Proton pump inhibitors therapy and the risk of pneumonia: a systematic review and meta‐analysis of randomized controlled trials and observational studies

ABSTRACT

Objective: We aimed to summarize the current evidence regarding the risk of pneumonia associated with proton pump inhibitors (PPI) treatment.

Methods: We searched PubMed, Embase, and CENTRAL from the 1970 through December 2017. We included both randomized controlled trials (RCTs) and observational studies. We used random-effect model to calculate the summary effect estimates and quantified the heterogeneity by I² statistics.

Results: A total of 7,643,982 patients from 10 RCTs and 48 observational studies were included in this meta-analysis. The primary meta-analysis demonstrated PPIs use was significantly associated with increased risk of pneumonia, but the heterogeneity was high (odds ratio [OR], 1.43; 95% confidence interval [CI], 1.30–1.57; I², 95.4%). The sensitivity analysis indicated PPIs were not statistically associated with increased risk of pneumonia among patients concomitantly taking nonsteroidal anti-inflammatory drugs (OR, 1.11; 95% CI, 0.94–1.31; I², 5.8%). The funnel plot demonstrated significant publication bias, especially for observational studies.

Conclusions: The presence of significant between-study heterogeneity and publication bias raised concerns regarding the validity of the primary meta-analytic result. Protopathic bias, or reverse causality, may cause overestimated association. Studies that adopted a design to account for protopathic bias did not show a significant association between PPI use and risk of pneumonia.

KEYWORDS:

• Meta-analysis
• pneumonia
• proton pump inhibitors
• protopathic bias

Acknowledgments

The authors would like to sincerely thank the staff of the Core Labs, the Department of Medical Research, National Taiwan University Hospital for technical assistance.

Author contributions

Cheng-Han Li and Cheng-Yi Fan involved in the data collection and extraction. Chih-Hung Wang and Cheng-Han Li performed the statistical analysis, interpreted the results and wrote the draft. Tze-Chun Hsu and Wan-Ting Hsu provided technical support of statistical analyses. Ronan Hsieh reviewed the manuscript and provided critical insights. Wei-Che Chang and Yu-Ya Lin helped with language editing and critically revised the manuscript. Chien-Chang Lee obtained funding, conceive the idea, designed the study, and guided the statistical analysis and manuscript writing, and supervise the whole process. All authors approved the final version of the manuscript and agree to be accountable for all aspects of the work.

Data availability statement

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplemental material

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Additional information

Funding

This manuscript was supported by the Taiwan National Ministry of Science and Technology (MOST 104-2314-B-002-039-MY3) and National Taiwan University Hospital (108-S4091).