Meta-Analysis
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 21, 2017; 23(35): 6500-6515
Published online Sep 21, 2017. doi: 10.3748/wjg.v23.i35.6500
Proton pump inhibitors therapy and risk of Clostridium difficile infection: Systematic review and meta-analysis
Anca Trifan, Carol Stanciu, Irina Girleanu, Oana Cristina Stoica, Ana Maria Singeap, Roxana Maxim, Stefan Andrei Chiriac, Alin Ciobica, Lucian Boiculese
Anca Trifan, Irina Girleanu, Oana Cristina Stoica, Ana Maria Singeap, Roxana Maxim, Stefan Andrei Chiriac, Institute of Gastroenterology and Hepatology, “St. Spiridon” Hospital, “Grigore T. Popa” University of Medicine and Pharmacy, 700111 Iasi, Romania
Carol Stanciu, Institute of Gastroenterology and Hepatology, “St. Spiridon” Hospital, 700111 Iasi, Romania
Alin Ciobica, Department of Research, Faculty of Biology, “Alexandru Ioan Cuza” University of Iasi, 700506 Iasi, Romania
Lucian Boiculese, Department of Preventive Medicine and Interdisciplinarity, “Grigore. T. Popa” University of Medicine and Pharmacy, 700111 Iasi, Romania
Author contributions: Trifan A and Stanciu C designed the study, contributed to the selection of studies, analyzed the data and wrote the manuscript; Stoica OC, Maxim R, Singeap AM, Girleanu I, Chiriac SA and Ciobica A were involved in the acquisition of data and contributed to the analysis and interpretation of data; Girleanu I, Stoica OC, Maxim R and Singeap AM drafted the manuscript; Boiculese L and Girleanu I contributed to the statistical analysis; all authors have read and approved the final version of the manuscript; all authors accept responsibility for its content.
Conflict-of-interest statement: The authors deny any conflict of interest.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Carol Stanciu, MD, FRCP, Professor, Institute of Gastroenterology and Hepatology,“St. Spiridon” Hospital, Independentei Street No. 1, 700111 Iasi, Romania. stanciucarol@yahoo.com
Telephone: +40-722-306020 Fax: +40-232-246611
Received: July 13, 2017
Peer-review started: July 17, 2017
First decision: August 10, 2017
Revised: August 11, 2017
Accepted: August 25, 2017
Article in press: August 25, 2017
Published online: September 21, 2017
Abstract
AIM

To perform a systematic review and meta-analysis on proton pump inhibitors (PPIs) therapy and the risk of Clostridium difficile infection (CDI).

METHODS

We conducted a systematic search of MEDLINE/PubMed and seven other databases through January 1990 to March 2017 for published studies that evaluated the association between PPIs and CDI. Adult case-control and cohort studies providing information on the association between PPI therapy and the development of CDI were included. Pooled odds ratios (ORs) estimates with 95% confidence intervals (CIs) were calculated using the random effect. Heterogeneity was assessed by I2 test and Cochran’s Q statistic. Potential publication bias was evaluated via funnel plot, and quality of studies by the Newcastle-Otawa Quality Assessment Scale (NOS).

RESULTS

Fifty-six studies (40 case-control and 16 cohort) involving 356683 patients met the inclusion criteria and were analyzed. Both the overall pooled estimates and subgroup analyses showed increased risk for CDI despite substantial statistical heterogeneity among studies. Meta-analysis of all studies combined showed a significant association between PPI users and the risk of CDI (pooled OR = 1.99, CI: 1.73-2.30, P < 0.001) as compared with non-users. The association remained significant in subgroup analyses: by design-case-control (OR = 2.00, CI: 1.68-2.38, P < 0.0001), and cohort (OR = 1.98, CI: 1.51-2.59, P < 0.0001); adjusted (OR = 1.95, CI: 1.67-2.27, P < 0.0001) and unadjusted (OR = 2.02, CI: 1.41-2.91, P < 0.0001); unicenter (OR = 2.18, CI: 1.72-2.75, P < 0.0001) and multicenter (OR = 1.82, CI: 1.51-2.19, P < 0.0001); age ≥ 65 years (OR = 1.93, CI: 1.40-2.68, P < 0.0001) and < 65 years (OR = 2.06, CI: 1.11-3.81, P < 0.01). No significant differences were found in subgroup analyses (test for heterogeneity): P = 0.93 for case-control vs cohort, P = 0.85 for adjusted vs unadjusted, P = 0.24 for unicenter vs multicenter, P = 0.86 for age ≥ 65 years and < 65 years. There was significant heterogeneity across studies (I2 = 85.4%, P < 0.001) as well as evidence of publication bias (funnel plot asymmetry test, P = 0.002).

CONCLUSION

This meta-analysis provides further evidence that PPI use is associated with an increased risk for development of CDI. Further high-quality, prospective studies are needed to assess whether this association is causal.

Keywords: Proton pump inhibitors, Clostridium difficile infection, Risk, Systematic review, Meta-analysis

Core tip: A possible association between the use of proton pump inhibitors (PPIs) and the risk of Clostridium difficile infection (CDI) have been su-ggested by several studies. This meta-analysis, including the largest number of studies published to date found the risk of CDI almost two-times higher in PPIs users than in nonusers. Because all the studies analyzed were observational, the causality could not be confirmed. Nevertheless, clinicians should be aware of such potential association and prescribe the PPIs only where they are clearly indicated.