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Long term proton pump inhibitor (PPI) use and incidence of gastric premalignant lesions

  1. Huan Song1,*,
  2. DongHao Lu1,
  3. JianWei Zhu2

Editorial Group: Cochrane Upper Gastrointestinal and Pancreatic Diseases Group

Published Online: 26 JUN 2013

DOI: 10.1002/14651858.CD010623


How to Cite

Song H, Lu D, Zhu J. Long term proton pump inhibitor (PPI) use and incidence of gastric premalignant lesions (Protocol). Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD010623. DOI: 10.1002/14651858.CD010623.

Author Information

  1. 1

    Karolinska Institutet, Department of Medical Epidemiology and Biostatistics, Stockholm, Sweden

  2. 2

    Shandong Provincial Hospital, Department of Orthopaedics, Jinan, Shandong, China

*Huan Song, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, Stockholm, SE-17177, Sweden. huan.song@ki.se.

Publication History

  1. Publication Status: New
  2. Published Online: 26 JUN 2013

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This is not the most recent version of the article. View current version (02 DEC 2014)

 

Background

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

Description of the condition

Gastric cancer, as the fourth most common cancer and second leading cause of cancer-related deaths worldwide (Ferlay 2010), is a fatal disease placing heavy burden on human health. Abundant stuides have shown that the intestinal type of gastric cancer is the most common histological type of gastric cancer among the older population (age > 50) and is developed through a well-recognised cascade of events (inflammation-metaplasia-dysplasia an-carcinoma sequence). Generally, this procedure is known as Correa cascade of multistep gastric carcinogenesis (Correa 1992; Kapadia 2003), where a progression, usually triggered by colonisation of Helicobacter pylori (H. pylori) - the most recognised risk factor for gastric cancer, may occur from normal mucosa, through chronic non-atrophic gastritis, atrophic gastritis, intestinal metaplasia, and dysplasia, to ultimately carcinoma. Pathologically, chronic gastritis should be diagnosed based on biopsy results which would indicate the presence of chronic inflammatory cells and the disappearance of normal glands. Subsequently, with the drop-out of glands and their replacement by intestinal glands, intestinal metaplasia occurs in the atrophic mucosa and is believed to constitute the background in which dysplasia and further carcinoma develop (Dinis-Ribeiro 2012). Since chronic gastric atrophy, intestinal metaplasia and epithelial dysplasia of stomach have been tightly associated with an increased risk of gastric cancer (Fukao 1993; Genta 1998; Kapadia 2003), concerns on premalignant lesions are considered to be vital for preventing the incidence and mortality of gastric cancer (Dinis-Ribeiro 2012).

Despite declining incidence rates of gastric cancer, an unexpectedly reverse trend regarding the incidence of noncardia gastric cancer among whites aged 25 to 39 years was described in the US (Anderson 2010). Cross-sectional population-based analyses l in Sweden during 1990 to 1999 revealed that while the incidence of noncardia gastric cancer fell, as expected, among 55 to 64 year-olds, the prevalence of atrophic gastritis surprisingly rose in those aged 35 to 44 years (Held 2004). Given that the prevalence of H. pylori infection was actually gradually decreased (Anne 2008; Shiota 2013), other potential causes related to gastric premalignant lesions need to be investigated.

 

Description of the intervention

Proton pump inhibitors (PPIs) are the most efficacious medications to reduce gastric acid secretion. Since their introduction in the late 1980s, they dramatically improved the medical treatment of acid-related gastric disorders (Wolfe 2000), including peptic ulcer disease (Dekkers 1999; Holt 1991; Poynard 1995;), eradication of H. pylori, treatment and prevention of gastroduodenal ulcers associated with non-steroidal anti-inflammatory drugs (NSAIDs) (Agrawal 2000; Rostom 2002), Zollinger-Ellison syndrome (Norton 1999), and management of gastroesophageal reflux disease (GERD) or Barret's oesophagus (Cooper 2006; Hetzel 1988; Marks 1994; Vigneri 1995; Wilkinson 1999). Nowadays, PPIs are one of the most commonly prescribed classes of medications worldwide. Apart from short-term application, maintenance therapy with PPIs is recommended and increasingly used in certain diseases, such as Zollinger-Ellison syndrome and GERD; especially for patients with erosive oesophagitis or Barret's oesophagus (Peters 1999; Horwhat 2007). GERD was reported to appear in one-third of adults (Haag 2003). For those patients who were consequently given the propensity of oesophagitis to relapse, maintenance acid-suppressive therapy is often necessary.

Gastric hydrogen potassium ATPase (H+/K+-ATPase) is a vital proton pump which enables the exchange of hydrogen (H+) and potassium (K+) ions across the canalicular membrane in acid-secreting parietal cells. Once absorbed by the small intestines, PPIs are distributed to the gastric parietal cells, where they are accumulated and protonated to active form in the acidic environment. The action of PPIs can irreversibly inhibit H+/K+-ATPase, and thus causes profound suppression of acid secretion (Dajani 2000). The most commonly used PPIs are listed in  Table 1.

Although PPIs are generally safe, their efficacy and safety of long-term use remains inconclusive (Suzuki 2008). Many potential adverse effects have been observed and widely discussed (Ali 2009; Thomson 2010). Briefly, the three main concerns regarding the long-term safety of the PPIs include the effects of prolonged PPI-induced hypergastrinaemia (an excess of gastrin in the blood), the effects of chronic hypochlorhydria (reduction in the hydrochloric acid content of gastric juice), and the possible association of PPIs with gastric atrophy.

 

How the intervention might work

Almost every patient develops hypergastrinaemia in response to profound acid-suppressive therapy (Sanduleanu 1999; Schenk 1998). With stimulation of prolonged hypergastrinaemia, hyperplasia of enterochromaffin-like cells could occur, especially in patients with H. pylori infection or with more markedly increase gastrin levels (Klinkenberg-Knol 2000). In rats, enterochromaffin-like cell hyperplasia can lead to dysplasia, and ultimately gastric carcinoid formation (Freston 1994). However, this phenomenon has never been described in humans. Long-term studies of omeprazole in patients with Zollinger-Ellison syndrome have found no increase in fasting serum gastrin concentrations and no evidence of gastric carcinoid tumours (Lloyd-Davies 1988; Maton 1989). Similarly, studies concerning PPI users for other diseases have not shown increased risk of carcinoids (Hassall 2011; Klinkenberg-Knol 2000). These findings indicate that gastric mucosal changes induced by enterochromaffin-like cell hyperplasia are benign changes. These lesions do not progress or only develop dysplastic changes in extremely rare case, and therefore have very limited clinical relevance.

Another safety concern with long-term PPI use is the effects of sustained hypochlorhydria. Firstly, prolonged gastric acid hyposecretion could result in clinically significant nutritional deficiencies. For example, deficiencies of vitamin B12, iron, calcium were commonly observed in patients with long-term PPI use. Secondly, the gastrointestinal acid secretion plays a protective role against infectious agents. Therefore, prolonged PPI-induced hypochlorhydria may also increase the risk of contracting gastrointestinaland respiratory microbial infection (community-acquired pneumonia and nosocomial pneumonia) (Kader 1998; Laheij 2004; Neal 1996; Reynaert 1995).

Recently, discussions on the long term safety of PPIs gradually shifted to the possible association between PPI treatment and gastritis. For instance, the propensity of omeprazole-treated patients to develop chronic atrophic gastritis has been proposed in many studies (Klinkenberg-Knol 2000; Kuipers 1996; Lundell 1999). One possible mechanism of this phenomenon is explained in terms of the interrelation between the acid secretion and H. pylori status. In subjects with suppressed acid secretion caused by maintenance PPI use or any other mechanism, H. pylori harbour both the antrum and body of the stomach, instead of antrum only. This unusual colonisation mode leads to a corpus predominant gastritis (Malfertheiner 2007), which could accelerate the process of gland loss and subsequently result in the appearance of atrophic gastritis. In Kuipers 1996, a steady gradual development of atrophic gastritis was observed among H.pylori positive patients with omeprazole maintenance therapy within the first year of treatment; at an average follow-up of five-year treatment, approximately one out of every three patients developed this condition. Consequently, eradication of H. pylori infection prior to long-term acid suppression with PPIs was suggested as a way to prevent the development of atrophic gastritis in recent studies (Moayyedi 2000; Schenk 2000). Since persistent corpus predominant gastritis and atrophy were considered as major risk factors for the development of gastric cancer (Sipponen 2007), the potential role of maintenance PPI use on the development of gastric premalignant lesions became the issue of much debate over the past decade.

Another factor that might potentially impact the development of premalignant lesions is non-Helicobacter bacterial overgrowth under the condition of sustained low gastric acid level. In subjects without long-term PPI use, it might occur after severe atrophic gastritis is developed. However, in PPI users, colonisation of various microbes probably happens at an earlier stage and are related to the further development of more severe gastritis (Sanduleanu 2001). Furthermore, potent carcinogens produced by these microbes, including nitrosamines and acetaldehyde, might also promote the information of precancerous lesions, or even cancer itself.

 

Why it is important to do this review

Since PPIs are widely used, safety issue about this medication should be seriously considered. The question whether or not the long-term use of PPIs could promote the development of gastric premalignant lesions has been widely investigated, but results are inconsistent. Limited insight on this problem leads to a dilemma in decision making for PPI treatment. Additionally, with the awareness that both the incidence of noncardia gastric cancer and the prevalence of atrophic gastritis tend to surprisingly increase among the young middle-age population, the possible association between long-term PPI use and gastric premalignant lesions deserves to be elucidated. We thus feel the need for a systematic review to address the question of long-term safety of PPIs regarding development of premalignant lesions in the stomach.

 

Objectives

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

  1. To compare the incidence of gastric premalignant lesions (i.e. atrophic gastritis, intestinal metaplasia and dysplasia) in patients on long-term (≥ 6 months) PPIs with those on no such therapy.
  2. To compare the incidence of gastric premalignant lesions in patients who had long-term PPI therapy with those without such treatment, in association with:
    1. presence of H. pylori infection;
    2. duration, type and dosage of PPI used;
    3. type of the underlying disease that the PPI is prescribed for (e.g. GERD, peptic ulcer disease).

 

Methods

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

Criteria for considering studies for this review

 

Types of studies

We will include randomised controlled trials (RCTs). We will include studies reported as full text, those published as abstract only, and unpublished data.

 

Types of participants

Adults (≥ 18 years of age) without any malignant or premalignant lesion at baseline, confirmed by endoscopy and/or biopsy sampling.

 

Types of interventions

The experimental intervention is PPI use for ≥ 6 months. Any study with at least one intervention arm and at least one valid control arm should be included. A valid control group should include one of the following subset of patients:

  1. with no treatment, or placebo;
  2. undergoing anti-reflux surgery, or endoscopic anti-reflux treatment;
  3. other anti-acid treatment: H2 blockers, or antacids.

Only oral therapies will be considered and they can be administered at different dosage.

 

Types of outcome measures

 

Primary outcomes

The incidence of gastric premalignant lesions, mainly including atrophic gastritis, Intestinal metaplasia, and dysplasia

 

Secondary outcomes

The associations between the presence of gastric premalignant lesions among long-term PPI users and:

  1. presence of H. pylori infection;
  2. duration, type and dosage of PPI used;
  3. presence of underlying disease, such as GERD and peptic ulcer disease.

 

Search methods for identification of studies

 

Electronic searches

We will conduct a literature search to identify all published and unpublished randomised controlled trials. The literature search will identify potential studies in all languages. We will translate the non-English language papers and fully assess them for potential inclusion in the review as necessary.

We will search the following electronic databases for identifying potential studies, from inception to April 2013:

  • Cochrane Central Register of Controlled Trials (CENTRAL) (Appendix 1);
  • MEDLINE (1966 to present) (Appendix 2);
  • EMBASE (1988 to present); and
  • CINAHL (1982 to present).

We will also conduct a search of ClinicalTrials.gov.

 

Searching other resources

We will handsearch the abstracts from 1995 to 2012 from the American Digestive Disease Week published in Gastroenterology and the United European Gastroenterology Week published in Gut.

We will check reference lists of all primary studies and review articles for additional references. We will contact authors of identified trials and ask them to identify other published and unpublished studies.

We will also contact manufacturers and experts in the field.

We will search for errata or retractions from eligible trials on http://www.ncbi.nlm.nih.gov/pubmed and report the date this was done within the review.

 

Data collection and analysis

We will perform statistical analysis in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), using the Cochrane Collaboration's statistical software,(Review Manager 2013).

 

Selection of studies

Two authors (HS, JZ) will independently screen titles and abstracts for inclusion all the potential studies we identify as a result of the search and code them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We will retrieve the full-text study reports/publication and two authors (HS, JZ) will independently screen the full text and identify studies for inclusion and identify and record reasons for exclusion of the ineligible studies. We will resolve any disagreement through discussion or, if required, we will consult a third author (DL). We will identify and exclude duplicates and collate multiple reports of the same study so that each study rather than each report is the unit of interest in the review. We will record the selection process in sufficient detail to complete a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram and 'Characteristics of excluded studies' tables.

 

Data extraction and management

We will use a standard data collection form for study characteristics and outcome data which has been piloted on at least one study in the review. One author (HS) will extract study characteristics from included studies. We will extract the following study characteristics.

  1. Methods: study design, total duration study and run in, number of study centres and location, study setting, withdrawals, date of study.
  2. Participants: number of participants, mean age, age range, gender, diagnosis at baseline, diagnostic criteria, inclusion criteria, exclusion criteria, date and reports of endoscopy and/or biopsy sampling.
  3. Interventions: intervention, comparison, concomitant medications, excluded medications.
  4. Outcomes: primary and secondary outcomes specified and collected, time points reported.
  5. Notes: funding for trial, notable conflicts of interest of trial authors.

Two authors (JZ, DL) will independently extract outcome data form included studies. We will note in the characteristics of included studies table if data outcome data was reported in an unusable way. We will resolve disagreements by consensus or by involving a third author (HS).

One author (HS) will copy across the data from the data collection form into Review Manager 2013. We will double check that the data is entered correctly by comparing the study reports with how the data are presented in the systematic review. A second author (JZ) will spot-check study characteristics for accuracy against the trial report.

 

Assessment of risk of bias in included studies

Two authors (HS, DL) will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Any disagreement will be resolved by discussion or by involving a third author (JZ). We will assess the risk of bias according to the following domains:

  1. random sequence generation;
  2. allocation concealment;
  3. blinding of participants and personnel;
  4. blinding of outcome assessment;
  5. incomplete outcome data;
  6. selective outcome reporting;
  7. other bias.

We will grade each potential source of bias as high, low or unclear and provide a quote form the study report together with a justification for our judgment in the risk of bias table. We will summarise the risk of bias judgements across different studies for each of the domains listed. We will consider blinding separately for different key outcomes where necessary. Where information on risk of bias relates to unpublished data or correspondence with a trialist, we will note this in the risk of bias table.

When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome.

 

Assesment of bias in conducting the systematic review

We will conduct the review according to this published protocol and report any deviations form it in the 'Differences between protocol and review' section of the systematic review.

 

Measures of treatment effect

We will analyse dichotomous data as odds ratios (ORs) with 95% confidence intervals (CIs) and continuous data as mean differences (MDs) or standardised mean differences (SMDs) with 95% CIs. We will ensure that higher scores for continuous outcomes have the same meaning for the particular outcome, explain the direction to the reader and report where the directions were reversed if this was necessary.

We will undertake meta-analyses only where this is meaningful i.e. if the treatments, participants and the underlying clinical question are similar enough for pooling to make sense.

A common way that trialists indicate when they have skewed data is by reporting medians and interquartile ranges. When we encounter this we will note that the data is skewed and consider the implication of this.

Where multiple trial arms are reported in a single trial, we will include only the relevant arms. If two comparisons (e.g. drug A versus placebo and drug B versus placebo) must be entered into the same meta-analysis, we will halve the control group to avoid double counting.

 

Unit of analysis issues

We will only consider RCTs. Non-standard designs, such as cluster randomised trials, will be assessed in order to avoid unit-of-analysis errors including:

  1. recruitment bias;
  2. baseline imbalance;
  3. loss of clusters;
  4. incorrect analysis; and
  5. comparability with individually randomised trials.

 

Dealing with missing data

We will contact investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. when a study is identified as abstract only).

 

Assessment of heterogeneity

Tests for heterogeneity will be carried out using the Chi2 test, with significance set at P < 0.1. The I2 statistic will be used to estimate the total variation across studies due to heterogeneity, where < 25% is considered as low-level, 25% to 50% as moderate-level, and > 50% as high-level heterogeneity (Higgins 2011). If high levels of heterogeneity (I² > 50%) are seen for the primary outcomes, we will explore possible sources of heterogeneity using the sensitivity and subgroup analyses described below.

 

Assessment of reporting biases

We will attempt to contact study authors asking them to provide missing outcome data. Where this is not possible, and the missing data are thought to introduce serious bias, the impact of including such studies in the overall assessment of results will be explored by a sensitivity analysis

If we are able to pool more than 10 trials, we will create and examine a funnel plot to explore possible publication biases.

 

Data synthesis

 

Summary of findings table

We will create a summary of findings table using the GRADEpro software (GRADEprofiler 2008). We will use the five (Grading of Recommendations Assessment, Development and Evaluation) GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of a body of evidence as it relates to the studies which contribute data to the meta-analyses for the pre-specified outcomes. We will use methods and recommendations described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will justify all decisions to down- or up-grade the quality of studies using footnotes and make comments to aid reader's understanding of the review where necessary. We will consider whether there is any additional outcome information that was not able to be incorporated into meta-analyses and note this in the comments and state if it supports or contradicts the information from the meta-analyses.

 

Subgroup analysis and investigation of heterogeneity

We plan to carry out the following subgroup analyses, where feasible:

  1. patients with/without H. pylori infection at baseline;
  2. different duration periods of PPI use (6 to 12 months / 1 to 3 years / more than 3 years);
  3. patients receiving PPI for different reasons, such as GERD, peptic ulcer disease, NSAID prophylaxis;
  4. different PPI doses, i.e. less than/equal to/more than 20 mg omeprazole.

The following outcomes will be used in subgroup analysis:

  1. the number of patients diagnosed as premalignant lesion during the maintenance use of PPI (more than six month) or their further follow-ups;
  2. the type and severity of the observed premalignant lesion.

 

Sensitivity analysis

We will perform sensitivity analysis defined a priori to assess the robustness of our conclusions. This will be achieved by repeating the analyses in order to explore the influence of the following factors on effect size:

  1. exclusion of unpublished studies;
  2. exclusion of lower quality studies (those at high or unclear risk of bias related to randomisation, blinding or attrition);
  3. use of different criteria to assess the occurrence or severity of premalignant lesions: exclusion of studies using unpublished criteria or criteria with no established reliability or validity;
  4. use of a fixed-effect model.

 

Reaching conclusions

We will base our conclusions only on findings from the quantitative or narrative synthesis of included studies for this review. We will avoid making recommendations for practice and our implications for research will give the reader a clear sense if where the focus of any future research in the area should be and what the remaining uncertainties are.

 

Acknowledgements

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

We thank Karin Dearness, Managing Editor, Cochrane Upper Gastrointestinal and Pancreatic Diseases Group for providing administrative and logistical support for the conduct of the current review, and Racquel Simpson, Trials Search Co-ordinator, Cochrane Upper Gastrointestinal and Pancreatic Diseases Group for developing and executing the search strategies.

 

Appendices

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

Appendix 1. CENTRAL search strategy

  1. *Precancerous Conditions/
  2. Gastritis, Atrophic/
  3. (gastric adj2 premalignant).tw.
  4. Metaplasia/
  5. (intestin* adj1 metaplasia).tw.
  6. dysplasia.tw.
  7. or/1-6
  8. Proton Pump Inhibitors/
  9. ((proton adj2 pump adj2 inhibitor$) or PPI or PPIs).tw.
  10. Omeprazole/
  11. (omeprazole or losec or nexium or prilosec or rapinex or zegerid or ocid or Lomac or Omepral or Omez).tw.
  12. Esomeprazole Sodium/
  13. (Esomeprazole or Nexium or Esotrex or Alenia or Escz or Esofag or Nexiam).tw.
  14. (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.
  15. (rabeprazole or aciphex or dexrabeprazole or pariet or Zechin or Rabecid or Nzole-D or Rabeloc).tw.
  16. (Dexlansoprazole or Kapidex or Dexilant).tw.
  17. (pantoprazole or protium or protonix or Pantotab or Pantopan or Pantozol or Pantor or Pantoloc or Astropan or Controloc or Pantecta or Inipomp or Somac or Pantodac or Zurcal or Zentro).tw.
  18. or/8-17
  19. 7 and 18

 

Appendix 2. MEDLINE search strategy

  1. *Precancerous Conditions/
  2. Gastritis, Atrophic/
  3. (gastric adj2 premalignant).tw.
  4. Metaplasia/
  5. (intestin* adj1 metaplasia).tw.
  6. dysplasia.tw.
  7. or/1-6
  8. Proton Pump Inhibitors/
  9. ((proton adj2 pump adj2 inhibitor$) or PPI or PPIs).tw.
  10. Omeprazole/
  11. (omeprazole or losec or nexium or prilosec or rapinex or zegerid or ocid or Lomac or Omepral or Omez).tw.
  12. Esomeprazole Sodium/
  13. (Esomeprazole or Nexium or Esotrex or Alenia or Escz or Esofag or Nexiam).tw.
  14. (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.
  15. (rabeprazole or aciphex or dexrabeprazole or pariet or Zechin or Rabecid or Nzole-D or Rabeloc).tw.
  16. (Dexlansoprazole or Kapidex or Dexilant).tw.
  17. (pantoprazole or protium or protonix or Pantotab or Pantopan or Pantozol or Pantor or Pantoloc or Astropan or Controloc or Pantecta or Inipomp or Somac or Pantodac or Zurcal or Zentro).tw.
  18. or/8-17
  19. 7 and 18
  20. randomized controlled trial.pt.
  21. controlled clinical trial.pt.
  22. randomized.ab.
  23. placebo.ab.
  24. drug therapy.fs.
  25. randomly.ab.
  26. trial.ab.
  27. groups.ab.
  28. or/20-27
  29. exp animals/ not humans.sh.
  30. 28 not 29
  31. 19 and 30

 

Appendix 3. EMBASE search strategy

  1. precancer/
  2. atrophic gastritis/
  3. (gastric adj2 premalignant).tw.
  4. intestine metaplasia/
  5. (intestin* adj1 metaplasia).tw.
  6. gastrointestinal dysplasia/
  7. or/1-6
  8. proton pump inhibitor/
  9. ((proton adj2 pump adj2 inhibitor$) or PPI or PPIs).tw.
  10. omeprazole/
  11. (omeprazole or losec or nexium or prilosec or rapinex or zegerid or ocid or Lomac or Omepral or Omez).tw.
  12. exp esomeprazole/
  13. (Esomeprazole or Nexium or Esotrex or Alenia or Escz or Esofag or Nexiam).tw.
  14. exp lansoprazole/
  15. (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.
  16. rabeprazole/
  17. (rabeprazole or aciphex or dexrabeprazole or pariet or Zechin or Rabecid or Nzole-D or Rabeloc).tw.
  18. (Dexlansoprazole or Kapidex or Dexilant).tw.
  19. pantoprazole/
  20. (pantoprazole or protium or protonix or Pantotab or Pantopan or Pantozol or Pantor or Pantoloc or Astropan or Controloc or Pantecta or Inipomp or Somac or Pantodac or Zurcal or Zentro).tw.
  21. or/8-20
  22. 7 and 21
  23. random:.tw. or placebo:.mp. or double-blind:.tw.
  24. 22 and 23

 

Contributions of authors

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

Conceiving the protocol: HS

Designing the protocol: HS

Coordinating the protocol: HS

Designing search strategies: RS

Writing the protocol: HS, JZ

Providing general advice on the protocol: DL

Performing previous work that was the foundation of the current study: HS, DL, JZ

 

Declarations of interest

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

None known.

 

Sources of support

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

Internal sources

  • Karolinska Institutet, Sweden.
  • Shandong Provincial Hospital, China.

 

External sources

  • No sources of support supplied

References

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Acknowledgements
  7. Appendices
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support
  11. Additional references
  12. References to other published versions of this review
Agrawal 2000
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Ali 2009
Anderson 2010
Anne 2008
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Cooper 2006
Correa 1992
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Dajani 2000
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Dekkers 1999
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References to other published versions of this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Acknowledgements
  7. Appendices
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support
  11. Additional references
  12. References to other published versions of this review
Eslami 2013
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