Effectiveness and Safety of Histamine H2 Receptor Antagonists: An Umbrella Review of Meta‐Analyses

Abstract Histamine H2 receptor antagonists (H2RAs) were widely used to inhibit gastric acid secretion, but its association with adverse events remains controversial and unclear. We conducted an umbrella review of meta‐analyses to systematically assess the quality and credibility of the correlations between H2RA use with the risk of adverse outcomes through searching 4 major databases from inception to April 30, 2022. Forty‐six individual meta‐analyses were identified, including 29 meta‐analyses of observation studies with 32 unique outcomes and 19 meta‐analyses of randomized controlled trials with 3 unique outcomes for comparing the H2RA versus non‐H2RA group. A Measurement Tool to Assess Systematic Reviews 2 rating for the included meta‐analyses showed that 4 of 46 meta‐analyses were assigned as high scores, 3 were assigned as “moderate,” and 25 were assigned as low scores. Grading of Recommendations Assessment, Development and Evaluation assessment for combined results demonstrated that 6 outcomes were rated as “moderate,” 9 outcomes were rated as “low,” and 17 outcomes were rated as “very low.” We confirmed significant associations of H2RA use with pneumonia, peritonitis, necrotizing enterocolitis, Clostridium difficile infection, liver cancer, gastric cancer, and hip fracture diseases. No associations for colorectal cancer, melanoma, kidney cancer, lung cancer, or common reproductive system cancer or renal, neurological, and cardiovascular system diseases were observed. We found a variety of evidence for the associations between H2RAs and adverse outcomes, which would give clinicians more positive guidance on prescription of H2RAs in clinical practice.