Umbrella review of 42 systematic reviews with meta‐analyses: the safety of proton pump inhibitors

Abstract

Summary Background Proton pump inhibitors (PPIs) are widely used to treat and prevent acid‐related disorders. Despite high efficacy, PPI safety has been increasingly scrutinised. However, no comprehensive review summarising investigations of various adverse events is available. Aims To perform an umbrella review to comprehensively assess associations between adverse events and PPI use. Methods In accordance with PRISMA, an umbrella review of systematic reviews with meta‐analyses was conducted. PubMed and EMBASE were searched from 2015 to July 2019. AMSTAR 2 and GRADE were used to assess quality and certainty of evidence. Author‐reported quality assessments were also reviewed. Results Forty‐two systematic reviews with meta‐analyses, supported predominantly by observational evidence, were included. The most comprehensive studies reported statistically significant associations with PPI use for several outcomes, including: fractures (eg, hip; RR = 1.20; 95% CI = 1.14‐1.28; n = 2 103 800), kidney disease (eg, acute kidney injury; RR = 1.61; 95% CI = 1.16‐2.22; n = 2 396 640), infections (eg, Clostridioides difficile; OR = 1.99; 95% CI = 1.73‐2.30; n = 356 683), gastric cancer (OR = 2.50; 95% CI = 1.74‐3.85; n = 943 070) and gastrointestinal events (eg, fundic gland polyps; OR = 2.46; 95% CI = 1.42‐4.27; n = 40 218). No associations with non‐gastric cancers, or neurological disease were concluded, with conflicting evidence for cardiovascular outcomes. Certainty based on GRADE was very low for most outcomes. Conclusions This review identified several published associations between PPIs and adverse outcomes, however, further investigation is needed to understand their clinical significance and the likelihood of causal relationship. If higher quality evidence is generated substantiating the potential risks, it may be necessary for clinicians to consider alternative treatment strategies, especially when PPI efficacy is suboptimal.

Association of proton‐pump inhibitor use with adverse health outcomes: A systematic umbrella review of meta‐analyses of cohort studies and randomised controlled trials

“…The included articles were published between 2009 and 2021. The descriptive characteristics of T A B L E 1 Criteria for quality of evidence classification in meta-analysis of observational studies [10][11][12][13] Category Criteria…”

Characteristics of Pharmacists’ Interventions Related to Proton-Pump Inhibitors in French Hospitals: An Observational Study

“…There is no increase in PPI acceptance over time (no correlation shown in multivariate analysis) while misuse and adverse effects and drug interactions are increasingly described in the scientific literature [ 1 , 3 – 5 , 8 , 10 , 27 ]. Data from the literature underlined that lack of time and perceiving PPIs as “harmless” affect physicians' decision making [ 29 ].…”

“…)-negative peptic ulcer disease, treatment and prophylaxis of NSAID-associated gastric ulcers, and management of gastric acid hypersecretory states [1]. Despite their efficacy, long-term use of PPIs has been linked to several adverse effects [1,[3][4][5].…”

People exposed to proton pump inhibitors shortly preceding COVID-19 diagnosis are not at an increased risk of subsequent hospitalizations and mortality: a nation-wide matched cohort study

“…Biological plausibility for the presumed PPI - COVID-19 relationship is based on reduced antiviral resistance due to prolonged gastrointestinal hypochlorhydria and subsequently increased pulmonary colonization [5, 6, 8]. Theoretically, the (presumed) effects on gut microbiome and micronutrient deficiencies [7, 8] might contribute. Two questions about pre-morbid PPI use seem to naturally arise from this mechanistic rationale: one pertaining to the risk of infection and the other one to the risk of severe COVID-19.…”

“…Long-term PPI use has been suggested associated with the risk of worsening or incidence of variety of diseased conditions [5, 6]. Two recent comprehensive evaluations demonstrated that quality of evidence relating PPIs as potential causes to these adverse events was “low” or “very low” predominantly for the following reasons: mostly observational data, modest effects commonly burdened by residual confounding, bias by indication, protopathic bias and data inconsistency [2, 7].…”