Proton Pump Inhibitors and Gastric Cancer Incidence: A Population-based Cohort Study

Date of ISAC Approval: 
Lay Summary: 
Acid suppressant drugs, including proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs), are used to manage stomach conditions, such as peptic ulcer disease and gastroesophageal reflux disease. These drugs are very commonly prescribed; PPIs in particular are one of the most commonly used medications worldwide. While typically indicated for short-term use, some evidence suggests that they are increasingly being used for longer periods, often times in individuals without underlying disease or for longer durations than necessary. This uptake in use has become increasingly concerning, given that use of PPIs may be associated with some serious complications, including gastric cancer. While several real-world studies have been conducted to address this safety question, the evidence remains limited given the poor quality of previous studies. Thus, we will conduct a large, population-based cohort study to address this safety question in the real-world setting. We will compare new users of PPIs to new users of H2RAs and follow-patients over a 30-year study period to determine whether use of PPIs is associated with an increased risk of gastric cancer. As patients with gastric conditions are already at an increased risk of gastric cancer, this large study will provide concerned stakeholders with much needed information on the safety profile of these drugs in a timely and cost-effective fashion.
Technical Summary: 
Proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) are commonly prescribed to manage several gastric conditions. While treatment guidelines suggest short treatment courses for most indications, recent evidence indicates that PPIs are increasingly being used inappropriately, either for longer periods than necessary or by individuals without an indication for use. This overuse is especially concerning in light of recent safety signals associated with the use of PPIs, including a potential association with gastric cancer. As gastric cancer is associated with poor survival, this safety issue is particularly contentious. While several observational studies previously attempted to investigate this safety signal, evidence remains limited by methodological flaws present in early studies, including confounding by indication, immortal time bias and time window bias. Thus, the objective of this large population-based cohort study is to assess whether the use of PPIs, in comparison to the use of H2RAs, is associated with gastric cancer. To address this, we will assemble a cohort of patients newly treated with PPIs or H2RAs between 1990 (the first full year that both drugs were available) and 2018, with follow-up until 2019. New users of PPIs will be compared to new users of H2RAs, and all exposures will be lagged by one year for cancer latency. To control for confounding, we will reweigh the cohort using high-dimensional propensity scores, which will adjust for more than 200 potential confounders. Patients will be followed from one year after the date of their first prescription until an incident diagnosis of gastric cancer, one year after switch from PPI to H2RA or vice versa, death from any cause, end of coverage, or end of the study period (December 31, 2019), whichever occurs first. Cox proportional hazards models will be used to estimate weighted hazard ratios of incident gastric cancer, comparing PPIs to H2RAs.
Health Outcomes to be Measured: 
The primary outcome is incident gastric cancer, which will be identified using Read codes. The secondary outcome will consider gastric-cardia and gastric non-cardia cancers, separately.

Samy Suissa - Chief Investigator - McGill University
Alan Barkun - Collaborator - McGill University
Devin Abrahami - Collaborator - McGill University
Dr Emily McDonald - Collaborator - McGill University
Dr Laurent Azoulay - Corresponding Applicant - McGill University
Professor Mireille Schnitzer - Collaborator - University Of Montreal