

 

Primary outcomes

  1. Symptom resolution for all groups of patients

 

Secondary outcomes

  1. Healing of reflux oesophagitis in erosive oesophagitis
  2. Improvement in symptoms (in erosive oesophagitis and NERD patients)
  3. Improvement of GERD-related sleep disturbances (if reported)
  4. Quality of life changes
  5. Dropout rate
  6. PPI-related short term adverse events (if reported)

Primary and secondary outcomes in this review will be reported using the standard definitions provided by each trial to report outcomes. Any heterogeneity will be further explored and taken into account.

 

Search methods for identification of studies

 

Electronic searches

The principal electronic search will be undertaken according to the Cochrane Upper Gastrointestinal and Pancreatic Diseases Review Group module (published in The Cochrane Library).

The following databases will be searched:

  1. Cochrane Controlled Trials Register (CENTRAL) (Appendix 1);
  2. MEDLINE (Appendix 2);
  3. EMBASE (Appendix 3);
  4. CINAHL (Appendix 4).

A search strategy consisting of a combination of subject headings and text words related to the title words will be developed and conducted according to the Cochrane Handbook for Systematic Reviews of Interventions. Standard methodological filters will be applied to identify RCTs.

The metaRegister of controlled trials will also be searched for relevant unpublished or ongoing trials.

 

Searching other resources

Experts in the field who are registered with the Cochrane Upper Gastrointestinal and Pancreatic Diseases Review Group will be contacted for leads on unpublished studies.

 

Data collection and analysis

 

Selection of studies

The lead review author will screen titles and trial abstracts that have been identified by the search strategy for articles that could possibly be eligible for the review. The review author will then screen the full articles of selected trials to confirm eligibility, using pre-designed eligibility forms. A second review author masked to the initial assessment will also evaluate all full articles for eligibility. Any discrepancies between the two review authors will be discussed further and a consensus view will be taken.

 

Data extraction and management

Data will be extracted independently by two review authors. Disagreements will be recorded and resolved by consensus.  

The following features will be extracted.

  • Setting: primary or secondary care.
  • Country of origin.
  • Method of randomisation.
  • Adequacy of allocation concealment.
  • Inclusion and exclusion criteria used.
  • Baseline comparability between treatment groups.
  • Treatments compared and number of patients in each arm.
  • Dropouts reported and the reasons.
  • Dose and duration of study medications.
  • Proportion of patients with partial symptom improvement, symptom resolution, healing of reflux oesophagitis, resolution or partial improvement of sleep disturbances, quality of life changes per treatment group.
  • Grading system for reflux oesophagitis, if present.
  • GORD questionnaires used, validated or not.
  • PPI-related adverse events, the total number reported.

 

Assessment of risk of bias in included studies

The risk of bias of included trials will be independently assessed by two review authors using the approach recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). Disagreements will be recorded and resolved by consensus.

 

Measures of treatment effect

Meta-analysis will only be attempted if there are two or more trials of similar comparisons reporting the same outcomes. The impact of interventions on binary outcomes will be expressed as relative risks (RR) with 95% confidence intervals (CI). Changes in quality of life will be expressed as mean difference with 95% CI.

 

Unit of analysis issues

We do not anticipate any unit of analysis issues. Non-standard designs such as cross-over trials, cluster-randomised trials and non-randomised studies will not be considered for analysis.

 

Dealing with missing data

The original authors will be contacted for any missing data or missing participant information. Sensitivity analyses will be performed and the potential impact of missing data on the findings of the review will be addressed in the Discussion section, as recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008).

 

Assessment of heterogeneity

The heterogeneity will be assessed by the heterogeneity test (Chi²) and the I² statistic. We will consider P ≤ 0.10 or I² ≥ 50% as indicating important heterogeneity.

 

Assessment of reporting biases

Publication bias and other small study effects biases will be assessed visually by funnel plot asymmetry and statistically by Egger's test (Davey Smith 1997).

 

Data synthesis

Meta-analysis will be attempted by the Mantel-Haenszel method using the RevMan software (RevMan 2011) if there are sufficient trials of similar comparisons reporting the same outcomes. We will use the random-effects model and conduct a sensitivity analysis using the fixed-effect model. We will summarize the magnitude of, and our confidence in, the treatment effects using the GRADE approach.

 

Subgroup analysis and investigation of heterogeneity

We intend to have separate analyses on symptom resolution for the following.

  • Each group of patients (clinical diagnosis of GORD, erosive oesophagitis, NERD).
  • Dose of drug, as we expect the higher doses to be more effective than lower doses.
  • Duration and timing of treatment, if reported.

 

Sensitivity analysis

  1. We will conduct a sensitivity analysis making plausible assumptions regarding the outcome missing data.
  2. We will repeat all our analysis using the fixed-effect model.

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Appendices
  6. Contributions of authors
  7. Declarations of interest
  8. Sources of support
 

Appendix 1. CENTRAL search strategy

  1. *gastroesophageal reflux/ or *regurgitation, gastric/
  2. ((gastroesophageal or gastro-oesophageal or gastro-oesophageal or gastroesophageal) adj3 reflux).tw.
  3. (GERD or GORD).tw.
  4. (acid adj2 reflux).tw.
  5. (heartburn or pyrosis).tw.
  6. *Esophagitis, Peptic/
  7. (oesophagitis or oesophagitis or "non-erosive reflux disease" or "non erosive reflux disease" or "non-erosive gastroesophageal reflux disease" or "non erosive gastroesophageal reflux disease" or "non-erosive gastroesophageal reflux disease" or "non erosive gastroesophageal reflux disease").tw.
  8. or/1-7
  9. *Proton Pump Inhibitors/
  10. ("Proton Pump Inhibitors" or "Proton Pump Inhibitor" or "Proton-Pump Inhibitors" or "Proton-Pump Inhibitor" or PPI or PPIs).tw.
  11. (Esomeprazole or Nexium or Esotrex).mp.
  12. (lansoprazole or lansoprazole or agopton or bamalite or Inhibitol or Levant or Lupizole or lanzor or monolitum or ogast or ogastro or opiren or prevacid or prezal or pro ulco or promeco or takepron or ulpax or zoton).tw.
  13. (Dexlansoprazole or Kapidex or Dexilant).mp.
  14. *Omeprazole/
  15. (losec or lomac or nexium or ocid or Lomac or Omepral or Omez or prilosec or rapinex or zegerid).tw.
  16. (pantoprazole or protium iv or protonix or Somac or Pantoloc or Pantozol or Zurcal or Zentro).tw.
  17. (rabeprazole or aciphex or dexrabeprazole or pariet or Zechin or Rabecid or Nzole-D or Rabeloc).mp.
  18. or/9-17
  19. 8 and 18

 

Appendix 2. MEDLINE search strategy

  1. randomized controlled trial.pt.
  2. controlled clinical trial.pt.
  3. randomized.ab.
  4. placebo.ab.
  5. clinical trials as topic.sh.
  6. randomly.ab.
  7. trial.ti.
  8. or/1-7
  9. exp animals/ not humans.sh.
  10. 8 not 9
  11. *gastroesophageal reflux/ or *regurgitation, gastric/
  12. ((gastroesophageal or gastro-esophageal or gastro-oesophageal or gastrooesophageal) adj3 reflux).tw.
  13. (GERD or GORD).tw.
  14. (acid adj2 reflux).tw.
  15. (heartburn or pyrosis).tw.
  16. *Esophagitis, Peptic/
  17. (oesophagitis or oesophagitis or "non-erosive reflux disease" or "non erosive reflux disease" or "non-erosive gastroesophageal reflux disease" or "non erosive gastroesophageal reflux disease" or "non-erosive gastroesophageal reflux disease" or "non erosive gastroesophageal reflux disease").tw.
  18. or/11-17
  19. *Proton Pump Inhibitors/
  20. ("Proton Pump Inhibitors" or "Proton Pump Inhibitor" or "Proton-Pump Inhibitors" or "Proton-Pump Inhibitor" or PPI or PPIs).tw.
  21. (Esomeprazole or Nexium or Esotrex).mp.
  22. (lansoprazole or lanzoprazole or agopton or bamalite or Inhibitol or Levant or Lupizole or lanzor or monolitum or ogast or ogastro or opiren or prevacid or prezal or pro ulco or promeco or takepron or ulpax or zoton).tw.
  23. (Dexlansoprazole or Kapidex or Dexilant).mp.
  24. *Omeprazole/
  25. (losec or lomac or nexium or ocid or Lomac or Omepral or Omez or prilosec or rapinex or zegerid).tw.
  26. (pantoprazole or protium iv or protonix or Somac or Pantoloc or Pantozol or Zurcal or Zentro).tw.
  27. (rabeprazole or aciphex or dexrabeprazole or pariet or Zechin or Rabecid or Nzole-D or Rabeloc).mp.
  28. or/19-27
  29. 18 and 28
  30. 10 and 29

 

Appendix 3. EMBASE search strategy

  1. *gastroesophageal reflux/ or *non erosive reflux disease/ or *reflux oesophagitis/
  2. (GERD or GORD).tw.
  3. (heartburn or pyrosis).tw.
  4. (oesophagitis or oesophagitis or "non-erosive reflux disease" or "nonerosive reflux disease" or "non-erosive gastroesophageal reflux disease" or "nonerosive gastroesophageal reflux disease" or "non-erosive gastrooesophageal reflux disease" or "nonerosive gastrooesophageal reflux disease").tw.
  5. or/1-4
  6. *proton pump inhibitor/cm, dt [Drug Comparison, Drug Therapy]
  7. ("Proton Pump Inhibitors" or "Proton Pump Inhibitor" or "Proton-Pump Inhibitors" or "Proton-Pump Inhibitor").tw.
  8. *ESOMEPRAZOLE/dt [Drug Therapy]
  9. Esomeprazole.tw.
  10. *lansoprazole/dt [Drug Therapy]
  11. (lansoprazole or lanzoprazole).tw.
  12. Dexlansoprazole.mp.
  13. *omeprazole/dt [Drug Therapy]
  14. omeprazole.tw.
  15. *pantoprazole/dt [Drug Therapy]
  16. pantoprazole.tw.
  17. *rabeprazole/dt [Drug Therapy]
  18. rabeprazole.tw.
  19. or/6-18
  20. 5 and 19
  21. Clinical trial/
  22. Randomized controlled trial/
  23. Randomization/
  24. Single blind procedure/
  25. Double blind procedure/
  26. Crossover procedure/
  27. Placebo/
  28. Randomi?ed controlled trial$.tw.
  29. Rct.tw.
  30. Random allocation.tw.
  31. Randomly allocated.tw.
  32. Allocated randomly.tw.
  33. (allocated adj2 random).tw.
  34. Single blind$.tw.
  35. Double blind$.tw.
  36. ((treble or triple) adj blind$).tw.
  37. Placebo$.tw.
  38. Prospective study/
  39. or/21-38
  40. Case study/
  41. Case report.tw.
  42. Abstract report/ or letter/
  43. or/40-42
  44. 39 not 43
  45. 20 and 44

 

Appendix 4. CINAHL search strategy

S16         S7 and S15
S15         S8 or S9 or S10 or S11 or S12 or S13 or S14 
S14         rabeprazole 
S13         pantoprazole 
S12         Omeprazole 
S11         Dexlansoprazole 
S10         lansoprazole 
S9          Esomeprazole 
S8          Proton Pump Inhibitor* OR Proton-Pump Inhibitor* 
S7          S1 or S2 or S3 or S4 or S5 or S6 
S6          acid W2 reflux 
S5          GERD or GORD 
S4          (nonerosive gastroesophageal reflux disease) OR (non-erosive gastrooesophageal reflux disease) OR (nonerosive gastrooesophageal reflux disease) 
S3          (non-erosive reflux disease) OR (nonerosive reflux disease) OR (non-erosive gastroesophageal reflux disease)
S2          oesophagitis OR oesophagitis 
S1          gastric regurgitation 

 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Appendices
  6. Contributions of authors
  7. Declarations of interest
  8. Sources of support

Nada ElMazariky wrote the protocol.

Ignacio Neumann, Grigorios I Leontiadis, David Armstrong revised and edited the content.

Paul Moayeddi contributed the idea and previous review which this review is based on.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Appendices
  6. Contributions of authors
  7. Declarations of interest
  8. Sources of support

None

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Appendices
  6. Contributions of authors
  7. Declarations of interest
  8. Sources of support
 

Internal sources

  • McMaster University, Canada.

 

External sources

  • No sources of support supplied

References

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
  10. Additional references
  11. References to other published versions of this review
Chal 1995
  • Chal K, Stacey J, Sacks G. The effects of ranitidine on symptom relief and quality of life of patients with gastroesophageal reflux disease. British Journal of Clinical Practice 1995;49:73-7.
Davey Smith 1997
  • Davey Smith G, Egger M, Phillips AN. Meta-analysis. Beyond the grand mean?. BMJ 1997;315(7122):1610-4.
Dimenas 1993
  • Dimenas E. Methodological aspects of evaluation of quality of life in upper gastrointestinal disease. Scandinavian Journal of Gastroenterology 1993;28:18-21.
Fass 2002
  • Fass R, Ofman JJ. Gastroesophageal reflux disease—should we adopt a new conceptual framework?. American Journal of Gastroenterology 2002;97(8):1901-9.
Higgins 2008
  • Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions. Chichester: John Wiley & Sons, 2008.
Hunt 2007
  • Hunt RH, Tytgat GH, Malfertheiner P, Fock KM, Heading RC, Katelaris PH, et al. Whistler summary: ‘‘the slow rate of rapid progress’’. Journal of Clinical Gastroenterology 2007;41(6):539-45.
Kahrilas 2008
Moayyedi 2011
Mullin 2009
RevMan 2011
  • The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.1. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011.
Savarino 2008
  • Savarino V, Di Mario F, Scarpignato C. Proton pump inhibitors in GORD an overview of their pharmacology, efficacy and safety. Pharmacological Research 2008;59(3):135-53.
Shaheen 2006
  • Shaheen NJ, Hansen RA, Morgan DR, Gangarosa LM, Ringel Y, Thiny MT, et al. The burden of gastrointestinal and liver diseases. American Journal of Gastroenterology 2006;101(9):2128-38.
    Direct Link:
Tew 1997
  • Tew S, Jamieson GG, Pilowsky I, Myers J. The illness behavior of patients with gastroesophageal reflux disease with and without endoscopic esophagitis. Diseases of the Esophagus 1997;10(1):9-15.
Vakil 2006
  • Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R, Global Consensus Group. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence based consensus. American Journal of Gastroenterology 2006;101(8):1900-20.
    Direct Link:
van Pinxteren 2010
  • van Pinxteren B, Sigterman KE, Bonis P, Lau J, Numans ME. Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease. Cochrane Database of Systematic Reviews 2010, Issue 11. [DOI: 10.1002/14651858.CD002095.pub4]
Zamir 2005
  • Zamir D. Gatroesophageal reflux. European Journal of Internal Medicine 2005;16(6):391-401.

References to other published versions of this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
  10. Additional references
  11. References to other published versions of this review
Donnellan 2010