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Helicobacter pylori eradication failure may have confounded the recent large-scale health database study that showed proton pump inhibitors increase gastric cancer risk
  1. Hidekazu Suzuki1,
  2. Juntaro Matsuzaki2
  1. 1 Fellowship Training Center, Medical Education Center, Keio University School of Medicine, Tokyo, Japan
  2. 2 Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
  1. Correspondence to Professor Hidekazu Suzuki, Fellowship Training Center, Medical Education Center, Keio University School of Medicine, Tokyo 160-8582, Japan; hsuzuki.a6{at}

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The current guidelines recommend that when patients require long-term use of proton pump inhibitors (PPIs), Helicobacter pylori (H. pylori) should be eradicated beforehand because it improves atrophic gastritis, a precancerous lesion.1 2 The recent analysis by Cheung et al 3 of the data of more than 60 000 adults registered in a territory-wide health database in Hong Kong who underwent H. pylori eradication showed that the long-term use of PPIs increased the risk of gastric cancer by 2.4-fold. Moreover, the risk of gastric cancer increased with the dose and duration of PPI use. The fact that long-term PPI administration increases the risk of gastric cancer even after H. pylori eradication is unexpected.

However, the study has some limitations. First, although it is based on a large sample, it is an observational study rather than a prospective randomised interventional study. As a result, the clinical backgrounds of the PPI user and non-user groups differed markedly. For example, the median age of the PPI user and non-PPI user groups differed by approximately 10 years (64.1 vs 54.3 years). This large difference suggests that the PPI user group had more time to develop atrophic gastritis. Although efforts were made in the study to adjust for confounding factors by using propensity scores, it remains possible that uninvestigated clinical factors have confounded the results.

Second, it is possible that the PPI user group contained patients who still had H. pylori. According to the article,3 the authors only analysed the prescription history of eradication therapy: the adherence of the patients to treatment and the treatment outcome (success or failure), as determined by using the urea breath test or the stool antigen test, were not analysed. Indeed, the authors defined failure of H. pylori eradication therapy as the need for subsequent prescriptions of repeated courses of clarithromycin-based triple therapy, a second-line therapy (bismuth-based quadruple therapy or PPI-levofloxacin-amoxicillin) or a third-line therapy (rifabutin-based therapy),4 and excluded these patients from the analysis. Based on this definition, however, it remains possible that some H. pylori-positive patients were included in the study (eg, those who did not actually take the medication after prescription or who did not undergo eradication confirmation testing).5 In essence, this definition simply means that H. pylori-negative patients who underwent second-line or third-line eradication were excluded. Thus, the success of eradication cannot be unequivocally determined by examining the prescription history alone, and it remains possible that a proportion of the cohort still had H. pylori. Importantly, it seems more than likely that these patients were particularly concentrated in the PPI user group because recent studies have confirmed that H. pylori infection is one of the causes of dyspeptic symptoms (ie, H. pylori-associated dyspepsia)6–8 and non-eradicated cases are likely to have sustained dyspeptic symptoms.

Therefore, it is premature at this time to conclude that PPI itself increases the risk of gastric cancer and that we should change treatment guidelines. Validation of these observations in other cohorts is essential.


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  • Competing interests The authors received scholarship funds for the research from Daiichi-Sankyo, Co., EA Pharm. Co., Otsuka Pharma Co., Tsumura Co. and received service honoraria from Astellas Pharma, Co., AstraZeneca KK, EA Pharma Co., Mylan EPD, Co., Otsuka Pharm. Co., Takeda Pharm Co., Ltd., and Tsumura, Co.

  • Provenance and peer review Not commissioned; internally peer reviewed.

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