Impact of proton pump inhibitors on the risk of small bowel or colorectal bleeding: A systematic review and meta‐analysis

BACKGROUND: Several studies have suggested that the mucosal protective effects of proton pump inhibitors (PPIs) do not extend beyond the duodenum; however, PPIs may cause lower gastrointestinal (LGI) injury, although these relationships have not yet been fully elucidated. METHODS: We searched all the relevant studies published until September 2022 that examined the risk of PPIs for LGI bleeding. We performed a meta‐analysis of the risk of LGI bleeding (small bowel (SB) or colorectal bleeding) between PPI users and non‐users. A subgroup analysis of patients consuming aspirin or nonsteroidal anti‐inflammatory drugs (NSAIDs) was also performed. RESULTS: Twelve studies with 341,063 participants were included in this meta‐analysis. The use of PPIs was associated with the risk of LGI bleeding (odds ratio [OR] [95% confidence interval [CI]] = 1.42 [1.16–1.73]; hazard ratio [HR] [95% CI] = 3.23 [1.56–6.71]). An association between PPI use and the risk of LGI bleeding was also identified in the subgroup of aspirin or NSAID users (OR [95% CI] = 1.64 [1.49–1.80]; HR [95% CI] = 6.55 [2.01–21.33]). In the bleeding site‐specific analyses, the risk of SB bleeding was associated with PPI use (OR [95% CI] = 1.54 [1.30–1.84]). CONCLUSIONS: PPI use was associated with an increased risk of LGI bleeding, particularly SB bleeding. This association was particularly pronounced among aspirin and NSAID users. Inappropriate PPI prescriptions should be avoided in patients with LGI bleeding and a low risk of upper gastrointestinal disease.