Comparison of the Safety of Proton Pump Inhibitors and Histamine Type 2-Receptor Antagonists in the Prevention of Gastrointestinal Complications

This study aims to compare the efficacy and safety of proton pump inhibitors (PPIs) and histamine type 2-receptor antagonists (H2RAs) in preventing gastrointestinal (GI) complications, particularly bleeding, in high-risk patient populations, including ICU patients and individuals taking aspirin, dual antiplatelet therapy (DAPT), or nonsteroidal anti-inflammatory drugs (NSAIDs). A literature review was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Cochrane-aligned principles. Meta-analyses, systematic reviews, randomized controlled trials, and large cohort studies published between 1997 and 2025 were included. Searches were performed in PubMed, Cochrane Library, MEDLINE, Embase, and SpringerLink to identify studies comparing PPIs and H2RAs with respect to prophylactic effectiveness and adverse outcomes, including infections, pneumonia, and mortality. Data were synthesized narratively with emphasis on studies of higher methodological quality. Overall, the reviewed evidence generally suggested that PPIs reduce clinically significant bleeding more effectively than H2RAs in ICU settings and in patients receiving aspirin or DAPT. Among NSAID users, PPIs were also more effective for ulcer healing and prevention. In contrast, several analyses indicated higher rates of certain adverse events among PPI recipients, particularly infections and possibly pneumonia, while H2RAs appeared to have a more favorable safety profile for these outcomes. Mortality findings were inconsistent across studies, with some large trials reporting no meaningful differences between drug classes. In conclusion, PPIs may offer greater protection against bleeding and ulceration than H2RAs but can be associated with a higher risk of selected adverse events. Prophylactic therapy should be individualized by balancing expected benefits with patient-specific risks, including infection risk and concurrent antiplatelet therapy.