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, 7 (12), e50836

Association Between Proton Pump Inhibitor Therapy and Clostridium Difficile Infection: A Contemporary Systematic Review and Meta-Analysis


Association Between Proton Pump Inhibitor Therapy and Clostridium Difficile Infection: A Contemporary Systematic Review and Meta-Analysis

Imad M Tleyjeh et al. PLoS One.


Introduction: Emerging epidemiological evidence suggests that proton pump inhibitor (PPI) acid-suppression therapy is associated with an increased risk of Clostridium difficile infection (CDI).

Methods: Ovid MEDLINE, EMBASE, ISI Web of Science, and Scopus were searched from 1990 to January 2012 for analytical studies that reported an adjusted effect estimate of the association between PPI use and CDI. We performed random-effect meta-analyses. We used the GRADE framework to interpret the findings.

Results: We identified 47 eligible citations (37 case-control and 14 cohort studies) with corresponding 51 effect estimates. The pooled OR was 1.65, 95% CI (1.47, 1.85), I(2) = 89.9%, with evidence of publication bias suggested by a contour funnel plot. A novel regression based method was used to adjust for publication bias and resulted in an adjusted pooled OR of 1.51 (95% CI, 1.26-1.83). In a speculative analysis that assumes that this association is based on causality, and based on published baseline CDI incidence, the risk of CDI would be very low in the general population taking PPIs with an estimated NNH of 3925 at 1 year.

Conclusions: In this rigorously conducted systemic review and meta-analysis, we found very low quality evidence (GRADE class) for an association between PPI use and CDI that does not support a cause-effect relationship.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.


Figure 1
Figure 1. Flow diagram of eligible studies.
Figure 2
Figure 2. Forest Plot of the Meta analyses of The Association Between CDI and Proton Pump Inhibitors Based on 51 Observations.
Figure 3
Figure 3. Contour enhanced funnel plot of the association between the effect-estimates and its standard errors:
* Contour enhanced funnel plots with implementation of regression adjustment model (adjusted effect at top where SE is 0).* The contour lines differentiate the significance and non-significance regions in the plot at 1%, 5% and 10% significance levels. *Vertical lines show average effect-estimates from random effect (red), and fixed effect models (blue). *A regression line (black) is added for regression based adjustment (With adjusted effect estimate and 95% CI at top where SE is 0). Abbreviations: FEMA: Fixed effect meta-analysis, REMA: Random effect meta-analysis, Reg: Regression line.
Figure 4
Figure 4. Influence of a hypothetical dichotomous confounder present in 20% (panel A) and 50% (panel B) of the study population, unaccounted for in the adjustments already performed in the individual studies.
The graphs indicate what combinations of OREC and RR that would be necessary for the confounder to fully account for the observed association between proton pump inhibitor (PPI) use and CDAD after adjustment for publication bias. Abbreviations: OREC, odds ratio of exposure to the confounder in PPI non-users vs. acid-suppression users; RRCD, relative risk of CDAD in individuals exposed to the confounder vs. non-exposed.

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The authors have no funding or support to report.