Final CAT

by Jaspreet k Sra

PICO Search Assignment Worksheet Name: Jaspreet Kaur Sra 

Brief description of patient problem/setting (summarize the case very briefly):

60 year old male with a PMHx of GERD, HTN, HLD and a recent H. Pylori infection. He presented with worsening GERD and was prescribed Omeprazole as he was already taking  H2RA. He was concerned about the change and is worried about cancer due to the new medication. 

Search Question:

Do using PPIs cause the patient to have an increased risk of gastric cancer? 

Question Type: What kind of question is this? (boxes now checkable in Word)

Prevalence  Screening Diagnosis

Prognosis Treatment Harms

I will attempt to find either a meta-analysis or systematic review as those provide the highest level of evidence. I would aim to find RCTs as that would provide valid evidence. Being able to find these within a meta-analysis or systematic review will help me best answer my question and the patient’s concerns. The next step would be to find an observational study.  I based my choices off of the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence. 

PICO search terms:

PICO
Patients taking PPIs Acid suppressing agents Control Gastric cancer 
Patients with GERD PPI  Digestive cancer 
PPI use   Cancer 

Search tools and strategy used:

Filters/limits applied:

  • Recent publications within the past 5 years
  • Recent publications within the past 10 years
  • Review
  • Full Article
  • Journal

Databases used:

  • PubMed
    1. PPI and cancer → 5265
      1. Filters: 10 years, full text, RCT, systematic review, meta-analysis → 150
      2. Filters: 20 years, full text, RCT, systematic review, meta-analysis, case reports, observational study → 108
    2. PPI and Gastric Cancer → 633
      1. Filters: 20 years, full text, RCT, systematic review, meta-analysis, case reports, observational study → 102
  • ScienceDirect
    1. Elderly PPI usage and cancer → 1293
      1. Filters: 10 years, review articles, research articles  → 251
    2. Omeprazole and gastric cancer → 2024
      1. Filters: 10 years, review articles, research articles, case reports →984
  • Wiley Online Library
    1. Gastric cancer and PPI → 4600
      1. Filters: 10 years, journal → 2486
  • Google Scholar
    1. digestive tract cancer and PPI → 20000
      1. Filters: 10 years, any article  → 5670
      2. Filters: 10 years, review article → 1280

I narrowed down the choices by trying to  focus on the meta-analysis, systematic reviews and RCTs. I was able to find one article that was a meta-analysis of RCTs. However, there was a lack of RCTS that studied PPIs and cancer. I came across more case control and cohort studies. I also tried to use studies that had large sample sizes and the least amount of bias and confounding variables. However, it was very difficult to find such articles. It is very difficult to control certain variables. I used the word PPI over omeprazole as that provided more results. Depending on the site that I used I added on filters such as systematic review, meta-analysis. I also had to change the terms I used throughout my search. I used fewer terms rather than all the terms because the results would come out to be very limited. Aside from being limited, the articles were not in correlation with the question.  Google scholar and Wiley online library gave a large amount of results. However, when I added filters the results were not in correlation with the types of studies that could answer the PICO question. Hence, I had to search through the large results to find the articles that helped answer the PICO question. I did attempt to narrow them down further by typing in terms such as “meta-analysis or systematic review” with the terms. This also  helped me narrow down the important articles. This did limit the results to specific studies hence I looked through these sites with and without the terms in the search box. 

Article 1 

Citation: Segna, D., Brusselaers, N., Glaus, D., Krupka, N., & Misselwitz, B. (2021). Association between proton-pump inhibitors and the risk of gastric cancer: a systematic review with meta-analysis. Therapeutic advances in gastroenterology, 14, 17562848211051463. https://doi.org/10.1177/17562848211051463
Type of Study: Systematic Review with Meta- Analysis 
AbstractIntroduction:The use of proton-pump inhibitors (PPI) may be associated with an increased risk of gastric cancer (GC).Objective:To review and meta-analyze available literature investigating the association between PPI use and GC risk.Methods:Two independent reviewers systematically searched Ovid MEDLINE, EMBASE, and Cochrane Library (inception to July 2020) for case-control and cohort studies assessing the association between PPI use and GC according to a predefined protocol in PROSPERO (CRD42018102536). Reviewers independently assessed study quality, extracted data, and meta-analysed available and newly calculated odds ratios (ORs) using a random-effects model, and stratified for GC site (cardia versus non-cardia) and PPI duration (<1 year, 1–3 years, >3 years).Results:We screened 2,396 records and included five retrospective cohort and eight case-control studies comprising 1,662,881 individuals in our meta-analysis. In random-effect models, we found an increased GC risk in PPI users [OR: 1.94, 95% confidence interval (95% CI): 1.47–2.56] with high statistical heterogeneity (I2 = 82%) and overall moderate risk of bias. Stratified analyses indicated a significant risk increase in non-cardia (OR: 2.20, 95% CI: 1.44–3.36, I2 = 77%) with a similar non-significant trend in cardia regions (OR: 1.77, 95% CI: 0.72–4.36, I2 = 66%). There was no GC increase with longer durations of PPI exposure (<1 year: OR: 2.29, 95% CI: 2.13–2.47, I2 = 0%; 1–3 years: OR: 1.46, 95% CI: 0.53–4.01, I2 = 35%; >3 years: OR: 2.08, 95% CI: 0.56–7.77, I2 = 61%).Conclusion:We found a twofold increased GC risk among PPI users, but this association does not confirm causation and studies are highly heterogeneous. PPI should only be prescribed when strictly indicated.
Reason for Selection:  This study was a meta-analysis  which provides the highest level of evidence.  1,662,881 individuals were included  in the study which is a very large sample size. The studies  used large populations databases in Asia, Europe, and North America, which increases generalizability.
Key Points:Articles that were selected were cohort and case-control studies that assessed the association between PPI use and GC risk. The studies were comprised of individuals that have had considerable PPI use and a control group with no or only rare PPI use.  The burden PPI exposure was measured by duration, frequency, and dosage.Eight case-control and  five retrospective cohort studies were selectedAssociation between GC and PPI use: Stratified analyses according to study design showed a higher GC risk estimate in the five included retrospective cohort studies (OR: 2.76, 95% CI: 1.56–4.88, I2 = 63%, p = 0.03) than in the eight included case-control studies  (OR: 1.59, 95% CI: 1.23–2.05, I2 = 81%, p < 0.01) Association between GC and PPI use according to PPI duration: There was no trend for a duration-dependent effect of PPI use <1 year: OR: 2.29, 95% CI: 2.13–2.47, I2 = 0%, p = 0.971–3 years: OR: 1.46, 95% CI: 0.53–4.01, I2 = 35%, p = 0.21 >3 years: OR: 2.08, 95% CI: 0.56–7.77, I2 = 61%, p = 0.08The meta-analysis found an almost two fold increased GC risk among PPI users compared with controls. However,  there was substantial heterogeneity in study designs, populations, definitionsof exposure and outcome, and residual confounding as well as a potential publication bias which is why causation cannot be proven.

Article 2 

Citation: Song, H., Zhu, J., & Lu, D. (2014). Long-term proton pump inhibitor (PPI) use and the development of gastric pre-malignant lesions. The Cochrane database of systematic reviews, (12), CD010623. https://doi.org/10.1002/14651858.CD010623.pub2
Type of Study: Meta – Analysis 
AbstractBackground Proton pump inhibitors (PPIs) are the most effective drugs to reduce gastric acid secretion. PPIs are one of the most commonly prescribed classes of medications worldwide. Apart from short-term application, maintenance therapy with PPIs is recommended and increasingly used in certain diseases, such as Zollinger-Ellison syndrome and gastro-oesophageal reflux disease, especially for people with erosive oesophagitis or Barrett’s esophagus. Although PPIs are generally safe, their efficacy and safety of long-term use remains unclear. The question of whether the long-term use of PPIs could promote the development of gastric pre-malignant lesions has been widely investigated, but results are inconsistent. Limited insight on this problem leads to a dilemma in decision making for long-term PPI prescription. Objectives To compare the development or progression of gastric pre-malignant lesions, such as atrophic gastritis, intestinal metaplasia, enterochromaffin-like (ECL) cell hyperplasia, and dysplasia, in people taking long-term (six months or greater) PPI maintenance therapy. Data collection and analysis Two review authors independently performed selection of eligible trials, assessment of trial quality, and data extraction. We calculated odds ratios (OR) for analysis of dichotomous data and mean differences for continuous data, with 95% confidence intervals (CI). Main results We included seven trials (1789 participants). Four studies had high risk of bias and the risk of bias in the other three trials was unclear. In addition, it was difficult to assess possible reporting bias. We pooled 1070 participants from four RCTs to evaluate corporal atrophy development revealing an insignificantly increased OR of 1.50 (95% CI 0.59 to 3.80; P value = 0.39; low-quality evidence) for long-term PPI users relative to non-PPI users. In five eligible trials, corporal intestinal metaplasia was assessed among 1408 participants, also with uncertain results (OR 1.46; 95% CI 0.43 to 5.03; P value = 0.55; low-quality evidence). However, by pooling data of 1705 participants from six RCTs, our meta-analysis showed that participants with PPI maintenance treatment were more likely to experience either diffuse (simple) (OR 5.01; 95% CI 1.54 to 16.26; P value = 0.007; very-low-quality evidence) or linear/micronodular (focal) ECL hyperplasia (OR 3.98; 95% CI 1.31 to 12.16; P value = 0.02; low-quality evidence) than controls. No participant showed any dysplastic or neoplastic change in any included studies. Authors’ conclusions There is presently no clear evidence that the long-term use of PPIs can cause or accelerate the progression of corpus gastric atrophy or intestinal metaplasia, although results were imprecise. People with PPI maintenance treatment may have a higher possibility of experiencing either diffuse (simple) or linear/micronodular (focal) ECL cell hyperplasia. However, the clinical importance of this outcome is currently uncertain.
Reason for Selection: The reason I selected this article is because it was a meta-analysis of  RCTs. Along with a large sample size, it also discussed the potential for bias in each of the articles. 
Key Points:Seven trials were included in this meta-analysis which were RCTS.In all of the studied included  pathological changes of stomach mucosa were measured both at baseline (the beginning of maintenance treatment) and the completion of follow-up. Five trials assessed corporal intestinal metaplasia among 1408 participants. Only a few participants (seven from PPI group versus three from control group) scored worse on their final biopsies, and there was no evidence that the worsening scores of intestinal metaplasia were associated with long-term PPI use. 1705 participants from six RCTs, our meta-analysis showed that participants with PPI maintenance treatment  compared to control were more likely to experience either diffuse (OR 5.01; 95% CI 1.54 to 16.26; P value = 0.007; very-low-quality evidence) linear/micronodular (focal) ECL hyperplasia (OR 3.98; 95% CI 1.31 to 12.16; P value = 0.02; low-quality evidence)There is no clear evidence that the long- term use of proton pump inhibitors (PPIs) can cause or accelerate the progression of corpus gastric atrophy or intestinal metaplasia

Article 3: 

Citation:Abrahami, D., McDonald, E. G., Schnitzer, M. E., Barkun, A. N., Suissa, S., & Azoulay, L. (2022). Proton pump inhibitors and risk of gastric cancer: population-based cohort study. Gut, 71(1), 16–24. https://doi.org/10.1136/gutjnl-2021-325097 
Type of Study: Cohort Study 
AbstractObjective: To determine whether new users of proton pump inhibitors (PPIs) are at an increased risk of gastric cancer compared with new users of histamine-2 receptor antagonists (H2RAs).
Design: Using the UK Clinical Practice Research Datalink, we conducted a population-based cohort study using a new-user active comparator design. From 1 January 1990 to 30 April 2018, we identified 973 281 new users of PPIs and 193 306 new users of H2RAs. Cox proportional hazards models were fit to estimate HRs and 95% CIs of gastric cancer, and the number needed to harm was estimated using the Kaplan-Meier method. The models were weighted using standardized mortality ratio weights using calendar time-specific propensity scores. Secondary analyses assessed duration and dose-response associations.
Results: After a median follow-up of 5.0 years, the use of PPIs was associated with a 45% increased risk of gastric cancer compared with the use of H2RAs (HR 1.45, 95% CI 1.06 to 1.98). The number needed to harm was 2121 and 1191 for five and 10 years after treatment initiation, respectively. The HRs increased with cumulative duration, cumulative omeprazole equivalents and time since treatment initiation. The results were consistent across several sensitivity analyses.
Conclusion: The findings of this large population-based cohort study indicate that the use of PPIs is associated with an increased risk of gastric cancer compared with the use of H2RAs, although the absolute risk remains low.
Reason for Selection:  Although this study was conducted in the UK, the population in UK and US is very similar. The study was published and approved from Canada which implies the appropriate standards were used. Although this study compares PPI with H2RAs, it still discusses the risk of cancer with PPIs which is the aim of this PICO. 
Key Points:new users of PPIs are at a 45% increased risk of gastric cancer (HR 1.45, 95% CI 1.06 to 1.98) compared with new users of H2RAs, with a number needed to harm of 2121 and 1191 for five and 10 years after treatment initiation,Those patients were excluded for whom a PPI and an H2RA were prescribed concomitantly at cohort entry, history of gastric cancer, rare inherited cancer syndromes or Zollinger-Ellison syndromeAll patients were followed starting 1 year after cohort entry until an incident diagnosis of gastric cancerSample size of the cohort study was 973 281 of new PPI users and 198 306 of new H2RAs users . These exposure groups were followed for a median duration of 5.1 years. The crude HR was below the null value (HR: 0.92), the use of PPIs was associated with an increased risk of gastric cancer after adjusting for calendar year strata In the fully adjusted model, the use of PPIs was associated with a 45% increased risk of gastric cancer, compared with the use of H2RAs. PPI users had a higher cumulative incidence of gastric cancer than H2RA users. 

Article 4 

Citation: Zeng, R., Cheng, Y., Luo, D., Wang, J., Yang, J., Jiang, L., Zhuo, Z., Guo, K., Wu, H., Leung, F. W., Sha, W., & Chen, H. (2021). Comprehensive analysis of proton pump inhibitors and risk of digestive tract cancers. European journal of cancer (Oxford, England : 1990), 156, 190–201.
Type of Study: Systematic review and meta-analysis
Background: For the past two decades, dispute on whether proton pump inhibitor (PPI) leads to digestive tract cancer remains, and emerging studies in recent years still demonstrate inconsistent results, which continues to perpetuate concerns over the safety of PPI use. We performed a systematic review and meta-analysis, with comprehensive evaluation by Bradford Hill criteria of causation, to assess the effect of PPI use on digestive tract cancers.
Methods: Medline, Embase and Web of Science databases were searched for observational studies published up to 15th January 2021. Pooled relative risks (RRs) were estimated via random effects models. Cumulative defined daily dose- and duration-risk relationships using restricted cubic spline and fractional polynomial models were investigated. Bradford Hill criteria were applied to evaluate causation. PROSPERO Registration: CRD42020211103.
Results: Thirty-two publications containing 4,355,254 participants were included. PPI use is associated with an increased risk of overall digestive tract cancers (RR = 1.63, 95% confidence interval (CI) 1.33 to 2.00). PPI use is correlated with increased risks of gastric cancer (RR = 1.78, 95% CI 1.38 to 2.31), pancreatic cancer (RR = 1.72, 95% CI 1.05 to 2.82) and liver cancer (RR = 1.62, 95% CI 1.04 to 2.52), but not of esophageal cancer (RR = 2.06, 95% CI 0.65 to 6.57) and colorectal cancer (RR = 1.24, 95% CI 0.93 to 1.66). The association between PPI and digestive tract cancers is stronger in people with minimal exposure. When cumulative defined daily dose or duration increases, the risks decline and become non-significant. Evaluation by Bradford Hill criteria indicates weak evidence of causation.
Conclusions: A causal relationship between PPI use and digestive tract cancers is not supported by the evidence in the current review. Concerns over carcinogenic side-effects of PPI might be unfounded.
Reason for Selection: I chose this study because it provides the highest level of evidence. It also included studies mostly from US, but other countries as well which allows it to be more applicable to a variety of individuals. 
Key Points:20 case control and 14 cohort studies were selected. These studies  contained information on PPIs and digestive tract cancer risks. There were a total 106,888 cases. A significantly increased risk was observed, for regular PPI use (RR Z 1.63, 95% CI 1.33 to 2.00), with a higher risk in cohort studies (RR Z 1.70, 95% CI 1.30 to 2.22) than that in case control studies. However, assessment by Bradford Hill criteria indicates weak causality between PPI use and digestive tract cancer risks. The data in the current report does not  support the hypothesis that increased dose and duration of PPI exposure are associated with the risk of digestive tract cancers.A lower cumulative dose or duration of PPI use is associated with a higher risk of developing digestive tract cancers, whereas no association is found under the highest level of PPI use.The data indicates that the long term use of PPIs is free of digestive tract cancer risks

Article 5 

Citation: Ahn, J. S., Eom, C. S., Jeon, C. Y., & Park, S. M. (2013). Acid suppressive drugs and gastric cancer: a meta-analysis of observational studies. World journal of gastroenterology, 19(16), 2560–2568. https://doi.org/10.3748/wjg.v19.i16.2560
Type of Study: Meta-analysis
AbstractAIM: To evaluate the association between acid suppressive drug use and the development of gastric cancer.METHODS: A systematic search of relevant studies that were published through June 2012 was conducted using the MEDLINE (PubMed), EMBASE, and Cochrane Library databases. The search included observational studies on the use of histamine 2-receptor antagonists (H2RAs) or proton pump inhibitors and the associated risk of gastric cancer, which was measured using the adjusted odds ratio (OR) or the relative risk and 95%CI. An independent extraction was performed by two of the authors, and a consensus was reached.RESULTS: Of 4595 screened articles, 11 observational studies (n = 94558) with 5980 gastric cancer patients were included in the final analyses. When all the studies were pooled, acid suppressive drug use was associated with an increased risk of gastric cancer risk (adjusted OR = 1.42; 95%CI: 1.29-1.56, I2 = 48.9%, P = 0.034). The overall risk of gastric cancer increased among H2RA users (adjusted OR = 1.40; 95%CI: 1.24-1.59, I2 = 59.5%, P = 0.008) and PPI users (adjusted OR = 1.39; 95%CI: 1.19-1.64, I2 = 0.0%, P = 0.377).CONCLUSION: Acid suppressive drugs are associated with an increased risk of gastric cancer. Further studies are needed to test the effect of acid suppressive drugs on gastric cancer.
Reason for Selection:  I selected this article because it is a meta-analysis of case control and cohort studies which will provide appropriate evidence to answer the question. 
Key Points:This study included case-control studies and cohort studies that investigated the association between acid suppressive drug use and gastric cancer risk It included 9 case- control and 2 cohort studies There was an increased risk of gastric cancer was found with H2RA use and with PPI use. The use of PPIs was associated with an increased risk of gastric cancer in case-control studies [adjusted OR = 1.44; 95%CI: 1.21-1.71, n = 2, I2 = 23.5% ). A significant positive association was observed between the use of acid suppressive drugs and non-cardia cancer risk [adjusted OR = 1.42; 95%CI: 1.12-1.79, n = 6, I2 = 0.0% ], whereas a marginal significance was observed in gastroesophageal junction cancer and the use of acid suppressive drugs [adjusted OR = 2.28; 95%CI: 0.97-5.35, n = 2, I2 = 0.0%]. An H2-receptor antagonist use and proton pump inhibitor use were associated with an increased risk of gastric cancer. An increased risk of non-cardia gastric cancer was observed in patients who used acid suppressive drugs, whereas acid suppressive drug use was not associated with the risk of gastric cardia cancer

Article 6  

Citation: Poulsen, A. H., Christensen, S., McLaughlin, J. K., Thomsen, R. W., Sørensen, H. T., Olsen, J. H., & Friis, S. (2009). Proton pump inhibitors and risk of gastric cancer: a population-based cohort study. British journal of cancer, 100(9), 1503–1507. https://doi.org/10.1038/sj.bjc.6605024
Type of Study: Population-based cohort study
AbstractProton pump inhibitor (PPI) use leads to hypergastrinemia, which has been associated with gastrointestinal neoplasia. We evaluated the association between PPI use and risk of gastric cancer using population-based health-care registers in North Jutland, Denmark, during 1990–2003. We compared incidence rates among new users of PPI (n=18 790) or histamine-2-antagonists (H2RAs) (n=17 478) and non-users of either drug. Poisson regression analysis was used to estimate incidence rate ratios (IRRs) adjusted for multiple confounders. We incorporated a 1-year lag time to address potential reverse causation. We identified 109 gastric cancer cases among PPI users and 52 cases among H2RA users. After incorporating the 1-year lag time, we observed IRRs for gastric cancer of 1.2 (95% CI: 0.8–2.0) among PPI users and 1.2 (95% CI: 0.8–1.8) among H2RA users compared with non-users. These estimates are in contrast to significant overall IRRs of 9.0 and 2.8, respectively, without the lag time. In lag time analyses, increased IRRs were observed among PPI users with the largest number of prescriptions or the longest follow-up compared with H2RA users or non-users. Although our results point to a major influence of reverse causation and confounding by indication on the association between PPI use and gastric cancer incidence, the finding of increased incidence among PPI users with most prescriptions and longest follow-up warrants further investigation.
Reason for Selection: I selected this study because it was a cohort study. Although it was based in Denmark, a log- linear Poisson regression analysis was used to compute incidence ratio (IRRs) for gastric cancer. To minimize the potential influence of protopathic bias, on PPI use a 1 year lag time was incorporated which was done by subtracting 1 year from the date of gastric cancer diagnosis. In  order to account for unmeasured confounding factors, IRR estimates were computed in direct comparisons of PPI users in equivalent strata prescription frequency and length of follow up. Furthermore, the population of the USA is very diverse hence a study from Denmark will be applicable to the population here. 
Key Points: Individuals aged 40–84 years were selected and those that has a history of cancer were  excluded. All analyses were adjusted for calendar period (1990–1996, 1997–2003), gender, age (40–49, 50–59, 60–69 and 70–85 years), history of H. pylori eradication therapy, gastroscopy (⩾1 year before gastric cancer diagnosis or other censoring event), COPD,  alcohol-related admission or therapy  and ever use of NSAIDs (0–1, 2+ prescriptions). The proxy variables for heavy smoking and alcohol abuse had no appreciable effect on the risk estimates and were therefore dropped from the final models.The proxy variables for heavy smoking and alcohol abuse had no appreciable effect on the risk estimates and were therefore dropped from the final models. Subjects were allowed to change between categories of covariates and exposure variables over time. Within each categorical level all variables were treated as time independentThe overall (not taking lag time into account) IRR of gastric cancer was 9.0 (95% CI: 6.9–11.7) among PPI users and 2.8 (95% CI: 2.0–3.7) among H2RA users, compared with non-users (<2 prescriptions) of both PPI and H2RA (data not shown)There was an increased risk estimates among PPI users with the most prescriptions or longest follow-up when compared with non-users of acid-suppressive drugs or with H2RA users.Findings include how excess gastric cancer among with the greatest number of PPI prescriptions or longest follow-up, even after taking a 1-year lag time into account, would be compatible with a causal association with gastric cancer. 

Summary of the Evidence:

Author (Date)Level of EvidenceSample/Setting(# of subjects/ studies, cohort definition etc. )Outcome(s) studiedKey FindingsLimitations and Biases
Daniel Segna , Nele Brusselaers , Damian Glaus, Niklas Krupkaand Benjamin MisselwitzSystematic Review with Meta- Analysis 1,662,881Individuals Gastric Cancer There was an association between GC and PPI use. It showed a higher GC risk estimate in the five included retrospective cohort studies (OR: 2.76, 95% CI: 1.56–4.88, I2 = 63%, p = 0.03) than in the eight included case-control studies  (OR: 1.59, 95% CI: 1.23–2.05, I2 = 81%, p < 0.01) Association between GC and PPI use according to PPI duration: There was no trend for a duration-dependent effect of PPI use <1 year: OR: 2.29, 95% CI: 2.13–2.47, I2 = 0%, p = 0.971–3 years: OR: 1.46, 95% CI: 0.53–4.01, I2 = 35%, p = 0.21 >3 years: OR: 2.08, 95% CI: 0.56–7.77, I2 = 61%, p = 0.08The meta-analysis found an almost two fold increased GC risk among PPI users compared with controls. However,  there was substantial heterogeneity in study designs, populations, definitionsof exposure and outcome, and residual confounding as well as a potential publication bias which is why causation cannot be proven.Thetrue effect of PPI to the carcinogenesis of cardiacGC may be weakened by the treatment of gastrooesophageal reflux, which represents a commonrisk factor for distal oesophageal adenocarcinoma.However, there was no clear duration-dependentrisk increase in PPI users with discrepant resultsin individual studies.Stratified analyses according to PPI duration were not homogeneous in terms of PPI duration. While  standardized cut-offs  were used for PPI duration (<1 year, 1–3 years, ⩾3 years),mixed different PPI durations in various categories enabling for the integration of  some studies but  not all subgroups. However, this approach is potentially misleading due to the missing standardization of PPI durations. Furthermore, only the subgroups with a PPI use ⩾3 years and ⩾1 year were considered from the retrospective cohort study by Cheung et al so that one of the largest retrospective cohort studies was only partly considered in this stratified analysis. Inconsistent inclusion criteria for HP subgroups was used for the  stratified meta-analysis for HP status with current and past HP infection: while the authors classified two entire cohorts with probable – but not confirmed – HP eradication as ‘past HP infection’ groups  only a fraction of the study population was analysed in the other studies which markedly enhances the risk of misclassification and selective reporting which impacts the generalizability of the data.
Several limitations occurred due to very heterogeneous original studies concerning study design, quality, cases and controls definitions, PPI indications, quantification of PPI exposure, and effect sizes, which may also result in highly heterogeneous pooled OR and prevalence in the included studies. Some original publications did not provide risk estimates or did only report incomplete information on the exposure and outcome distribution within the study population. We attempted to overcome this issue by calculating new unadjusted OR based on the published figures, and by contacting the corresponding authors for additional information. Nevertheless, unadjusted point estimates exhibit the risk of confounding and should be interpreted cautiously.
Huan Song Jianwei Zhu Dong Hao LuMeta – Analysis 1789 participantsDevelopment of gastric premalignant lesionsThere was no clear evidence to support the notion that the long‐term use of PPIs could promote the development of pre‐cancerous lesions. However, there was a potentially elevated risk of developing a thickening of the stomach lining (hyperplasia) among participants with long‐term PPI use, which is considered as a possible pre‐condition of gastric carcinoid (a relatively benign (non‐cancerous) tumour that develops within the stomach lining).Seven RCTs were included Most of them provided little or no information on allocation concealment. Many trials had a large proportion of missing data. Since all relevant studies were primarily concerned on the effectiveness of PPI maintenance treatment, not the safety issues of PPIs, they did not exclude participants with pre‐malignant lesion at baseline.The interest outcomes of the cases  were not the main outcomes of those trials. The quality of data reporting was poor. Three studies included less than 75% randomised participants for analysis. None of the included studies used ITT analyses.In two trials comparing PPI with surgery, blinding of participants and researchers was not feasible, so it was classified them as having high risk of bias 
Abrahami, D., McDonald, E. G., Schnitzer, M. E., Barkun, A. N., Suissa, S., & Azoulay, LCohort Study 973 281 new users of PPIs and 193 306 new users of H2RAsrisk of gastric cancernew users of PPIs are at a 45% increased risk of gastric cancer (HR 1.45, 95% CI 1.06 to 1.98) compared with new users of H2RAs, with a number needed to harm of 2121 and 1191 for five and 10 years after treatment initiation,Those patients were excluded for whom a PPI and an H2RA were prescribed concomitantly at cohort entry, history of gastric cancer, rare inherited cancer syndromes or Zollinger-Ellison syndromeAll patients were followed starting 1 year after cohort entry until an incident diagnosis of gastric cancerSample size of the cohort study was 973 281 of new PPI users and 198 306 of new H2RAs users . These exposure groups were followed for a median duration of 5.1 years. The crude HR was below the null value (HR: 0.92), the use of PPIs was associated with an increased risk of gastric cancer after adjusting for calendar year strata In the fully adjusted model, the use of PPIs was associated with a 45% increased risk of gastric cancer, compared with the use of H2RAs. PPI users had a higher cumulative incidence of gastric cancer than H2RA users.It was not possible to directly assess treatment adherence, although this possible source of exposure misclassification is unlikely to be differential between the exposure groups. Giiven the observational nature of this study, residual confounding remains possible. While confounding from calendar time explained most of the observed difference between the crude and adjusted estimates the potential impact of confounding from unmeasured or unknown confounders, including race and ethnicity could not be measured. 
Zeng, R., Cheng, Y., Luo, D., Wang, J., Yang, J., Jiang, L., Zhuo, Z., Guo, K., Wu, H., Leung, F. W., Sha, W., & Chen, HSystematic review and meta-analysis4,355,254 participantsrisk of digestive tract cancers20 case control and 14 cohort studies were selected. These studies  contained information on PPIs and digestive tract cancer risks. There were a total 106,888 cases. A significantly increased risk was observed, for regular PPI use (RR Z 1.63, 95% CI 1.33 to 2.00), with a higher risk in cohort studies (RR Z 1.70, 95% CI 1.30 to 2.22) than that in case control studies. However, assessment by Bradford Hill criteria indicates weak causality between PPI use and digestive tract cancer risks. The data in the current report does not  support the hypothesis that increased dose and duration of PPI exposure are associated with the risk of digestive tract cancers.A lower cumulative dose or duration of PPI use is associated with a higher risk of developing digestive tract cancers, whereas no association is found under the highest level of PPI use.The data indicates that the long term use of PPIs is free of digestive tract cancer risksThe subgroup analysis for a certain interval of cDDD and duration could not be performed because of the varied information among studies. For better communication of research findings, HRs, ORs and RRs were considered as equivalent measures of risk estimates based on previous literature Because of the limited number of studies, including information about cDDD and duration of PPI use with corresponding risk estimates, dose-response analysis for each type of cancer was impractical. Future research could provide more relevant data. Moreover, most of the included studies did not provide information on over-the-counter PPIs, which is also critical for evaluation.
Jeong Soo Ahn, Chun-Sick Eom, Christie Y Jeon, and Sang Min ParkMeta-analysis11 observational studies (n = 94558) To evaluate the association between acid suppressive drug use and the development of gastric cancer.This study included case-control studies and cohort studies that investigated the association between acid suppressive drug use and gastric cancer risk It included 9 case- control and 2 cohort studies There was an increased risk of gastric cancer was found with H2RA use and with PPI use. The use of PPIs was associated with an increased risk of gastric cancer in case-control studies [adjusted OR = 1.44; 95%CI: 1.21-1.71, n = 2, I2 = 23.5% ). A significant positive association was observed between the use of acid suppressive drugs and non-cardia cancer risk [adjusted OR = 1.42; 95%CI: 1.12-1.79, n = 6, I2 = 0.0% ], whereas a marginal significance was observed in gastroesophageal junction cancer and the use of acid suppressive drugs [adjusted OR = 2.28; 95%CI: 0.97-5.35, n = 2, I2 = 0.0%]. An H2-receptor antagonist use and proton pump inhibitor use were associated with an increased risk of gastric cancer. An increased risk of non-cardia gastric cancer was observed in patients who used acid suppressive drugs, whereas acid suppressive drug use was not associated with the risk of gastric cardia cancerMost of the studies in the  meta-analysis were observational studies. Observational studies, even when well-controlled, are susceptible to various biases, which may reduce the quality of the analysis. Second, most of the studies in the meta-analysis came from Western countries. The occurrence of gastric cancer is rapidly increasing in the United States and in Western Europe. However, this disease is a more significant public health problem in Asia. Third, we did not have access to individual data on dose-response relationships that may have affected gastric acid production. Finally, we could not evaluate the effect of underlying gastric conditions, e.g., H. pylori infection, because these data were not presented in each study.
Poulsen, A. H., Christensen, S., McLaughlin, J. K., Thomsen, R. W., Sørensen, H. T., Olsen, J. H., & Friis, S. Population-based cohort study280 872 individuals.Gastric cancer riskThe overall (not taking lag time into account) IRR of gastric cancer was 9.0 (95% CI: 6.9–11.7) among PPI users and 2.8 (95% CI: 2.0–3.7) among H2RA users, compared with non-users (<2 prescriptions) of both PPI and H2RA (data not shown)There was an increased risk estimates among PPI users with the most prescriptions or longest follow-up when compared with non-users of acid-suppressive drugs or with H2RA users.Findings include how excess gastric cancer among with the greatest number of PPI prescriptions or longest follow-up, even after taking a 1-year lag time into account, would be compatible with a causal association with gastric cancer. The main limitations were the small number of long-term users of PPI, the inability to address subtypes of gastric cancer, and the inability to adjust for indication of use of PPI and H2RA. It was also not possible to evaluate the influence of H. pylori infection, but only for those study subjects who underwent eradication therapy, thus residual confounding by untreated H. pylori infection may have influenced the results. It was not possible to adjust for dietary factors, and only proxy measures for tobacco and alcohol use. The study had relatively low-statistical precision.

Weight of evidence: 

Article 1: There was a twofold increased GC risk among PPI users, but this association does not confirm causation and studies are highly heterogeneous. PPI should only be prescribed when strictly indicated. I chose this article because it was a recent meta-analysis in which 1,662,881 individuals were included and was inclusive of a diverse population.  However, several  limitations occurred due to very heterogeneous original studies concerning study design, quality, cases and controls definitions, PPI indications, quantification of PPI exposure, and effect sizes, which may also result in highly heterogeneous pooled OR and prevalence in the included studies. 

Article 2: There is presently no clear evidence that the long-term use of PPIs can cause or accelerate the progression of corpus gastric atrophy or intestinal metaplasia, although results were imprecise. People with PPI maintenance treatment may have a higher possibility of experiencing either diffuse (simple) or linear/micronodular (focal) ECL cell hyperplasia. However, the clinical importance of this outcome is currently uncertain. This article looked at the long term impact of PPI use and was a meta-analysis. However,  weakness of this study is that  they did not exclude participants with pre‐malignant lesion at baseline.  Three studies included less than 75% randomized participants for analysis. Furthermore, two trials were not blinded hence here was a high risk of bias. 

Article 3 : The findings of this large population-based cohort study indicate that the use of PPIs is associated with an increased risk of gastric cancer compared with the use of H2RAs, although the absolute risk remains low. This was a cohort study and it had limitations such as it was not possible to directly assess treatment adherence. Since this study was an observational study, confounding variables remain possible 

Article 4: A causal relationship between PPI use and digestive tract cancers is not supported by the evidence. Concerns over carcinogenic side-effects of PPI might be unfounded. This was a systematic review and meta-analysis which a large sample size of  4,355,254 participants. There was limited information about the duration of PPI use  with corresponding risk estimates. The dose response analysis for each type of cancer was impractical. 

Article 5 : Acid suppressive drugs are associated with an increased risk of gastric cancer. Further studies are needed to test the effect of acid suppressive drugs on gastric cancer.This was a meta-analysis article case-control studies and cohort studies. Most of the studies were observations and hence, susceptible to various biases. 

Article 6 : There was an increased risk estimate of gastric cancer  among PPI users with the most prescriptions or longest follow-up when compared with non-users of acid-suppressive drugs or with H2RA users. This was a population-based cohort study. However,  the  limitations were that there was a small number of long-term users of PPI, unable to differentiate  subtypes of gastric cancer, and the inability to adjust for indication of use of PPI and H2RA. 

Bottom Line- 

Article 1, 3, 5 and 6 discuss that there is a relationship of PPIs with gastric cancer.   Article 1 was a recent meta-analysis of 1,662,881 individuals. Article 3 is a cohort based study. Article 5 was a meta-analysis which consisted of case control and cohort studies. Article 6 was a population based cohort study. Although confounding variables and biases existed the articles were of good quality with large sample sizes. Article 2 had a high risk of bias. Article 4 was a meta-analysis that concluded that there was no association between PPIs and gastric cancer. However, comparatively the weight of one article does not outweigh the evidence of the other 4 articles. 

The overarching conclusion is that there is an association of gastric cancer with PPIs.  However, it is not possible to conclude that PPIs cause gastric cancer. Based on the current research studies that have large sample sizes and are of the highest level of evidence have concluded that there is an association of PPIs with gastric cancer. These studies did not conclude a causal relationship as limitations and confounding variables exist which are hard to control. 

There are a variety of factors that can take part in a patient’s diagnosis of gastric or digestive tract cancer. However, excessive caution in using PPIs might delay treatment of digestive tract disorders.  Further RCTS need to be conducted in order to have a valid conclusion about a causal relationship with PPIs and cancer.  Clinically, since there is some association of gastric cancer with PPIs, it would be best to take into consideration the patient’s medical history before prescribing a PPI. This included the patient’s family history. If there is a history of cancer, I would discuss it with the patient. Furthermore, I would discuss with the patient the current research and what it is concluding. Based on this, I would let the patient make an informed decision about taking a proton pump inhibitor.