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Study flow diagram for RCTs
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Figure 1

Study flow diagram for RCTs

'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies.
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Figure 2

'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies.

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study.
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Figure 3

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study.

Comparison 1 H. pylori eradication vs control ‐ main analyses, Outcome 1 Incidence of gastric cancer ‐ modified ITT analysis.
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Analysis 1.1

Comparison 1 H. pylori eradication vs control ‐ main analyses, Outcome 1 Incidence of gastric cancer ‐ modified ITT analysis.

Comparison 1 H. pylori eradication vs control ‐ main analyses, Outcome 2 Incidence of gastric cancer ‐ complete case analysis.
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Analysis 1.2

Comparison 1 H. pylori eradication vs control ‐ main analyses, Outcome 2 Incidence of gastric cancer ‐ complete case analysis.

Comparison 1 H. pylori eradication vs control ‐ main analyses, Outcome 3 Death from gastric cancer ‐ modified ITT analysis.
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Analysis 1.3

Comparison 1 H. pylori eradication vs control ‐ main analyses, Outcome 3 Death from gastric cancer ‐ modified ITT analysis.

Comparison 1 H. pylori eradication vs control ‐ main analyses, Outcome 4 Death from all causes ‐ modified ITT analysis.
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Analysis 1.4

Comparison 1 H. pylori eradication vs control ‐ main analyses, Outcome 4 Death from all causes ‐ modified ITT analysis.

Comparison 1 H. pylori eradication vs control ‐ main analyses, Outcome 5 Incidence of oesophageal squamous cell carcinoma ‐ modified ITT analysis.
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Analysis 1.5

Comparison 1 H. pylori eradication vs control ‐ main analyses, Outcome 5 Incidence of oesophageal squamous cell carcinoma ‐ modified ITT analysis.

Comparison 2 H. pylori eradication vs control ‐ subgroup analysis according to presence or absence of pre‐neoplastic lesions at baseline, Outcome 1 Incidence of gastric cancer according to presence or absence of pre‐neoplastic lesions at baseline.
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Analysis 2.1

Comparison 2 H. pylori eradication vs control ‐ subgroup analysis according to presence or absence of pre‐neoplastic lesions at baseline, Outcome 1 Incidence of gastric cancer according to presence or absence of pre‐neoplastic lesions at baseline.

Comparison 3 H. pylori eradication vs control ‐ subgroup analysis according to use of vitamins or antioxidants, Outcome 1 Incidence of gastric cancer according to use of vitamins or anti‐oxidants.
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Analysis 3.1

Comparison 3 H. pylori eradication vs control ‐ subgroup analysis according to use of vitamins or antioxidants, Outcome 1 Incidence of gastric cancer according to use of vitamins or anti‐oxidants.

Comparison 4 H. pylori eradication vs control ‐ sensitivity analyses, Outcome 1 Incidence of gastric cancer ‐ modified ITT analysis substituting the 10‐year follow‐up data from Zhou 2008 with the 5‐year follow‐up data from Leung 2004.
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Analysis 4.1

Comparison 4 H. pylori eradication vs control ‐ sensitivity analyses, Outcome 1 Incidence of gastric cancer ‐ modified ITT analysis substituting the 10‐year follow‐up data from Zhou 2008 with the 5‐year follow‐up data from Leung 2004.

Comparison 4 H. pylori eradication vs control ‐ sensitivity analyses, Outcome 2 Incidence of gastric cancer ‐ complete case analysis substituting the 10‐year follow‐up data from Zhou 2008 with the 5‐year follow‐up data from Leung 2004.
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Analysis 4.2

Comparison 4 H. pylori eradication vs control ‐ sensitivity analyses, Outcome 2 Incidence of gastric cancer ‐ complete case analysis substituting the 10‐year follow‐up data from Zhou 2008 with the 5‐year follow‐up data from Leung 2004.

Comparison 4 H. pylori eradication vs control ‐ sensitivity analyses, Outcome 3 Incidence of gastric cancer‐ modified ITT analysis including the two arms of celecoxib from Wong 2012.
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Analysis 4.3

Comparison 4 H. pylori eradication vs control ‐ sensitivity analyses, Outcome 3 Incidence of gastric cancer‐ modified ITT analysis including the two arms of celecoxib from Wong 2012.

Comparison 4 H. pylori eradication vs control ‐ sensitivity analyses, Outcome 4 Incidence of gastric cancer ‐ modified ITT analysis including all randomised patients from Correa 2000 and You 2006 who were found subsequently to be ineligible or did not receive treatment.
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Analysis 4.4

Comparison 4 H. pylori eradication vs control ‐ sensitivity analyses, Outcome 4 Incidence of gastric cancer ‐ modified ITT analysis including all randomised patients from Correa 2000 and You 2006 who were found subsequently to be ineligible or did not receive treatment.

Comparison 4 H. pylori eradication vs control ‐ sensitivity analyses, Outcome 5 Incidence of gastric cancer ‐ missing data imputation based on various assumptions.
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Analysis 4.5

Comparison 4 H. pylori eradication vs control ‐ sensitivity analyses, Outcome 5 Incidence of gastric cancer ‐ missing data imputation based on various assumptions.

Summary of findings for the main comparison. H. pylori eradication therapy compared to control for the prevention of gastric neoplasia in healthy asymptomatic infected individuals

H. pylori eradication therapy compared to control for the prevention of gastric neoplasia in healthy asymptomatic infected individuals

Patient or population: healthy asymptomatic H. pylori‐infected individuals
Settings: general population1
Intervention:H. pylori eradication therapy to prevent subsequent gastric cancer 2
Comparison: control

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

H. pylori eradication therapy to prevent subsequent gastric cancer

Incidence of gastric cancer ‐ modified ITT analysis
Histological examination
Follow‐up: 4 to 14.7 years

24 per 1000

16 per 1000
(11 to 23)

RR 0.66
(0.46 to 0.95)

6497
(6 studies)

⊕⊕⊕⊝
moderate3,4,5,6

Number needed to treat to benefit was 124 (95% CI 78 to 843)

Death from gastric cancer ‐ modified ITT analysis

16 per 1000

11 per 1000
(6 to 18)

RR 0.67
(0.4 to 1.11)

4475
(3 studies)

⊕⊕⊕⊝
moderate4,6,7

Death from all causes ‐ modified ITT analysis

67 per 1000

73 per 1000
(58 to 92)

RR 1.09
(0.86 to 1.38)

5253
(4 studies)

⊕⊕⊕⊝
moderate4,6,7

Incidence of oesophageal squamous cell carcinoma ‐ modified ITT analysis

1 per 1000

2 per 1000
(0 to 27)

RR 1.99
(0.18 to 21.91)

1630
(1 study)

⊕⊕⊕⊝
moderate8

Adverse events

See comment

See comment

Not estimable

0
(0)

See comment

Adverse events were poorly reported across the studies and could not be summarised.

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; ITT: intention‐to‐treat; RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: 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.
Very low quality: We are very uncertain about the estimate.

1 As all but one study was conducted in East Asia, it is not possible to assess the effect of searching for and eradicating H. pylori in Western populations.
2 Modified ITT analysis.
3 The quality of evidence was downgraded from high to moderate due to serious risk of bias: Three trials were at low risk of bias, one trial was at unclear risk, and two trials were at high risk of bias. In addition, because of the factorial design of some of the trials, it is difficult to determine whether the reduction in relative risk of subsequent gastric cancer was due to H. pylori eradication therapy alone. The eradication regimens used varied considerably between the individual trials, although this reflects the fact that several of these studies were designed before the widespread adoption of proton pump inhibitor triple therapy, which was first described in 1994, as the gold standard for H. pylori eradication.
4 No significant heterogeneity was seen between studies.
5 The beneficial effect seemed to be more pronounced in the two studies that co‐administered antioxidants and vitamins to participants, but it should be noted that one of these contained the majority of gastric cancers and had the longest duration of follow‐up. There was no significant benefit of H. pylori eradication therapy in preventing subsequent occurrence of gastric cancer when only those participants either with or without preneoplastic lesions at baseline were considered in the analysis. There were no significant subgroup differences.
6 Funnel plots were not produced, as there were less than 10 studies included in the analyses.
7 The quality of evidence was downgraded from high to moderate due to serious risk of bias: one trial was at high risk of bias, one trial was at unclear risk.
8 Only one study was available for this outcome, with wide 95% CI.

Figures and Tables -
Summary of findings for the main comparison. H. pylori eradication therapy compared to control for the prevention of gastric neoplasia in healthy asymptomatic infected individuals
Comparison 1. H. pylori eradication vs control ‐ main analyses

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Incidence of gastric cancer ‐ modified ITT analysis Show forest plot

6

6497

Risk Ratio (M‐H, Random, 95% CI)

0.66 [0.46, 0.95]

2 Incidence of gastric cancer ‐ complete case analysis Show forest plot

6

6038

Risk Ratio (M‐H, Random, 95% CI)

0.66 [0.46, 0.94]

3 Death from gastric cancer ‐ modified ITT analysis Show forest plot

3

4475

Risk Ratio (M‐H, Random, 95% CI)

0.67 [0.40, 1.11]

4 Death from all causes ‐ modified ITT analysis Show forest plot

4

5253

Risk Ratio (M‐H, Random, 95% CI)

1.09 [0.86, 1.38]

5 Incidence of oesophageal squamous cell carcinoma ‐ modified ITT analysis Show forest plot

1

1630

Risk Ratio (M‐H, Random, 95% CI)

1.99 [0.18, 21.91]

Figures and Tables -
Comparison 1. H. pylori eradication vs control ‐ main analyses
Comparison 2. H. pylori eradication vs control ‐ subgroup analysis according to presence or absence of pre‐neoplastic lesions at baseline

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Incidence of gastric cancer according to presence or absence of pre‐neoplastic lesions at baseline Show forest plot

6

6481

Risk Ratio (M‐H, Random, 95% CI)

0.72 [0.45, 1.17]

1.1 Patients with precancerous lesions

4

3425

Risk Ratio (M‐H, Random, 95% CI)

0.86 [0.47, 1.59]

1.2 Patients with out precancerous lesions

2

1812

Risk Ratio (M‐H, Random, 95% CI)

0.42 [0.02, 7.69]

1.3 Mixed patients with and without precancerous lesions or ulcer (can't separate)

2

1244

Risk Ratio (M‐H, Random, 95% CI)

0.38 [0.12, 1.23]

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Comparison 2. H. pylori eradication vs control ‐ subgroup analysis according to presence or absence of pre‐neoplastic lesions at baseline
Comparison 3. H. pylori eradication vs control ‐ subgroup analysis according to use of vitamins or antioxidants

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Incidence of gastric cancer according to use of vitamins or anti‐oxidants Show forest plot

6

6497

Risk Ratio (M‐H, Random, 95% CI)

0.67 [0.45, 1.01]

1.1 Without antioxidants

6

4160

Risk Ratio (M‐H, Random, 95% CI)

0.82 [0.46, 1.45]

1.2 With antioxidants

2

2337

Risk Ratio (M‐H, Random, 95% CI)

0.52 [0.31, 0.87]

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Comparison 3. H. pylori eradication vs control ‐ subgroup analysis according to use of vitamins or antioxidants
Comparison 4. H. pylori eradication vs control ‐ sensitivity analyses

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Incidence of gastric cancer ‐ modified ITT analysis substituting the 10‐year follow‐up data from Zhou 2008 with the 5‐year follow‐up data from Leung 2004 Show forest plot

6

6532

Risk Ratio (M‐H, Random, 95% CI)

0.69 [0.49, 0.98]

2 Incidence of gastric cancer ‐ complete case analysis substituting the 10‐year follow‐up data from Zhou 2008 with the 5‐year follow‐up data from Leung 2004 Show forest plot

6

5921

Risk Ratio (M‐H, Random, 95% CI)

0.69 [0.48, 0.98]

3 Incidence of gastric cancer‐ modified ITT analysis including the two arms of celecoxib from Wong 2012 Show forest plot

6

7008

Risk Ratio (M‐H, Random, 95% CI)

0.69 [0.48, 0.97]

4 Incidence of gastric cancer ‐ modified ITT analysis including all randomised patients from Correa 2000 and You 2006 who were found subsequently to be ineligible or did not receive treatment Show forest plot

6

6648

Risk Ratio (M‐H, Random, 95% CI)

0.67 [0.47, 0.95]

5 Incidence of gastric cancer ‐ missing data imputation based on various assumptions Show forest plot

6

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

5.1 Assuming incidence of gastric cancer for missing participants in both arms same as observed in the trial control arm

6

6497

Risk Ratio (M‐H, Random, 95% CI)

0.66 [0.47, 0.94]

5.2 Assuming incidence of gastric cancer for missing participants in treatment arm same as observed in the trial control arm, but no new gastric cancer cases in the control arm among those with missing data

6

6497

Risk Ratio (M‐H, Random, 95% CI)

0.69 [0.48, 0.98]

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Comparison 4. H. pylori eradication vs control ‐ sensitivity analyses