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Summary effect sizes from a random\u2010effects model, between\u2010study heterogeneity, 95% prediction interval, small\u2010study effect, excess significance and credibility ceilings were devised to classify the credibility of evidence from meta\u2010analyses of cohort studies, whereas the GRADE approach was used for meta\u2010analyses of RCTs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In meta\u2010analyses of cohort studies, 52 of the 91 examined associations were statistically significant (<jats:italic>P<\/jats:italic>\u00a0\u2264\u2009.05). Convincing evidence emerged from main analysis for the association between PPI use and risk of all\u2010site fracture and chronic kidney disease in the elderly population. However, none of these associations remained supported by convincing evidence after sensitivity analyses. The use of PPI is also associated with an increased risk of mortality due to COVID\u201019 infection and other related adverse outcomes, but the quality of evidence was weak. In meta\u2010analyses of RCTs, 38 of the 63 examined associations were statistically significant. However, no associations were supported by high or moderate\u2010quality evidence.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study's findings imply that most putative adverse outcomes associated with PPI use may not be supported by high\u2010quality evidence and are likely to have been affected by underlying confounding factors. Future research is needed to confirm the causal association between PPI use and risk of fracture and chronic kidney disease.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.15103","type":"journal-article","created":{"date-parts":[[2021,10,9]],"date-time":"2021-10-09T03:02:06Z","timestamp":1633748526000},"page":"1551-1566","source":"Crossref","is-referenced-by-count":45,"title":["Association of proton\u2010pump inhibitor use with adverse health outcomes: A systematic umbrella review of meta\u2010analyses of cohort studies and randomised controlled trials"],"prefix":"10.1111","volume":"88","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7009-7907","authenticated-orcid":false,"given":"Sajesh K.","family":"Veettil","sequence":"first","affiliation":[{"name":"Department of Pharmacotherapy, College of Pharmacy University of Utah  Salt Lake City UT 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