Results of the search

In 2013, we identified 1560 citations with six eligible RCTs. In the February 2020 updated search, we identified 716 citations with one new RCT, using the search strategy outlined above (Figure 1). We reviewed the titles and abstracts and thought 56 articles in 2013 and 12 records in 2020 to be potentially eligible for inclusion. Of these 68 articles, 16 were not RCTs (Hamajima 2002; Hsu 2007; Juibari 2003; Kamangar 2006; Kato 2006; Kim 2008; Leung 2018; Mabe 2009; Ogura 2008; Ohkusa 2001; Take 2005; Take 2007; Takenaka 2007; Uemura 2001; Uemura 2002; Yanaoka 2009); three were RCTs comparing the interventions of interest, but their primary objective was to study the effect of H. pylori eradication therapy on dyspepsia in the community, and they did not report any gastric cancer data (Harvey 2004; Moayyedi 2000; Wildner‐Christensen 2003); and two were RCTs, but with no incident gastric cancers occurring during follow‐up, and therefore did not meet our eligibility criteria for inclusion (Fischbach 2001; Miehlke 2001). In the latter five studies, we contacted the lead or senior authors to ask for the most up‐to‐date information from the most recent follow‐up point of the study, in order to ensure that we were not excluding these articles injudiciously. In all cases, the authors responded and stated that there had been no incident gastric cancers reported at the last point of follow‐up. One RCT presented data on those who had H.pylori eradicated in intervention group vs those H.pylori negative in control group after 3 years, instead of presenting data in all randomized subjects; subjects were those who admitted to hospital or came to hospital for H.pylori testing, instead of general population (Tang 2010). One was a protocol of a RCT that will randomize participants to test and treat vs controls, instead of eradication vs control (Leja 2017) Another four articles were duplicate publications of studies already classified as ineligible. (Ford 2005; Imanzadeh 2004; Lane 2006; Mason 2002). Four studies were RCTs conducted among patients undergoing endoscopic mucosal resection of early gastric cancer (Choi 2014; Choi 2018a; Choi 2018b; Fukase 2008), rather than healthy asymptomatic infected participants, and the final article did not compare the interventions of interest (Fischbach 2009). In the updated search, two articles were protocols from Korea for "HEPTER study" (HELPER study) and one article was protocol from China (Pan 2016)for an ongoing randomised trial.

Figure 1

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Study flow diagram: review update

This left 33 separate papers, reporting on seven separate RCTs that compared H. pylori eradication therapy with placebo or no treatment and providing data on subsequent incidence of gastric cancer, which therefore appeared to be eligible for inclusion. In the previous version of this review, 19 of 29 of these articles were preliminary or duplicate publications, or protocols of eligible RCTs, and provided no new information or did not report outcomes of interest, and were therefore excluded from the meta‐analysis (Feng 2008; Li 2013; Mera 2005; Ruiz 2001; Saito 2003; Sung 2000; Sung 2002; Wang 2009; Wong 2002; Wong 2012b; You 2001; Zhang 1998; Zhang 2006; Zhou 2003a; Zhou 2003b; Zhou 2003c; Zhou 2005a; Zhou 2005b; Zhou 2005c), leaving 10 papers that reported unique and extractable data (Correa 2000‐Correa 2001; Correa 2001; Gail 1998; Zhou 2008; Ma 2012; Saito 2005; Wong 2004; Wong 2012b; You 2006 ; Zhou 2008). One of these studies only reported adverse events data (Gail 1998). In the updated search, one article provided 22‐year follow‐up data (Li 2019) for one of the previously included RCTs and one record (Li 2014) reported 15‐ year follow‐up data in subgroups for the same RCT (You 2006) that included in published version with follow‐up data up to 14.7 years. Data from this study (You 2006 ‐ Li 2019) is being update to the 22‐year follow up data (Li 2019). For another RCT that included in the previous version (Leung 2004‐Zhou 2014), data from a conference abstract (Zhou 2008) with 10‐year follow up data were used. In the update search, the conference abstract was fully published in 2014 (Zhou 2014) but no new data is added to the meta‐analysis. One new RCT is identified in the update search (Choi 2020). Therefore, seven studies (Choi 2020; Correa 2000‐Correa 2001; Leung 2004‐Zhou 2014; Saito 2005; Wong 2004; Wong 2012a;You 2006 ‐ Li 2019) with eleven references contributed data to the analyses concerning incidence of gastric cancer in this systematic review.

Included studies

Please see Characteristics of included studies table. Three of the trials, reported in five separate publications, were of factorial design with some participants randomised to receive vitamins, antioxidants, or celecoxib in addition to H. pylori eradication therapy (Correa 2000‐Correa 2001; Wong 2012a; You 2006 ‐ Li 2019). Only one study was conducted in non‐Asians, among a population at high risk of gastric cancer in Colombia (Correa 2000‐Correa 2001). The shortest duration of follow‐up was greater than or equal to 4 years (Saito 2005), and the longest was 22 years (You 2006 ‐ Li 2019). The largest study contained 2258 participants (You 2006 ‐ Li 2019), and the smallest 513 participants (Wong 2012a).

Excluded studies

Please see Characteristics of excluded studies table.

Allocation

Blinding

Blinding of participants, health providers, data collectors, and outcome assessors should be possible for this type of eradication study. We considered five double‐blind, placebo‐controlled studies to be at low risk of bias for blinding of participants and personnel, as well as blinding of outcome assessors (Choi 2020; Leung 2004‐Zhou 2014; Wong 2004; Wong 2012a; You 2006 ‐ Li 2019). Pathologists were blinded in three studies (Choi 2020; Correa 2000‐Correa 2001; Leung 2004‐Zhou 2014), two of which were considered a double‐blind study because a placebo was used (Choi 2020; Leung 2004‐Zhou 2014). We considered Correa 2000‐Correa 2001 to be at high risk of bias for blinding of participants and personnel because an appropriate placebo was not available for bismuth subsalicylate, and double blinding only applied to the dietary supplements versus placebo part of the trial. We considered this study to be at low risk of bias for blinding of outcome assessment because pathologists were blinded. One study, in abstract form, had uncertain risk of bias for blinding (Saito 2005).

Incomplete outcome data

We considered one study to be at high risk of bias for incomplete outcome data (Leung 2004‐Zhou 2014). Data from Zhou 2014 were used for the main analysis due to the longer follow‐up period. However, the 10‐year follow‐up data reported in Zhou 2014 had a smaller sample size, and fewer gastric cancer cases, than those in the earlier full publication (Leung 2004). According to Leung 2004, 152 (75 vs 77) were lost to follow‐up; these participants were considered as no gastric cancer in the ITT analysis. After 10 years, 378 subjects had completed the study (Zhou 2014). Therefore, in total there would be more than 31% participants lost to follow‐up. We considered three studies to be at unclear risk of bias (Correa 2000‐Correa 2001; Saito 2005; You 2006 ‐ Li 2019). In one study, the average rate of loss was 4.3% per year over the 6‐year trial; withdrawals in the 72 months of follow‐up were 117 (26.8%) versus 104 (25%) in all H. pylori eradication arms versus control arms (Correa 2000‐Correa 2001). However, it is likely that participants who had cancer would have come back for treatment, although these individuals did not complete follow‐up. One conference proceeding did not provide detailed information (Saito 2005). We considered four studies to be at low risk of bias, because the numbers of participants who were lost to follow‐up were balanced between treatment arms and were fewer than 20% (Choi 2020; Wong 2004; Wong 2012a; You 2006 ‐ Li 2019).

Selective reporting

Four studies reported all important outcomes, and we therefore considered them to be at low risk of bias for selective reporting (Choi 2020; Wong 2004; Wong 2012a; You 2006 ‐ Li 2019). We considered three studies to be at unclear risk of bias. In one of these studies, death from gastric cancer was not reported (Correa 2000‐Correa 2001). In another study, mortality data were reported in the 2004 full publication (Leung 2004), but not in the 2014 article (Zhou 2014), which led to an inconsistent sample size between the incidence of gastric cancer and mortality analyses (Leung 2004‐Zhou 2014). One study, reported in abstract form, did not provide any mortality data (Saito 2005).

Other potential sources of bias

We considered one study to be at high risk of bias for other potential sources of bias, due to inconsistent data noted between serial publications (Leung 2004‐Zhou 2014). We identified a total of 11 publications from this study (Leung 2004; Sung 2000; Sung 2002; Zhou 2003a; Zhou 2003b; Zhou 2003c; Zhou 2005a; Zhou 2005b; Zhou 2005c; Zhou 2008; Zhou 2014), with the latest publications reporting data out to 10 years of follow‐up, Zhou 2008 and Zhou 2014, having a smaller sample size and fewer gastric cancer cases than the 2004 full publication. Specifically, 10 gastric cancer cases were reported at 5 years, compared with only nine at 10 years. We considered two studies to be at unclear risk for other potential sources of bias. One was in abstract format (Saito 2005), and the other demonstrated an inconsistent sample size between the full publication, which reported data at 7.5 years (817 versus 813) (Wong 2004), and the conference abstract, which reported data at 7 years (819 versus 809) (Wong 2002). We considered the other four studies to be at low risk of bias.

Effect of H. pylori eradication therapy, compared with placebo or no therapy, on development of subsequent gastric cancer

All seven trials reported a dichotomous outcome for subsequent incidence of gastric cancer. In our primary, modified intention‐to‐treat (ITT) analysis, we included all arms in the two trials of factorial design that also randomised participants to receive antioxidants or vitamins, as well as the 10‐year follow‐up data from Zhou 2014. Overall, 68 (1.6%) of 4206 participants assigned to eradication therapy subsequently developed gastric cancer, compared with 125 (3.0%) of 4117 participants allocated to placebo or no treatment. There was no statistically significant heterogeneity between individual trial results (heterogeneity test, I² = 0%, P = 0.61). H. pylori eradication therapy reduced the risk of gastric cancer in healthy asymptomatic infected individuals (risk ratio (RR) 0.54; 95% confidence interval (CI) 0.40 to 0.72) (NNTB = 72; 95% CI 55 to 118) (Analysis 1.1). The certainty of the evidence was moderate (summary of findings Table 1) with the evidence being downgraded because 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.

We performed several sensitivity analyses when pooling data from these seven trials. In our complete case analysis, where all participants for whom data were missing or unavailable were excluded from the analysis altogether, the RR of developing subsequent gastric cancer was 0.53 (95% CI 0.40 to 0.71) (Analysis 1.2). When we performed a modified ITT analysis, substituting the 10‐year follow‐up data from Zhou 2014 with the 5‐year follow‐up data from Leung 2004., the RR of developing gastric cancer was 0.56 (95% CI 0.42 to 0.74) (Analysis 4.1). When we performed a complete case analysis, but substituted the 10‐year follow‐up data from Zhou 2014 with the 5‐year follow‐up data from Leung 2004, the RR was 0.55 (95% CI 0.41 to 0.74) (Analysis 4.2). When we performed a modified ITT analysis, but also included the celecoxib arms from the trial by Wong 2012, the RR was 0.55 (95% CI 0.41 to 0.74) (Analysis 4.3). When we included all randomised participants from Correa 2000‐Correa 2001 and You 2006 ‐ Li 2019 in the analysis, that is we also included participants who were found to be ineligible after randomisation or those who did not take any medication (the most strict ITT definition), the RR was 0.54 (95% CI 0.40 to 0.72) (Analysis 4.4). Finally, we performed two data imputation analyses. If we assumed the incidence of gastric cancer for missing participants in both arms was the same as that observed in the trial control arm, the RR was 0.55 (95% CI 0.41 to 0.73). If we assumed the incidence of gastric cancer for missing participants in the treatment arm was the same as that observed in the trial control arm, but there were no new gastric cancer cases in the control arm among those with missing data, the RR was 0.56 (95% CI 0.42 to 0.74) (Analysis 4.5). We can therefore be reasonably confident that our conclusions are robust, regardless of the assumptions made about missing data.

Effect of H. pylori eradication therapy, compared with placebo or no therapy, on development of subsequent gastric cancer according to presence or absence of preneoplastic lesions at baseline

We found no evidence of any benefit of H. pylori eradication therapy in preventing the subsequent occurrence of gastric cancer when we considered only those with preneoplastic lesions at baseline in the analysis. Overall, 42 (2.4%) of 1734 participants assigned to eradication therapy subsequently developed gastric cancer, compared with 57 (3.4%) of 1691 participants allocated to placebo or no treatment (RR 0.86; 95% CI 0.47 to 1.59) (Analysis 2.1). There was no statistically significant heterogeneity between individual trial results (heterogeneity test, I² = 23%, P = 0.27). Nor was there evidence of any benefit of H. pylori eradication therapy in preventing subsequent occurrence of gastric cancer when only those participants without preneoplastic lesions at baseline were considered in the analysis. Four (0.4%) of 894 participants randomised to receive eradication therapy subsequently developed gastric cancer, compared with nine (1.0%) of 918 participants who were assigned to placebo (RR 0.42; 95% CI 0.02 to 7.69) (Analysis 2.1). There was statistically significant heterogeneity between individual trial results (heterogeneity test, I² = 70%, P = 0.07). Three studies were included in the subgroup of "mixed" patients with and without precancerous lesions. Of them, Choi 2020 reported that they excluded patients with gastric dysplasia, but stated in the protocol that patients both with or without precancerous lesions (atrophy and intestinal metaplasia) would be included and compared. However, no such data were provided in the final report, so we considered this study to include "mixed" patients, both with and without precancerous lesions. In this subgroup analysis the pooled RR was 0.42 (95% CI 0.22 to 0.78; test for heterogeneity, I² = 0%, P = 0.85) (Analysis 2.1). There was no significant difference between the subgroups (I² = 0%, P = 0.85). It should be noted that there would be reduced power to detect significant differences in these subgroup analyses.

Effect of H. pylori eradication therapy, compared with placebo or no therapy, on development of subsequent gastric cancer according to whether participants were co‐administered vitamins or antioxidants

We found no evidence of any benefit of H. pylori eradication therapy in preventing subsequent occurrence of gastric cancer when we considered only those participants who received eradication therapy alone in the analysis. Overall, 40 (1.3%) of 3082 participants assigned to eradication therapy alone subsequently developed gastric cancer, compared with 58 (2.0%) of 2958 participants allocated to placebo or no treatment alone (RR 0.69; 95% CI 0.41 to 1.14). There was no statistically significant heterogeneity between individual trial results (heterogeneity test, I² = 22%, P = 0.26) (Analysis 3.1). However, when we considered those participants receiving eradication therapy in combination with antioxidants or vitamins in the analysis, 21 (1.8%) of 1178 participants randomised to receive eradication therapy and antioxidants or vitamins subsequently developed gastric cancer, compared with 41 (3.5%) of 1159 participants who were assigned to placebo or no treatment plus antioxidants or vitamins (RR 0.52; 95% CI 0.31 to 0.87). There was no statistically significant heterogeneity between individual trial results (heterogeneity test, I² = 0%, P = 0.51) (Analysis 3.1). There was no significant difference between the subgroups (I² = 0%, P = 0.46). Again, it should be noted that there would be reduced power to detect significant differences in these subgroup analyses, .

Effect of H. pylori eradication therapy, compared with placebo or no therapy, on development of subsequent oesophageal cancer

Only two trials reported these data (Wong 2004;You 2006 ‐ Li 2019). 16 (0.8%) of 1947 participants assigned to eradication therapy developed oesophageal cancer, compared with 13 (0.7%) of 1941 participants allocated to placebo (RR 1.22; 95% CI 0.59 to 2.54, P = 0.68). All three cases were squamous cell cancers in Wong 2004 but histological subtype was not clear in You 2006 ‐ Li 2019 (Analysis 1.5). The certainty of the evidence is moderate (summary of findings Table 1) with the evidence being downgraded because of imprecision.

Effect of H. pylori eradication therapy, compared with placebo or no therapy, on death from gastric cancer

Four studies, containing 6301 participants, provided data on mortality from gastric cancer (Choi 2020; Leung 2004‐Zhou 2014; Wong 2004; You 2006 ‐ Li 2019). Follow‐up ranged from 5 years to 22 years. Overall, there were 36 deaths (1.1%) from gastric cancer among 3154 participants randomised to eradication therapy, compared with 59 (1.2%) deaths in 3147 participants receiving placebo. There was no statistically significant heterogeneity between individual trial results (heterogeneity test, I² = 0%, P = 0.95). There was evidence of benefit of H. pylori eradication therapy in preventing death from gastric cancer in healthy asymptomatic infected individuals (RR 0.61; 95% CI 0.40 to 0.92) (Analysis 1.3). The NNTB was 137 (95% CI 89 to 667).Certainty of the evidence is moderate (summary of findings Table 1) and this was downgraded .

Effect of H. pylori eradication therapy, compared with placebo or no therapy, on all‐cause mortality

Five studies, containing 7079 participants, provided data on all‐cause mortality (Choi 2020; Correa 2000‐Correa 2001; Wong 2004; Wong 2012a; You 2006 ‐ Li 2019). Follow‐up ranged from 6 to 22 years. Overall, 315 (8.9%) of 3551 participants receiving eradication therapy were dead at last point of follow‐up, compared with 323 (9.2%) of 3528 participants receiving placebo or no treatment. There was no statistically significant heterogeneity between individual trial results (heterogeneity test, I² = 0%, P = 0.50). There was no evidence of any benefit of H. pylori eradication therapy in preventing death from any cause in healthy asymptomatic infected individuals (RR 0.97; 95% CI 0.85 to 1.12) (Analysis 1.4). Certainty of the evidence is moderate (summary of findings Table 1) and downgraded because three of the studies were either unclear or high risk of bias.

Adverse events with H. pylori eradication therapy, compared with placebo or no therapy

Only two of the studies we identified reported individual adverse events data with eradication therapy compared with placebo or no treatment (Choi 2020; Gail 1998). Gail 1998 reported that there was no difference in the incidence of adverse events with eradication therapy, with the exception of skin rash, which occurred in 3.1% of those receiving eradication therapy compared with 0.1% of those allocated placebo. Choi 2020 reported that any adverse event was higher in the eradication group (53.0% vs 19.1% P <0.001), and that any adverse event ≥ grade 3 occurred in 0.8% vs 0.1% (P = 0.04). Another study reported that side effects were monitored closely, and none of any clinical importance were detected, although no dichotomous data were reported to support this statement (Correa 2000‐Correa 2001).