Proton pump inhibitor: The dual role in gastric cancer

Table 1 Summary of clinical studies associating gastric cancer with long-term use of proton pump inhibitors

Author, year	Study design, country	Study period	Source of database	No. of case and control	Information of PPI	Adjustment	Main outcomes
Garcia-Rodriguez et al[24], 2006	Nested case-control, retrospective, United Kingdom	1994-2001	The general practitioners research database in the United Kingdom	522/10000	Duration, indication	Age, sex, calendar year, smoking, alcohol consumption, body mass index, gastro-esophageal reflux, hiatal hernia, peptic ulcer, and dyspepsia	OR for gastric cardia adenocarcinoma: 1.06 (0.57-2.00); gastric non-cardia adenocarcinoma: 1.75 (1.10-2.79)
Tamim et al[25], 2008	Case control, retrospective, Canada	1995-2003	Quebec health insurance plan	1598/12991	Type, dose, exposure time	Number of drug prescriptions, total length of hospitalizations, number of visits to GPs, specialists, and emergency rooms during the year before the diagnosis	Adjusted OR: 1.40 (1.08-1.51); 1st quartile: 1.66 (1.24-2.23); 2nd quartile: 1.37 (1.00-1.88); 3rd quartile: 1.57 (1.17-2.10); 4th quartile: 1.20 (0.85-1.70)
Poulsen et al[26], 2009	Population-based cohort, retrospective, Denmark	1990-2003	Danish National Health-care System	109/not reported	Type, year of follow-up, no. of prescription	Age, gender, calendar period, gastroscopy (≥ 1 yr before censoring events), use of NSAIDs and H. pylori eradication	IRR for gastric cancer: 1.2 (0.8-2.0) among PPI users with the largest number of prescriptions (15+) or the longest follow-up (5+)
Cheung et al[29], 2018	Population-based cohort study, retrospective, Hong Kong	2003-2012	Clinical Data Analysis and Reporting System of the Hong Kong Hospital Authority	153/63397	Frequency, duration	Age of receiving H. pylori eradication therapy, sex, smoking, alcohol use, comorbidities, concomitant medications	HR for gastric cancer: 2.44 (1.42-4.20); ≥ 1 yr: 5.04 (1.23-20.61); ≥ 2 yr: 6.65 (1.62-27.26); ≥ 3 yr: 8.34 (2.02-34.41). The adjusted absolute risk difference for PPIs vs nonPPIs use: 4.29 (1.25-9.54) per 10000 person-yr.
Brusselaers et al[33], 2017	Population-based cohort study, retrospective, Sweden	2005-2012	The Swedish Prescribed Drug Registry	2219/794848	Indication, cumulative defined daily dosages, estimated number of days	Age, sex, calendar period, indication of PPI, maintenance use (≥ 180 d) of aspirin or other NSAIDs	SIR: 3.38 (3.23-3.53) in both sexes, all age groups and all indication groups; < 1 yr: 12.82 (12.19-13.47); 1.0-2.9 yr: 2.19 (1.98 to 2.42); 3.0-4.9 yr: 1.10 (0.91-1.31); ≥ 2 yr: 0.61 (0.52-0.72)

PPI: Proton pump inhibitor; OR: Odds ratio; GP: General physician; NSAID: Nonsteroidal anti-inflammatory drug; H. pylori: Helicobacter pylori; IRR: Incidence rate ratio; HR: Hazard ratio; SIR: Standardized incidence ratio.