Acid suppressant drugs, including proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs), are among the most commonly prescribed drugs worldwide. Both drug classes have been used to manage symptoms of stomach conditions, including peptic ulcer disease and dyspepsia, for over three decades. However, there are concerns about the increasing uptake of PPIs in particular. Recent evidence suggests that PPIs are overprescribed in individuals without an evidence-based indication for use, or for much longer than the 4 to 8-week duration recommended for most conditions. While PPIs are generally considered to be well tolerated, a potential link between their use and certain gastrointestinal cancers remains, including colorectal cancer. The existing real-world evidence on the potential association between PPIs and colorectal cancer is both limited and inconsistent. Existing studies are limited by small sample sizes, short durations of follow-up, and other methodological concerns. Thus, we will conduct a large population-based cohort study to determine whether the use of PPIs, when compared to the use of H2RAs, is associated with colorectal cancer. This study will provide a necessary addition to the safety profile of PPIs in a cost-effective and timely manner.
Proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) are acid suppressant drugs used in the management of several gastric conditions. While both drug classes are among the most prescribed drugs worldwide, emerging evidence suggests that PPIs are inappropriately used and overprescribed in certain patient populations. This increased uptake is especially concerning in light of potential serious adverse outcomes that have been associated with their use, including a potential association with colorectal cancer. Indeed, chronic acid suppression through continuous PPI use causes hypergastrinemia, which is known to be associated with colorectal cancer. To date, the few observational studies that have investigated this potential association had important methodological shortcomings. Thus, the objective of this large population-based cohort study is to address whether use of PPIs, compared to use of H2RAs, is associated with an increased risk of colorectal cancer.
To address this, we will assemble a cohort of patients newly treated with PPIs or H2RAs between January 1, 1990 (the first full year that both drugs were available) and April 30, 2018, with follow-up until April 30, 2019. Cohort entry will be defined as the date of this first prescription during the study period. To minimize confounding by indication, PPI users will be compared to H2RAs, an active comparator, and the cohort will be reweighed using propensity scores. Given the insidious nature of the outcome and to minimize the potential for reverse causality, all patients will be followed starting one year after cohort entry, until an incidence diagnosis of colorectal cancer, death, end of data availability, or April 30, 2019, whichever occurs first. Cox proportional hazards models will be used to estimate weighted hazard ratios and 95% confidence intervals of colorectal cancer associated with the use of PPIs, compared with use of H2RAs.
The primary outcome is incident colorectal cancer, which will be identified using Read codes (Appendix I).
The secondary outcome will consider colon and rectal cancers separately.
Samy Suissa - Chief Investigator - Sir Mortimer B Davis Jewish General Hospital
Laurent Azoulay - Corresponding Applicant - McGill University
Alan Barkun - Collaborator - McGill University
Devin Abrahami - Collaborator - McGill University
Emily McDonald - Collaborator - McGill University
Mireille Schnitzer - Collaborator - University Of Montreal