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Received: 3 November 2022    First decision: 22 November 2022    Accepted: 6 December 2022

DOI: 10.1111/apt.17360

Meta-­analysis: Use of proton pump inhibitors and risk of gastric

cancer in patients requiring gastric acid suppression

Daniele Piovani1,2  | Andreas G. Tsantes3,4  | Holger J. Schunemann1,5,6  |

Stefanos Bonovas1,2

1
Department of Biomedical Sciences,
Humanitas University, Milan, Italy
2
IRCCS Humanitas Research Hospital, Milan,
Italy
3
Laboratory of Haematology and Blood
Bank Unit, “Attiko” University Hospital,
School of Medicine, National and
Kapodistrian University of Athens, Athens,
Greece
4
Microbiology Department, “Saint Savvas”
Oncology Hospital, Athens, Greece
5
Michael G DeGroote Cochrane Canada
and McMaster GRADE Centres, McMaster
University, Hamilton, Ontario, Canada
6
Department of Health Research Methods,
Evidence and Impact, McMaster University,
Hamilton, Ontario, Canada
Correspondence
Daniele Piovani, Department of Biomedical
Sciences, Humanitas University, Via Rita
Levi Montalcini 4, 20072 Pieve Emanuele,
Milan, Italy.
Email: daniele.piovani@humanitasresearch.it
Summary
Background: Proton-­pump inhibitors (PPIs) are suspected to increase the risk of gas-
tric cancer.
Aim: To assess the risk of gastric cancer associated with the use of PPIs.
Methods: We systematically searched Medline/PubMed, Embase and Scopus data-
bases (until June 1, 2022) for randomised and non-­randomised studies (NRS) of the
association between PPIs and gastric cancer having considered Histamine-­2 receptor
antagonists (H2RAs) users as controls. We chose this comparison to minimise con-
founding by indication, and focus on patients requiring gastric acid suppression. Two
authors independently extracted study data and assessed each study's risk of bias.
Maximally-­adjusted relative risk (RR) estimates were extracted. Heterogeneity and
small-­study effect were examined, and summary estimates were calculated using ran-
dom-­and fixed-­effect models. Stratified analyses and meta-­regression were employed
to explore heterogeneity. We used GRADE to evaluate the certainty of evidence.
Results: Of 8375 records, 12 NRS (>6 million patients; 11,554 gastric cancers) and
two randomised clinical trials (498 patients; 1 gastric cancer) fulfilled the eligibility
criteria. Randomised evidence was very imprecise and provided very-­low certainty
evidence. Meta-­analysis of six NRS providing a comprehensive adjustment for con-
founding (2.5 million patients; 7372 gastric cancers) did not show any association be-
tween PPIs and gastric cancer (RRrandom = 1.07, 0.97–­1.19; RRfixed = 1.05, 0.98–­1.12).
The certainty of the evidence was low. No convincing evidence of dose–­response,
or increased risk with long-­term use, was found. Lack of or minimal adjustment for
confounding was associated with larger effect sizes.
Conclusions: We found no association between PPIs and gastric cancer in NRS hav-
ing adequately controlled for confounding. Published studies may suffer residual
confounding.
Systematic review registration: CRD42022335971.

The Handling Editor for this article was Dr Rohit Loomba, and it was accepted for publication after full peer-­review.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction
in any medium, provided the original work is properly cited and is not used for commercial purposes.
© 2022 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

Aliment Pharmacol Ther. 2022;00:1–13.  |

wileyonlinelibrary.com/journal/apt     1
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2       PIOVANI et al.
1 |  I NTRO D U C TI O N
Proton pump inhibitors (PPIs) represent the treatment of choice for the
management of acid-­related conditions of the upper gastrointestinal
tract and are amongst the most widely prescribed drugs in the world.1,2
In the last two decades, studies have suggested increased risks of multi-
ple health outcomes associated with the use of PPIs,3 including contro-
versial data on all cause-­mortality.4–­6 Gastric cancer is one of the most
long-­debated adverse health outcomes of exposure to PPIs. This ma-
lignancy has been the fourth leading cause of cancer death worldwide
in 2020, with more than 1 million new cases and almost 800 thousand
deaths per year.7 Due to their pharmacodynamic action, PPIs are asso-
ciated with hypergastrinemia,8 a condition that has been linked with
9
the proliferation of enterochromaffin-­like cells, suggestive effects on
gastric athrophy,8 and changes in gut microbiota composition and gas-
tric mucosal immunology.10,11 For these reasons, exposure to PPIs has
been suspected to increase the risk of gastric cancer in humans.
Observational studies and meta-­analyses investigating this as-
sociation using as control individuals unexposed to PPIs have shown
an increased risk of gastric cancer.12–­17 Nonetheless, the use of such
a comparator group has been duly criticised.18 Patients with gastric
conditions (e.g. treated with PPIs) may be at increased risk of stom-
ach cancer with respect to the general population.19 Additionally, the
symptoms of an early, undiagnosed gastric cancer may be managed
initially with anti-­acid treatments, thus resulting in likely reverse cau-
sality, especially if an appropriate lag-­time is not considered in the
analysis. These issues can greatly inflate the association of interest.
Few large observational studies have recently investigated the
incidence of gastric cancer in users of PPIs vs. Histamin-­2 receptor
18,20,21
antagonists (H2RAs). H2RAs show a much lower incidence of
hypergastrinemia and no gastric atrophy, 22 but may identify patients
at similar risk of gastric cancer as compared with those exposed to
PPIs, thus acting as an appropriate active comparator to investigate
this association. Unfortunately, these studies often report conflict-
ing results,18,20,21 thus significant uncertainty still persists regarding
the role of PPIs on gastric cancer development. For this reason, we
performed a systematic review and meta-­analysis of studies that
have investigated the risk of gastric cancer amongst PPI users em-
ploying H2RA users as the active comparator group.
2 |  M E TH O DS
Our study protocol is registered with PROSPERO
(CRD42022335971). The study followed guidance published by the
Cochrane Collaboration, 23 adhered to the PRISMA guidelines24 and
the MOOSE checklist. 25
2.1 | Search strategy
We systematically searched Medline/PubMed, Embase and Scopus
databases, from inception to 1 June 2022, to identify pertinent
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studies assessing the risk of gastric cancer in PPI users vs. H2RA
users. Search terms included: proton pump inhibitor(s), omeprazole,
esomeprazole, lansoprazole, rabeprazole or pantoprazole, combined
with neoplasm(s), cancer(s), tumour(s), tumour(s), malignancy, malig-
nancies or neoplasia, combined with a broad list of terms identify-
ing randomised controlled trials (RCTs) and non-­randomised studies
of interventions. This search was complemented by a second one
focusing on head-­to-­head trials of PPIs vs. H2RAs. We included rel-
evant variants, acronyms, truncated and MeSH terms. The detailed
search algorithms are presented in Figure  S1. Reference lists of
retrieved articles including systematic and narrative reviews were
hand-­searched. We excluded editorial articles, conference papers,
and studies not conducted in humans. No language restriction was
imposed.
2.2 | Study selection
We considered eligible any prospective or retrospective non-­
randomised studies of interventions (i.e. cohort, case–­control,
nested case–­control, case-­cohort) investigating the association be-
tween the use of any PPI and gastric cancer employing H2RA users
as the comparator group. Studies considering H2RA users as the ex-
posed group and PPI users as the comparator group were also eligible.
We also considered eligible any head-­to-­head RCT of any PPI vs.
any H2RA conducted on any population without gastric cancer at
enrolment with (i) a follow-­up duration of at least 1 year, (ii) a mini-
mum of 100 patients enrolled, and (iii) information on the occurrence
of any gastric cancer, or death due to gastric cancer. RCTs with a
follow-­up duration of <1 year were deemed inappropriate to an-
swer our research question due to the long disease latency. Given
the need to isolate the potential effect of PPIs on gastric cancer
development, we did not consider crossover trials or maintenance
studies in which the induction phase was performed with PPIs for
all participants.
Two investigators (DP and AT) independently screened titles and
abstracts of the articles identified in the search and excluded those
clearly irrelevant. Potentially eligible studies were retrieved in full
text and critically reviewed for inclusion by both authors. Any dis-
crepancy was discussed with the guarantor of the article (SB), and an
agreement was reached by consensus.
2.3 | Data extraction
Two authors (DP and AT) extracted independently the following data
from each study into a standardised data extraction form: citation
data; study design; population characteristics; underlying condition;
exposure(s) definition(s); outcome(s); number of individuals exposed
to PPIs/H2RAs and person-­time of follow-­up if applicable/available;
number of individuals who developed gastric cancer amongst those
exposed to PPIs/H2RAs; follow-­up length; lag-­time considered be-
tween exposure and outcome; relative risk estimate(s) with 95%

PIOVANI et al.
confidence intervals (CIs); method of control for confounding fac-
tors (i.e. stratification, matching, restriction, multivariable analysis,
propensity score matching or weighting); confounders considered;
period of time; geographic setting; any relevant note regarding
methodological limitations. Any pertinent effect estimate elucidat-
ing dose–­response, or risk with long-­term use, was also extracted or,
whenever possible, calculated.
2.4 | Risk of exposure misclassification
PPIs and H2RAs are used for similar indications, thus concomitant
use and switch between these drug classes are common. If not ad-
dressed properly, this issue may bias the relative risk estimates re-
ported in such studies toward the null (i.e. dilution of effect). The
lowest risk of misclassification was obtained by studies using an
exclusive definition of exposure for H2RA users (i.e. no PPI pre-
scription allowed, or, if a switch occurred, the follow-­up time was
censored). Studies including H2RA users also those with ≤2 prescrip-
tions of PPIs or <30 cumulative defined daily doses were rated at
moderate risk of misclassification. All other studies in which H2RA
users were allowed to have received ≥30 cumulative defined daily
doses or >2 prescriptions of any PPI, or reported no details on this
issue were rated at high risk of misclassification.
2.5 | Study risk of bias
We used a modified Newcastle-­Ottawa scale26 to assess the risk
of bias of non-­randomised studies of interventions on the basis
of selection of study groups, comparability, and ascertainment of
exposure(s) and outcome(s). An additional domain was added to the
standard Newcastle-­Ottawa scale to also assess the risk of exposure
misclassification, as described in the previous section. We assigned
two points in case of low risk of misclassification, one point in case
of moderate risk, and no points in case of high risk. This brought the
maximum possible score to 11 points corresponding to the lowest
risk of bias assessment (a standard Newcastle-­Ottawa scale has a
maximum of 9 points). Studies reaching at least 8 points were con-
sidered at low risk of bias. The Cochrane risk-­of-­bias ROB 2.0 tool for
randomised trials was used to assess the risk of bias in randomised
27
studies. Two authors (DP and AT) independently assessed the risk
of bias.
2.6 | Certainty of the evidence
We used the Grading of Recommendations Assessment,
Development, and Evaluation (GRADE) approach to assess the cer-
28–­31
tainty of the body of the available evidence (quality of evidence).
All investigators discussed and reviewed GRADE assessments.
The certainty of evidence in each association was categorised into
four levels of very low, low, moderate or high.
|
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      3
2.7 | Data synthesis and analysis
2.7.1 | Statistical synthesis of effect estimates
We extracted any pertinent relative risk (RR) estimate available
from each study, but only maximally-­adjusted risk estimates were
retained for the main analysis, as appropriate. Whenever it was
not possible to discern with certainty which was the maximally-­
adjusted relative risk estimate, we selected the one considered by
the authors as the main analysis and extracted the alternative ef-
fect estimate to conduct sensitivity analysis. Besides age and sex,
the most important confounders were deemed covariates lying
on the causal pathway of gastric cancer development (i.e. H. py-
lori/eradication therapy, gastric ulcer, atrophic gastritis, intestinal
metaplasia, alcohol use, smoking, obesity/body mass index, family
history of gastric cancer, gastrointestinal bleeding, ethnicity/race,
detailed indication for acid suppressant drug use). When an ad-
justed relative risk was not reported for the association of interest,
we calculated the unadjusted (crude) effect estimate and its 95%
CI, as appropriate. We included studies reporting different meas-
ures of effect (i.e. risk ratio, odds ratio, hazard ratio, and incidence
rate ratio). As gastric cancer occurrence is a rare outcome, these
measures of relative risk yield very similar estimates, hence a com-
prehensive quantitative evidence synthesis was deemed appropri-
ate. Separate analyses were conducted for studies that provided
adjusted as opposed to crude relative risk estimates. Observational
and randomised evidence were considered separately. In cases
in which the study design considered H2RA users as the exposed
group and PPI users as the comparator group, we calculated the
inverted relative risk estimate and 95% CI, as appropriate. To avoid
the risk of double counting, we avoided to synthesise studies using
the same database whenever a substantial overlap in the follow-­up
period and/or catching area was likely. In such cases, we retained
the study including the estimate corresponding to the largest sam-
ple/number of events.
Effect estimates were synthesised by means of random-­
effect meta-­a nalysis using the DerSimonian-­a nd-­L aird method
which yields conservative 95% CIs in the presence of heteroge-
neity. 32 We also computed and considered fixed-­e ffect estimates
(i.e. more precisely, common-­e ffect inverse variance model);
however, our main conclusions were based on the random-­e ffect
approach.
Heterogeneity across studies was investigated using the
Cochran's Q test, 33 with a conservative 0.10 level of significance,
and quantified with the τ (standard deviation of the underlying
effects across studies) and the I2 value, reporting the proportion
of the variability across studies that is due to between-­s tudy het-
erogeneity rather than chance. 34 We pragmatically assessed in-
consistency using GRADE guidance. If at least 10 studies were
synthesised and in the presence of substantial heterogeneity
(I2 > 60% or p Cochran's Q test < 0.10),
34
we used sub-­group analyses
and meta-­regression to investigate reasons for heterogeneity
by study year (baseline), geographical continent, study design,
 |
4       PIOVANI et al.
lag-­t ime, risk of bias assessment (modified Newcastle-­O ttawa
scale), handling of confounding as determined in the comparabil-
ity domain of the modified Newcastle-­O ttawa scale. For studies
presenting stratified analyses, we tested whether the relative risk
estimates of associations between PPI exposure and gastric can-
cer differed across strata using a test of interaction based on the
Cochran's Q test.
We carried out a sensitivity analysis by removing the studies
with the highest risk of bias (modified Newcastle-­O ttawa scale
score <8). To further examine the robustness of the results, we re-
moved every single study and recalculated the pooled-­effect esti-
mate (leave-­one-­o ut approach). 35 We also conducted a sensitivity
analysis removing the studies with even minimal potential overlap
in patients included.
If >10 studies were available, 36 we assessed the small-­s tudy
effect by inspecting the funnel plot and conducting the Egger's
test. 37 All analyses were performed with Stata 17 software
(StataCorp).
F I G U R E 1   Summary of the evidence search and selection process (flow chart). H2RA, histamine-­2 receptor antagonist; PPI, proton pump
inhibitor; RCT, randomised controlled trial.
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3 | R E S U LT S
3.1 | Literature flow
We identified 8375 articles from the literature search. After a de-
tailed screening of 230 articles in full-­text, 12 eligible observa-
tional studies (including over 6 million patients, and 11,554 gastric
cancers)12,18,20,21,38–­45 and two RCTs (498 patients, 1 gastric can-
cer) 46,47 were identified. The reasons for exclusions are shown in
Figure  1. The most common reason for the exclusion of observa-
tional studies was the lack of data regarding PPIs and/or H2RAs ex-
posure and the use of a comparison group that did not consist of
H2RA users. The most common reason for the exclusion of RCTs was
a follow-­up duration shorter than 1 year.
Of the 12 observational studies, 9 were retrospective cohort
studies18,20,38–­4 4 and three nested case–­control studies.12,21,45
Publication dates ranged from 2006 to 2022. Six studies were con-
ducted in Europe (UK [2], Denmark [2], Scotland, Sweden), three

PIOVANI et al.
studies in North America (United States [2], Canada) and three in
Asia (South Korea [2], Japan). Table  1 provides study characteris-
tics; Table  S1 provides the detailed modified Newcastle-­Ottawa
scale score for each study. The two retrospective cohort studies
by Seo et al44 and Shin et al20 used the database of the Korean
National Health Insurance Services and considered similar periods
of follow-­up, hence we retained the largest study20 and included 11
observational studies in the data synthesis.12,18,20,21,38–­43,45 Eight
studies were considered at low risk of bias and six at low risk of mis-
classification of exposure (Table S1).
3.2 | Association between PPI use and
gastric cancer
3.2.1 | Non-­randomised evidence
Six studies (2.5 million individuals; 7372 gastric cancers) adjusted
for age, sex and at least two additional covariates lying on the
causal pathway of gastric cancer development.18,20,21,38,41,43 These
studies were the least prone to residual confounding (i.e. maximum
score in the comparability domain of the modified Newcastle-­
Ottawa scale) and were considered at low risk of bias (modified
Newcastle-­O ttawa scale score ≥8), hence, they represented the
most reliable evidence. Meta-­analysis of these estimates did
not show any significantly increased risk of gastric cancer in PPI
users as compared to the H2RA users (RR random = 1.07, 0.97–­1.19;
RR fixed = 1.05, 0.98–­1.12). No important heterogeneity was noted
(τ 2 = 0.01; p Cochran's Q test = 0.15; I2 = 38%), Table 2, Figure 2. The
certainty in this random-­effect estimate using the GRADE ap-
proach was low, Table 3. The exclusion of studies with a minimal
potential overlap in populations12,43 yielded point effect estimates
ranging from 1.05 to 1.07 and the same conclusions regarding sta-
tistical significance (Figure S2).
Use of PPIs was not associated with cardia gastric cancer in the only
study showing comprehensive handling of confounding (aHR = 0.98,
0.82–­1.16) and in the two studies providing crude estimates or minimal
adjustment for confounding (RRrandom = 3.28, 0.28–­38.8; RRfixed = 1.47,
0.75–­2.91). Similar results for non-­cardia gastric cancer were shown
by the only study displaying comprehensive handling of confounding
(aHR  =  1.02, 0.81–­1.30) whilst synthesising the two studies provid-
ing crude estimates or minimal adjustment for confounding showed
conflicting conclusions depending on the model used (RRrandom = 2.36,
0.68–­8.18; RRfixed = 2.15, 1.42–­3.25; Table 3, Table S2).
For completeness, we present the meta-­analysis of the 11 stud-
ies amenable to data synthesis irrespectively of adjustment for
confounding. In this analysis, PPI users showed an increased risk of
gastric cancer (RRrandom = 1.33, 1.11–­1.59; Figure 2) as compared to
H2RA users, but with very-­low certainty evidence. This estimate
was at least partially affected by residual confounding and did not
represent the best evidence available. We also observed consider-
able heterogeneity (τ 2  =  0.06; pCochran's Q test < 0.001; I2  = 84%) and
funnel plot asymmetry indicating a small-­study effect (p  = 0.03;
|
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      5
Figure  S3). Sensitivity analyses excluding studies with a minimal
potential overlap in populations,12,43 or considering a different ad-
justed effect estimate from the study by Kim et al40 yielded point
effect estimates ranging from 1.09 to 1.34 and the same conclusions
regarding statistical significance (Figures S2 and S4).
Three studies (approximately 2.8  million participants; 1920
gastric cancers) adjusted at least for age and sex or, alternatively,
for at least two covariates lying on the causal pathway of gas-
tric cancer development, thus providing partially adjusted esti-
mates.12,40,45 In the two remaining studies (0.8 million participants;
2247 gastric cancers) the association of interest was summarised
by crude estimates. 39,42 Meta-­analysis of these five studies showed
an increased risk of gastric cancer amongst PPI users as compared
to H2RA users (RR random  =  1.76, 1.20–­2 .58; RRfixed  =  1.55, 1.38–­
1.74). Important heterogeneity was noted (τ 2  = 0.13; p Cochran's Q
test < 0.001; I2  = 84%), Figure  2 and Figure  S5. Evidence deriving
from this group of studies was severely prone to residual con-
founding. Our confidence in this random-­effect estimate was very
low (Table  3). The exclusion of studies with a minimal potential
overlap in populations, or considering a different adjusted effect
estimate from the study by Kim et al 40 yielded point RR estimates
ranging from 1.25 to 1.95 and the same conclusions regarding sta-
tistical significance (Figures S2 and S4).
3.3 | Results of meta-­regression and
robustness of results
Studies reporting crude or minimally adjusted effect estimates
showed significantly larger effect sizes (p < 0.001 and p = 0.030, re-
spectively) than those considering a more comprehensive list of con-
founders. Although the proportion of heterogeneity explained was
substantial (R 2 = 75.4%), we found evidence of residual heterogene-
ity (τ 2 = 0.015, p = 0.015; I2 = 57%). Studies rated at low risk of bias
(modified Newcastle-­Ottawa scale score ≥8) reported significantly
lower effect sizes (p = 0.020). Misclassification of exposure, baseline
study year, lag-­time used in the analysis, geographical continent, and
study design, were not significantly associated with differential rela-
tive risk estimates (Table S3, p > 0.05).
In a leave-­one-­out meta-­analysis, excluding the study by
Brusselaers et al39 (incidence rate ratio, IRR = 5.55; 3.17–­10.75) yielded
a summary random-­effect estimate of 1.22 (1.05–­1.41, Figure S6). This
study was responsible for the funnel plot asymmetry (Figure S5).
3.4 | Dose-­response and long-­term use
Six studies reported or provided enough data to calculate effect
estimates stratified by either number of prescriptions, cumulative
dose of PPI in terms of omeprazole-­equivalent doses, number of
cumulative defined daily doses, years of follow-­up, or years of ex-
posure. Different outcome measures, study design and exposure
definitions precluded pooling these effect estimates. The study by
 | 6      

TA B L E 1   Characteristics of observational studies investigating the association between the use of proton-­pump inhibitors (PPIs) and gastric cancer

Study, Effect
publication Study design Follow-­up length Total Diseased estimate Control for
year Country (period) Population Intervention/comparator (median) subjects subjects Lag timea (95% CI) confounders1 RoBb
2–­20
Abrahami UK Retrospective >40 years old; no Any PPI (new user, any 5.1 years (PPIs) 1,171,587 1410 1 year aHR = 1.45 11
et al., 2022 cohort cancer, no inherited dose) vs. any H2RA 4.2 years (H2RAs) (1.06–­1.98)
(1990–­2018) gastric cancer (new user, any dose)
syndromes or
Zollinger-­Ellison
2–­4, 7, 12, 14, 15, 19,
Adami et al., Denmark Retrospective >18 years old; no Any PPI (new user, any 12 years (PPIs) 911,290 2865 1 year aHR = 0.97 9
21, 22
2021 cohort cancer dose) vs. ranitidinec 14 years (0.86–­1.09)
(1996–­2018) (new user, any dose) (ranitidine)
Brusselaers Sweden Retrospective >18 years old; no Maintenance PPI (≥180 4.9 years (PPIs, 817,277 2231 No IRR = 5.55 No 7
et al., 2017 cohort cancer cDDD) vs. maintenance mean) 5.7 years (3.17–­10.75)
(2005–­2012) H2RA (≥180 cDDD) (H2RAs, mean)
2,3,21
Garcia-­ UK Nested case–­ >40 years old; no Any PPI (any dose) vs. any NR (cohort 1649 111 1 year aOR = 1.26 7
Rodriguez control cancer H2RA (any dose) included (0.82–­1.95)
et al., 2006 (1994–­2001) 4.3 million
p-­years of follow
up)
5,6,24
Kim et al., USA Retrospective >18 years old; no Omeprazole (any dose) vs. 10 years 2,760,076 1330 1 year aOR = 1.72 9
2021 cohort cancer ranitidinec (any dose) (maximum) (1.47–­2.04)
(2009–­2018)
2,3,5,23,25
Kumar et al., USA Retrospective Patients (veterans) with Any PPI (≥30 days) vs. 4.4 years 272,946 1475 3 months aHR = 1.09 9
2022 cohort H. pylori infection ranitidinec (≥30 days) (0.96–­1.22)
(1998–­2018)
2–­7, 26–­28
Liu et al., Scotland Nested case–­ Patients in primary Any PPI (any dose) vs. any 12 years (max) 3577 760 1 year aOR = 1.34 10
2020 control care; no cancer H2RA (any dose) (0.85–­2.09)
(1999–­2011)
Niikura et al., Japan Retrospective Patients who achieved Any PPI (any dose) vs. any 6.9 years (mean) 156 16 No OR = 1.44 No 4
2017 cohort long-­term H. pylori H2RA (any dose) (0.39–­5.37)
(1998–­2017) eradication
2–­4, 7, 14, 21, 29
Poulsen Denmark Retrospective >40 years old; no Any PPI (new user, ≥2 3.4 years (PPIs) 31,241 54 1 year aIRR = 1.30 10
et al., 2009 cohort cancer prescriptions) vs. any 5.0 years (H2RAs) (0.70–­2.30)
(1990–­2003) H2RA (new user, ≥2
prescriptions)
2–­9, 28–­32
Seo et al., South Korea Retrospective >18 years old; no Any PPI (new user, 4.3 years 10,134 15 1 year aHR = 1.60 10
2021 cohort cancer ≥30 days) vs. any H2RA (0.53–­5.30)
(2002–­2013) (new user, ≥30 days)
PIOVANI et al.

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 PIOVANI et al.

TA B L E 1   Continued

Study, Effect
publication Study design Follow-­up length Total Diseased estimate Control for
year Country (period) Population Intervention/comparator (median) subjects subjects Lag timea (95% CI) confounders1 RoBb
2–­5, 12, 13, 19, 21,
Shin et al., South Korea Retrospective >40 years old; no Any PPI (new user, ≥180 4.6 years (mean) 78,766 808 6 months aHR = 1.01 9
25, 26, 29,
2021 cohort cancer cDDD) vs. any H2RA (0.88–­1.16)
33, 34
(2004–­2015) (new user, ≥180 cDDD)
2, 3
Tamim et al., Canada Nested case–­ >65 years old; no Any PPI (any dose) vs. any 5 years (max) 2902 479 6 months aOR = 1.22 9
2008 control cancer H2RA (any dose) (1.001–­1.48)
(1995–­2003)

Note: 1Either through matching, stratification, restriction, or statistical analysis (multivariable regression and/or propensity score). This refers to the effect estimate of interest and not necessarily to the
primary analysis of the study. Variables controlled for: age, 2 sex,3 alcohol-­related disorders or alcohol consumption,4 smoking status, 5 body mass index/obesity,6 non-­gastrointestinal comorbidities,7
gastrointestinal comorbidities,8 gastric metaplasia,9 gastrointestinal bleeding,10 gastric surgery,11 detailed indication for acid suppressant drug use,12 use of metformin,13 non-­steroidal anti-­inflammatory
drugs,14 antiplatelets,15 cyclooxygenase-­2 inhibitors,16 synthetic prostaglandin analogues,17 selective serotonin reuptake inhibitors,18 anticoagulants,19 steroids, 20 calendar year or period, 21 marital
status, 22 ethnicity/race, 23 atrophic gastritis, 24 socioeconomic/poverty status, 25 statins, 26 oesophagitis, 27 peptic ulcer, 28 H. Pylori/eradication therapy, 29 family history of gastric cancer, 30 any prescribed
drug,31 esophagogastroduodenoscopy,32 Charlson comorbidity index, 33 time from medication start to 180 cDDD-­days (months).34
Abbreviations: a, adjusted; CI, confidence interval; cDDD, cumulative defined daily dose; HR, hazard ratio; H2RA, histamine-­2 receptor antagonist; IRR, incidence rate ratio; NR, not reported; OR, odds
ratio; PPI, proton pump inhibitor; p-­yrs, person-­years.
a
Lag time considered between exposure (i.e. study specific exposure definition) and diagnosis of gastric cancer.
b
Risk of bias assessment for observational studies: modified Newcastle-­Ottawa scale based on the selection of study groups, comparability, ascertainment of exposure(s), outcome(s) and risk of exposure
misclassification (Table S1 for details). The modified scale ranged from 0 points (highest risk of bias) to 11 points (lowest risk of bias).
c
This was the intervention group in the original study. The effect estimate has been inverted, as appropriate.
|       7

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 |

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8       PIOVANI et al.

TA B L E 2   Results of meta-­analysis of observational studies investigating the association between the use of proton pump inhibitors and
gastric cancer including the most relevant subgroup analyses

Small-­study Test of
Pooled effect estimate Test of homogeneity effect interactiona

RR (95% CI)
No. of Egger's
studies Random-­effects Fixed-­effects Q value p-­value I2 p-­value p-­value

Main analysis
Confounding (comparability domain)
Studies reporting adjusted RRb 6 1.07 (0.97–­1.19) 1.05 (0.98–­1.12) 8.1 0.15 38% NA 0.045
Studies reporting partially 3 1.41 (1.08–­1.84) 1.47 (1.31–­1.66) 3.3 0.07 70% NA
adjusted RRc
Studies reporting crude RRd 2 3.22 (0.88–­11.8) 4.36 (2.51–­7.59) 7.5 0.02 73% NA
Subgroup analyses
Risk of bias assessmente
Studies rated as at low RoB 8 1.21 (1.04–­1.42) 1.14 (1.07–­1.21) 38.3 <0.01 82% NA 0.28
Studies rated as at high RoB 3 2.23 (0.74–­6.73) 2.02 (1.44–­2.84) 15.3 <0.01 87% NA
f
Lag-­time in the analysis
Lag-­time ≥6 months 8 1.25 (1.04–­1.50) 1.16 (1.08–­1.24) 37.7 <0.01 81.4 NA 0.42
No lag-­time or <6 months 3 2.08 (0.61–­7.05) 1.16 (1.09–­1.23) 26.4 <0.01 92.4 NA
Study design
Retrospective cohort studies 8 1.38 (1.09–­1.73) 1.15 (1.08–­1.22) 63.2 <0.01 89% NA 0.48
Nested case–­control studies 3 1.24 (1.05–­1.47) 1.24 (1.05–­1.47) 0.2 0.93 0% NA
Geographic area
Europe 6 1.53 (1.04–­2.24) 1.10 (1.00–­1.22) 35.7 <0.01 86% NA 0.06
North America 3 1.22 (1.00–­1.48) 1.27 (1.16–­1.38) 19.6 <0.01 90% NA
Asia 2 1.01 (0.88–­1.16) 1.01 (0.88–­1.16) 0.3 0.60 0% NA
Baseline study year
1990s 7 1.11 (0.99–­1.25) 1.07 (0.99–­1.16) 8.5 0.21 29% NA 0.06
2000s 4 1.65 (1.11–­2.47) 1.29 (1.18–­1.42) 46.2 <0.01 94% NA

Abbreviations: CI, confidence interval; RR, relative risk; RoB, risk of bias; mNOS, modified Newcastle-­Ottawa scale.
a
Considering the random-­effect estimates.
b
The studies obtained two points for comparability in the modified Newcastle-­Ottawa scale. The effect estimate reported by these studies
considered age and sex AND at least two amongst recognised risk factors for gastric cancer (H. pylori/eradication therapy, gastric ulcer, atrophic
gastritis, intestinal metaplasia, alcohol use, smoking, obesity/BMI, family history of gastric cancer, gastrointestinal bleeding, ethnicity/race, detailed
indication for acid suppressant drug use).
c
The studies obtained one point for comparability in the modified Newcastle-­Ottawa scale. The effect estimate reported by these studies or
calculated by the authors of the current study considered age and sex OR at least two amongst recognised risk factors for gastric cancer (H. pylori/
eradication therapy, gastric ulcer, atrophic gastritis, intestinal metaplasia, alcohol use, smoking, obesity/BMI, family history of gastric cancer,
gastrointestinal bleeding, ethnicity/race, detailed indication for acid suppressant drug use).
d
The studies obtained zero points for comparability in the modified Newcastle-­Ottawa scale (i.e. the effect estimate reported by these studies or
calculated by the authors of the current study did not consider any confounding factor).
e
Risk of bias assessment for observational studies: modified Newcastle-­Ottawa scale based on the selection of study groups, comparability,
ascertainment of exposure(s), outcome(s) and risk of exposure misclassification (Table S1 for details). The modified scale ranged from zero points
(highest risk of bias) to 11 points (lowest risk of bias). Studies obtaining at least eight points were rated at low risk of bias.
f
Lag time considered between exposure (i.e. study specific exposure definition) and diagnosis of gastric cancer.

Abrahami et al18 reported a borderline significant dose–­response in
terms of cumulative exposure expressed in omeprazole-­equivalent
doses (<14,600 mg, aHR  =  1.33, 0.97–­1.83; 14,600–­28,199 mg,
aHR  =  2.05, 1.46–­2.89; ≥29,200 mg, aHR  =  2.34, 1.62–­3.37; p for
the difference = 0.049). A similar trend was noted regarding the cu-
mulative duration of PPI exposure (p  =  0.053). Notably, it is likely
that the reference group for the stratified analyses in this study
consisted of patients using any dose/duration of use of H2RAs,
and not progressively increasing categories of dose/duration of use
of H2RAs as it would have been more appropriate. Adami et al38
reported a stratified analysis in the opposite direction with lower
relative risk estimates at longer follow-­ups (<10 years of follow-­up,

PIOVANI et al.
F I G U R E 2   Forest plots for the association between PPI use and gastric cancer: Results from individual studies and meta-­analysis. The
RR and 95% CI for each study are displayed on a logarithmic scale. Pooled effect estimates are from random-­effect models. CI, confidence
interval; RR, relative risk.
aHR  =  1.39, 0.95–­2.04; >10 years of follow-­up, aHR  =  0.62, 0.38–­
1.01; p for the difference  =  0.01). The other four studies did not
report any evidence of dose–­response, or increased risk with long-­
term use (Table S4).12,20,43,45
3.5 | Randomised evidence
Two head-­to-­head RCTs were considered eligible. One study con-
ducted on H. pylori-­negative patients on low-­dose aspirin, with a
history of endoscopically confirmed ulcer bleeding, included 138 pa-
tients assigned to daily rabeprazole (20 mg) and 132 patients to fa-
motidine (40 mg). During a follow-­up time of 1 year, no gastric cancer
46
occurred. The second study conducted on H. pylori-­negative pa-
tients with a history of idiopathic peptic ulcer unexposed to NSAIDs
or aspirin included 114 patients assigned to lansoprazole (30 mg) and
114 patients to famotidine (40 mg). During a follow-­up of 2 years, one
47
patient receiving famotidine developed gastric cancer. The summary
effect estimate corresponded to a risk ratio of 0.33 (95% CI: 0.01–­8.1).
The body of randomised evidence was very imprecise and, in our as-
sessment, the 95% CI crossed more than three decision thresholds30
|
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      9
in absolute terms (i.e. when applying the relative estimate to the con-
trol arm of the non-­randomised studies). The evidence was also rated
down for population and intervention indirectness given that not all
patient populations and doses were evaluated and the outcome was
not assessed at a sufficiently long-­term time point. Thus, we rated the
evidence as of very-­low certainty and focused on non-­randomised
studies of interventions to draw conclusions.31
4 | D I S CU S S I O N
In this systematic review with meta-­analysis, we did not find statisti-
cal evidence of an association between PPIs and gastric cancer when
considering studies that addressed confounding in a comprehensive
manner. However, certainty in the summary effect estimate was low.
This body of evidence suggests that PPIs may result in trivial to no
difference in the risk of gastric cancer. This is the first meta-­analysis
on the topic of synthesising specifically studies that used an active
comparator, namely H2RAs, to limit the influence of confounding by
indication. Our conclusions were based on non-­randomised stud-
ies of interventions that provided adjusted estimates for age, sex
 TA B L E 3   GRADE evidence profile for the association between PPIs and gastric cancer
|

Participants (No. Publication Dose–­ Quality of

10      

Outcome studies) Risk of bias a Inconsistency Indirectness Imprecision bias Study event rate (%) response Summary RR (95% CI) Absolute-­adjusted (per 10.000) b evidence

Non-­r andomised evidence

Gastric cancer 2,469,407 (6 studies) c Not seriousd Not seriouse Not serious Not serious f NA g 7372/2, ­4 69,407 (0.30%) Noh aRR = 1.07 (0.97–1.19) c 2 more (from 1 less to 6 more) Lowi
j k l m g n j
3,582,060 (5 studies) Serious Serious Not serious Very serious NA 4167/3, 5
­ 82,060 (0.12%) No RR = 1.76 (1.20–­2 .58) 23 more (from 6 more to 47 more) Very lowo
c p q r g c
Cardia gastric cancer 911,290 (1 study) Not serious NA Not serious Not serious NA 1304/911, 2
­ 90 ­(0.14%) NA aRR = 0.98 (0.82–­1.16) 0 less (from 3 less to 2 more) Lowi
j s t u g j
818,937 (2 studies) Serious Serious Not serious Very serious NA 609/818, 9
­ 37 ­(0.07%) NA RR = 3.28 (0.28–­3 8.8) 34 more (from 11 less to 567 more) Very lowo
c p q r g c
Non-­c ardia gastric 911,290 (1 study) Not serious NA Not serious Not serious NA 644/911, ­290 ­(0.07%) NA aRR = 1.02 (0.81–­1.30) 0 more (from 3 less to 5 more) Lowi
cancer
818,966 (2 studies) j Seriouss Serious v Not serious Very seriousu NA g 1733/818, ­966 (­ 0.21%) NA RR = 2.36 (0.68–8.18) j 20 more (from 5 less to 108 more) Very lowo

Randomised evidence

Gastric cancer 498 (2 studies) Not serious w NA x Serious y Extremely seriousz NA 1/498 ­(0.20%) NA RR = 0.33 (0.01–8.1) 20 less (from 30 less to 213 more) Very lowaa

Abbreviations: CI, confidence interval; NA, not assessed; RR, relative risk.
a
Risk of bias assessment was performed by applying a modified Newcastle-­O ttawa scale (Table S1).
b
Absolute baseline risk for this population of patients was assumed to be 0.30% for gastric cancer (0.15% for cardia and 0.15% for non-­c ardia gastric cancer).
c
These studies handled confounding in a comprehensive manner by considering age, sex and at least two additional covariates lying on the causal pathway of gastric cancer development (i.e. H. Pylori/eradication therapy, gastric ulcer, atrophic gastritis,
intestinal metaplasia, alcohol use, smoking, obesity/BMI, family history of gastric cancer, gastrointestinal bleeding, ethnicity/race, detailed indication for acid suppressant drug use).
d
Six out of six studies were considered at low risk of bias. The six studies yielded scores ranging from 9 to 11 points (threshold for low risk of bias: ≥8). Not downgraded.
e 2
τ  = 0.01; p Cochran's Q test = 0.15; I2 = 38%; point estimates ranged from 0.97 to 1.46. Not downgraded.
f
Considering an absolute threshold for small effects of 0.06% and a baseline risk of 0.30%, the review size (N = 2,469,407) exceeded the review information size required for a sufficient precision in case of trivial effects (Nrequired > 349,198).30 Not downgraded.
g
Due to a small number of studies (N < 10), risk of publication bias not formally assessed.
h
Four out of six studies investigated dose–­response or risk associated with long-­term use. Some evidence of dose–­response was shown in one of the stratified analyses by Abrahami et al, however, it is likely that the reference group for the stratified
analyses in this study was constituted by individuals using any dose/duration of use of Histamine-­2 receptor antagonists (H2RAs), and not progressively increasing categories of dose/duration of use of H2RAs as it would have been more appropriate.
Conversely, the study by Adami et al. found lower risk estimate corresponding to longer follow-­ups. The studies by Shin et al. and Poulsen et al. did not show evidence of dose–­response or increased risk in the long term (Table S2).
i
Evidence coming from observational studies begins with a grade of “LOW”. Not downgraded or upgraded.
j
These studies were prone to residual confounding: they provided either crude or minimally adjusted estimates of effect.
k
Three out of five studies were considered at high risk of bias. The five studies yielded scores ranging from 4 to 9 (threshold for low risk of bias ≥8). Studies prone to residual confounding due to minimal or no handling of confounding. Downgraded.
l 2
τ  = 0.13; p Cochran's Q test < 0.01; I2 = 84%; point estimates ranged from 1.22 to 5.55. Downgraded.
m
The 95% confidence interval for the absolute effect crossed two of the thresholds across the range of categories of magnitude of effect (the three thresholds selected were absolute effects of 0.06% for small effect, 0.15% for moderate effect, 0.27%
for large effect). 30 Downgraded by two levels (very serious imprecision).
n
Two out of five studies investigated dose–­response or risk associated with long-­term use. The studies by Garcia-­Rodriguez et al and Tamim et al did not show evidence of dose–­response or increased risk in the long term (Table S2).
o
Evidence coming from observational studies begins with a grade of “LOW”. Downgraded for serious risk of bias, serious inconsistency, very serious imprecision.
p
The study by Adami et al obtained 9 points in the modified Newcastle-­O ttawa scale and was rated at low risk of bias. Not downgraded.
q
This effect estimate comes from one single study. Inconsistency could not be assessed. Not downgraded.
r
Considering an absolute threshold for small effects of 0.03% and a baseline risk of 0.15%, the review size (N = 911,290) exceeded the review information size required for a sufficient precision in case of trivial effects (Nrequired > 699,446).30 Not downgraded.
s
The studies by Brusselaers et al. and Garcia-­Rodriguez et al. obtained 7 points in the modified New-­c astle-­O ttawa and were rated at high risk of bias. Studies prone to residual confounding due to minimal or no handling of confounding. Downgraded.
t 2
τ  = 2.39; p Cochran's Q test = 0.07; I2 = 70%; point estimates ranged from 1.25 to 17.0. Downgraded.
u
The 95% confidence interval for the absolute effect crossed the three thresholds across the range of categories of magnitude of effect (the three thresholds selected were absolute effects of 0.03% for small effect, 0.075% for moderate effect, 0.135%
for large effect) including the null effect. 30 Downgraded by three levels (very serious imprecision).
v 2
τ  = 0.71; p Cochran's Q test < 0.01; I2 = 89%; point estimates ranged from 1.27 to 4.51. Downgraded.
w
The risk of bias was considered as not serious. For both randomised studies, the risk-­of-­bias judgement in the Cochrane risk-­of-­bias ROB 2.0 tool for randomised trials was rated as “some concerns”. There were few concerns regarding the “missing
outcome data” domain and low risk of bias for the other four domains. Not downgraded.
x
This effect estimate comes from two studies, however, only one event was found in the study by Wong et al.47 Inconsistency could not be assessed. Not downgraded.
y
Rated down due to population and intervention indirectness (i.e. few patient populations and doses were evaluated in these two studies and gastric cancer was not assessed at a sufficiently long-­term time point).
z
The 95% confidence interval for the absolute effect crossed at least three of the thresholds across the range of categories of magnitude of effect (the three thresholds selected were absolute effects of 0.06% for small effect, 0.15% for moderate
effect, 0.27% for large effect), 30 and was compatible with increases and reductions of effect of large magnitude. Downgraded by three levels (extremely serious imprecision).
aa
Evidence coming from randomised studies begins with a grade of “HIGH”. Downgraded by three levels due to extremely serious imprecision. 30
PIOVANI et al.

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PIOVANI et al.
and at least two additional covariates lying on the causal pathway
of gastric cancer development including approximately 2.5  million
individuals at risk. The results were robust across sensitivity analy-
ses. Accordingly, no convincing evidence of dose–­response, or of
increased risk with long-­term use, was found.
Concerns about a possible increased risk of gastric cancer in PPI
users date back to the 1980s. It was noted that PPIs were associated
with the proliferation of enterochromaffin-­like cells in rats,9 long-­
term treatment could yield hyperplasia of argyrophilic cells in hu-
48
mans, and that this effect was mediated by hypergastrinemia. Few
years later, Graham published the first reports of fundic polyps devel-
oped after long-­term use of omeprazole.49 A more recent systematic
review of RCTs including 1789 participants followed up for more than
6 months found some evidence of enterochromaffin-­like hyperplasia
but no dysplastic or neoplastic alterations.50 In our systematic review
of head-­to-­head RCTs of PPIs vs. H2RAs, we found only two eligible
trials with 1 gastric cancer event amongst patients receiving famoti-
47
dine. Nonetheless, these RCTs were not well-­suited to answer this
research question since gastric cancer was not evaluated at a suf-
ficiently long-­term time point. Also, these studies suffered extreme
imprecision and population and intervention indirectness.
Several observational studies have been performed in the last
three decades to investigate whether PPI use was associated with
gastric cancer. These studies have been synthesised in several
meta-­analyses16,17,51–­55 pooling primary studies considering individ-
uals unexposed to PPIs as the reference group. Although all these
meta-­analyses reported significant associations between PPI use
and gastric cancer, demonstrating causality is tricky in the absence
of randomisation. Amongst the authors, only Tran-­Duy et al clearly
warned about plausible confounding being the reason for the associ-
54
ation they had found, and Zeng et al concluded that, despite they
had found a significant association, they did not endorse a causal
relationship between PPI and gastric cancer.17
In this meta-­analysis, we focused on individuals requiring gas-
tric acid suppression and included studies considering H2RA users
as the comparator group, as these individuals may be at similar risk
of developing gastric cancer with respect to those exposed to PPIs.
This choice is well-­motivated by epidemiological considerations.
Exposure to PPIs may be associated with several known and un-
known prognostic factors for gastric cancer, hence comprehensive
handling of confounding becomes exceptionally difficult when using
unexposed individuals as the comparator group. Nonetheless, H2RAs
share certain characteristics with PPIs (i.e. acid suppression and in-
crease in gastrin, albeit of lower magnitude) which may potentially
increase the risk of gastric cancer. This may render demonstrating
an increased risk of PPIs with respect to H2RA users more difficult
to ascertain. Another limitation is the low certainty of evidence.
The reason is that non-­randomised studies are by definition prone
to residual and unmeasured confounding, hence this is an intrinsic
weakness of meta-­analyses of observational studies. Considering
the rarity of the event, however, performing exceptionally large
and lengthy randomised trials is unfeasible. The above-­mentioned
|
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      11
limitations warrant additional, carefully planned, prospective studies
analysed with a robust methodology.
The primary studies pooled to draw our main conclusions con-
sidered a certain lag-­time to limit reverse causality and time-­related
biases and followed patients for at least 4.5 years, thus providing
sufficient time for the outcome to develop. Despite different ex-
posure definitions (from one prescription of any PPI/H2RA up to at
least 180 cumulative defined daily doses of exposure to PPI/H2RA),
we found no heterogeneity across these six studies, and 5 of 6 stud-
ies showed estimates not excluding the null effect.
In agreement with our conclusions but in contrast with previ-
ous meta-­analyses, 52,53,55 no clear evidence of dose–­response, or
of increased risk associated with long-­term PPI use, was found in
the studies reporting stratified analyses. The presence of a sig-
nificant small-­s tudy effect highlighted by funnel plot asymmetry
was clearly due to the study by Brusselars et al, 39 which was not
amongst the six studies that constituted the best evidence avail-
able. Meta-­regression showed that insufficient or absent handling
of confounding was associated with larger estimates of RR, thus
suggesting that residual confounding was the most plausible reason
for larger effect estimates and not a genuine difference in effect.
Evidence for PPI overuse is growing, and comprehensive efforts
to reduce unnecessary PPI prescriptions are needed.1,2,56,57 Recent
claims of multiple adverse health outcomes associated with PPI use
have further raised the attention on the topic of overprescribing,
though, the certainty of the evidence for most of these claims is very
low.3 A clinical practice update of the American Gastroenterological
Association suggested recently that “the decision to discontinue
PPIs should be based solely on the lack of an indication for use, and
not because of concern for PPI-­associated adverse effects”.1 Our
findings further support this statement. Although the association
between PPI use and gastric cancer is one of the most debated
concerns of PPI use in the medical literature, in this comprehensive
systematic review with meta-­analysis we did not find evidence of
an association. Our findings are reassuring especially to all those
patients who have an indication for long-­term PPI use and need
persistent and effective acid gastric suppression to prevent serious
health consequences.
AC K N OW L E D G E M E N T S
We would like to thank Dr Stefano Alfonso Vitello for contributing to
conceptualize the research question. Open access funding provided
by BIBLIOSAN.
AU T H O R C O N T R I B U T I O N S
Andreas G. Tsantes: Conceptualization (equal); data curation (sup-
porting); investigation (supporting); writing –­ review and editing
(equal). Holger J. Schunemann: Conceptualization (equal); investiga-
tion (equal); writing –­review and editing (equal). Stefanos Bonovas:
Conceptualization (equal); data curation (equal); formal analysis
(equal); methodology (equal); supervision (lead); writing –­ review
and editing (equal).
 |
12       PIOVANI et al.
C O N FL I C T O F I N T E R E S T
All authors declare no conflict of interest related to this work to
disclose.
ORCID
Daniele Piovani  https://orcid.org/0000-0002-1414-6639
Andreas G. Tsantes  https://orcid.org/0000-0002-3695-0759
Holger J. Schunemann  https://orcid.org/0000-0003-3211-8479
Stefanos Bonovas  https://orcid.org/0000-0001-6102-6579
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S U P P O R T I N G I N FO R M AT I O N
Additional supporting information can be found online in the
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How to cite this article: Piovani D, Tsantes AG, Schunemann
HJ, Bonovas S. Meta-analysis: Use of proton pump inhibitors
and risk of gastric cancer in patients requiring gastric acid
suppression. Aliment Pharmacol Ther. 2022;00:1–­13. https://
doi.org/10.1111/apt.17360