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

Abstract

The aim was to perform an umbrella review to summarise the existing evidence on proton-pump inhibitor (PPI) use and adverse outcomes and to grade the certainty of evidence.Methods: Electronic databases were searched up to July 2021 for meta-analyses of cohort studies and/or randomised controlled trials (RCTs). Summary effect sizes from a random-effects model, between-study heterogeneity, 95% prediction interval, small-study effect, excess significance and credibility ceilings were devised to classify the credibility of evidence from meta-analyses of cohort studies, whereas the GRADE approach was used for meta-analyses of RCTs.Results: In meta-analyses of cohort studies, 52 of the 91 examined associations were statistically significant (P ≤ .05). Convincing evidence emerged from main analysis for the association between PPI use and risk of all-site 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-19 infection and other related adverse outcomes, but the quality of evidence was weak. In meta-analyses of RCTs, 38 of the 63 examined associations were statistically significant. However, no associations were supported by high or moderate-quality evidence.Conclusion: This study's findings imply that most putative adverse outcomes associated with PPI use may not be supported by high-quality 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.

H2 antagonists, proton pump inhibitors and COVID-19

“…However, in a recent meta-analysis, patients with current use of PPI showed significantly higher risk of SARS-CoV-2 infection than those without PPI use (Odds ratio 1.94, 95% confidence interval 1.59 to 2.36, p < 0.0001) when Korean nationwide cohort [18] is excluded as this cohort unduly affected association between PPI use and SARS-CoV-2 infection [19]. In addition, another meta-analysis and systematic review suggested that risk of mortality due to COVID-19 may be significantly higher in PPI users compared to non-PPI users although the quality of evidence was weak [20]. Liu and colleagues [21] found that salivary ACE2 mRNA levels were significantly higher in PPI users than non-PPI users.…”

Use of proton pump inhibitors and adverse clinical outcomes

“…2 by Veettil et al,. 1 they argued inappropriately that our analysis on the association between current or regular PPI use and severe COVID-19 outcomes was based on only seven studies of unknown numbers of cases in the "general population," with a OR of 1.8 (95% CI 1.08-2.97; I 2 = 71%).…”

“…Likewise, in their supplementary tab. S4, 1 information on the adjustment for confounding variables collected by Veettil et al 1 from each included meta-analysis was highly misleading. On the one hand, for a specific meta-analysis, adjusted confounding variables across cohort studies could vary substantially, which were not always necessary to be identical, rendering the specification of adjusted confounding variables for a specific meta-analysis instead of a specific cohort study highly unreasonable.…”

“…On the one hand, for a specific meta-analysis, adjusted confounding variables across cohort studies could vary substantially, which were not always necessary to be identical, rendering the specification of adjusted confounding variables for a specific meta-analysis instead of a specific cohort study highly unreasonable. On the other hand, regarding our previous analysis, we have already provided the information on confounders adjustment status for every observational study included in our analysis in our supplementary table 2 rather than being "not available" argued by Veettil et al 1 Moreover, in their fig. 2 by Veettil et al, 1 they claimed that they "identified a total of 9 associations between the use of PPI and COVID 19 adverse clinical outcomes," but it was not the case.…”

“…On the other hand, regarding our previous analysis, we have already provided the information on confounders adjustment status for every observational study included in our analysis in our supplementary table 2 rather than being "not available" argued by Veettil et al 1 Moreover, in their fig. 2 by Veettil et al, 1 they claimed that they "identified a total of 9 associations between the use of PPI and COVID 19 adverse clinical outcomes," but it was not the case. In their fig.…”