Gastric cancer is the fifth commonest cancer and the third leading cause of cancer-related death [1]. Although Helicobacter pylori (H. pylori) infection is one of the major risk factors of gastric cancer [2], H. pylori eradication could only reduce the risk of gastric cancer by around 40% [3, 4]. We have previously shown that aspirin, one of the most widely available chemopreventive agents, is associated with a reduced risk of gastric cancer in H. pylori-eradicated patients (hazard ratio [HR]: 0.30; 95% confidence interval [CI]: 0.15 – 0.61) [5]. However, aspirin increases the risk of upper gastrointestinal bleeding (UGIB), with an incidence rate of 0.91 cases per 1000 person-years in a recent population-based study from the United Kingdom [6]. It is suggested that aspirin users at high risk of UGIB (e.g. prior history of peptic ulcer disease, advanced age, concomitant usage of ulcerogenic agents) should be co-prescribed with proton pump inhibitors (PPIs) [7]. However, as long-term use of PPIs is associated with an increased gastric cancer risk even after H. pylori eradication (HR: 2.44; 95% CI 1.42-4.20) [8], it remains a major clinical dilemma whether PPIs should be co-prescribed with aspirin to reduce the risk of UGIB.
To address this unresolved issue, we have investigated the potential interaction of aspirin with PPIs on the risk of gastric cancer after H. pylori eradication, based on our previously described cohort who had received clarithromycin-based triple therapy (n = 63,397) [8]. The data were retrieved from the territory-wide electronic medical records, known as Clinical Data Analysis and Reporting System (CDARS), of the Hong Kong Hospital Authority. A significant number of populated-based studies have been published using this electronic healthcare database [9, 10]. We hypothesized that the harmful effect of PPIs (in terms of gastric cancer risk) could be negated by the usage of low-dose aspirin among H. pylori-eradicated subjects.
In the primary analysis, we used propensity score (PS) regression adjustment with trimming of the extreme PS strata in the Cox proportional hazards model to derive the adjusted HR of gastric cancer with PPI use. PS was the probability of being given PPIs conditional on other covariates including age of receiving H. pylori eradication therapy, sex, smoking, alcohol use, comorbidities (prior peptic ulcer disease, diabetes mellitus, hypertension, dyslipidemia, obesity, ischemic heart disease, atrial fibrillation, congestive heart failure, stroke, chronic renal failure and cirrhosis) and concomitant usage of medications (namely, aspirin, non-steroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitors, statins, metformin, clopidogrel and histamine-2 receptor antagonists). We constructed 20 categories of 5% each for the PS distribution and patients in the first and 20th PS strata were trimmed to further reduce biases. Sensitivity analyses were performed by PS regression adjustment without trimming and a multivariable Cox regression.
The median age of this cohort at the time of receiving H. pylori eradication therapy was 54.7 years (IQR: 46.0 - 65.4 years), and 46.5% were men. With a median follow-up of 7.6 years (IQR: 5.1 - 10.3 years) totaling 483,260 person-years, 153 (0.24%) patients developed gastric cancer after receiving H. pylori eradication therapy. Table 1 shows the gastric cancer risk with PPI use for the whole cohort and according to the usage of aspirin. For the whole cohort, the PS adjusted HR of gastric cancer with PPI use was 2.44 (95% CI: 1.42 - 4.20). Among non-aspirin users, the harmful effect of PPIs appeared to be even larger (HR 3.73; 95% CI: 2.11 - 6.60). PPI use, however, was not associated with an increase in gastric cancer risk among aspirin users (HR 0.35; 95% CI: 0.04 - 2.74). The test for subgroup difference indicates a significant difference between the association of PPIs with gastric cancer in aspirin and non-aspirin users (p-value for interaction: 0.010).
Table 1: Association between proton pump inhibitors and gastric cancer for the whole cohort and according to aspirin usage
Whole cohort |
||||||||||
Multivariable analysis (n = 63397, GC = 153) |
PS adjustment without trimming (n = 63397, GC = 153) |
PS adjustment with trimming (n = 57057, GC = 139) |
||||||||
HR |
95% CI |
p-value |
HR |
95% CI |
p-value |
HR |
95% CI |
p-value |
||
Non-PPI use |
Ref |
- |
- |
Ref |
- |
- |
Ref |
- |
- |
|
PPI use |
2.19 |
1.31 – 3.66 |
0.003 |
2.14 |
1.27 – 3.58 |
0.004 |
2.44 |
1.42 – 4.20 |
0.002 |
|
Non-aspirin use |
||||||||||
Multivariable analysis (n = 54432, GC = 133) |
PS adjustment without trimming (n = 54432, GC = 133) |
PS adjustment with trimming (n = 48988, GC = 115) |
||||||||
HR |
95% CI |
p-value |
HR |
95% CI |
p-value |
HR |
95% CI |
p-value |
||
Non-PPI use |
Ref |
- |
- |
Ref |
- |
- |
Ref |
- |
- |
|
PPI use |
3.27 |
1.93 – 5.53 |
<0.001 |
3.38 |
1.99 – 5.75 |
<0.001 |
3.73 |
2.11 – 6.60 |
<0.001 |
|
Aspirin use |
||||||||||
Multivariable analysis (n = 8965, GC = 20) |
PS adjustment without trimming (n = 8965, GC = 20) |
PS adjustment with trimming (n = 8067, GC = 16) |
||||||||
HR |
95% CI |
p-value |
HR |
95% CI |
p-value |
HR |
95% CI |
p-value |
||
Non-PPI use |
Ref |
- |
- |
Ref |
- |
- |
Ref |
- |
- |
|
PPI use |
0.53 |
0.12 – 2.37 |
0.402 |
0.52 |
0.11 – 2.34 |
0.392 |
0.35 |
0.04 – 2.74 |
0.318 |
|
Non-PPI use were defined as less than weekly use of PPIs; PPI use was defined as at least weekly use of PPIs. Abbreviations: PS, propensity score; GC, gastric cancer; HR, hazard ratio; 95% CI, 95% confidence interval; PPI, proton pump inhibitor.
In conclusion, we observed in this cohort of H. pylori-eradicated subjects that aspirin use appears to negate the potential harmful effect of PPIs on gastric cancer development. Hence, co-prescription of PPIs should still be recommended in H. pylori-eradicated patients at risk of aspirin-related UGIB without the concern of an increased gastric cancer risk.
Author contributions
Dr. Ka Shing Cheung was involved with study concept and design; analysis and interpretation of data; drafting of manuscript; and approval of the final version of the manuscript. Dr Wai K Leung were involved with the study concept and design; analysis and interpretation of data; drafting of manuscript; critical revision of the manuscript for important intellectual content; study supervision; and approval of the final version of the manuscript.
Conflicts of interest
There are no competing interests.
Funding support
WKL has received honorarium for attending advisory board meetings of Takeda and Abbott Laboratories.
References
1. World Health Organisation. Cancer Fact Sheets: Stomach Cancer. http://gco.iarc.fr/today/fact-sheets-cancers?cancer=5&type=0&sex=0
2. Helicobacter and Cancer Collaborative Group. Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control st udies nested within prospective cohorts. Gut. 2001; 49:347–53.
3. Cheung KS, Leung WK. Risk of gastric cancer development after eradication of Helicobacter pylori. World J Gastrointest Oncol. 2018; 10:115–23.
4. Lee YC, Chiang TH, Chou CK, Tu YK, Liao WC, Wu MS, Graham DY. Association Between Helicobacter pylori Eradication and Gastric Cancer Incidence: A Systematic Review and Meta-analysis. Gastroenterology. 2016; 150:1113–1124.e5.
5. Cheung KS, Chan EW, Wong AY, Chen L, Seto WK, Wong IC, Leung WK. Aspirin and Risk of Gastric Cancer After Helicobacter pylori Eradication: A Territory-Wide Study. J Natl Cancer Inst. 2018; 110:743–49.
6. Cea Soriano L, Lanas A, Soriano-Gabarró M, García Rodríguez LA. Incidence of Upper and Lower Gastrointestinal Bleeding in New Users of Low-Dose Aspirin. Clin Gastroenterol Hepatol. 2018 Jun 14. [Epub ahead of print].
7. Lanza FL, Chan FK, Quigley EM, and Practice Parameters Comm ittee of the American College of Gastroenterology. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol. 2009; 104:728–38.
8. Cheung KS, Chan EW, Wong AY, Chen L, Wong IC, Leung WK. Long-term proton pump inhibitors and risk of gastric cancer development after treatment for Helicobacter pylori: a population-based study. Gut. 2018; 67:28–35.
9. Cheung KS, Seto WK, Fung J, Mak LY, Lai CL, Yuen MF. Epidemiology and natural history of Wilson’s disease in the Chinese: A territory-based study in Hong Kong between 2000 and 2016. World J Gastroenterol. 2017; 23:7716–26.
10. Cheung KS, Seto WK, Fung J, Lai CL, Yuen MF. Epidemiology and Natural History of Primary Biliary Cholangitis in the Chinese: A Territory-Based Study in Hong Kong between 2000 and 2015. Clin Transl Gastroenterol. 2017; 8:e116.