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, 8 (3), e56498

The Association Between Histamine 2 Receptor Antagonist Use and Clostridium Difficile Infection: A Systematic Review and Meta-Analysis


The Association Between Histamine 2 Receptor Antagonist Use and Clostridium Difficile Infection: A Systematic Review and Meta-Analysis

Imad M Tleyjeh et al. PLoS One.

Erratum in

  • PLoS One. 2013;8(4). doi:10.1371/annotation/56f8945c-33f6-45bf-87ce-dd512f7c25b0. Abdulhak, Aref A Bin [corrected to Abdulhak, Aref Bin]


Background: Clostridium difficile infection (CDI) is a major health problem. Epidemiological evidence suggests that there is an association between acid suppression therapy and development of CDI.

Purpose: We sought to systematically review the literature that examined the association between histamine 2 receptor antagonists (H2RAs) and CDI.

Data source: We searched Medline, Current Contents, Embase, ISI Web of Science and Elsevier Scopus from 1990 to 2012 for all analytical studies that examined the association between H2RAs and CDI.

Study selection: Two authors independently reviewed the studies for eligibility.

Data extraction: Data about studies characteristics, adjusted effect estimates and quality were extracted.

Data synthesis: Thirty-five observations from 33 eligible studies that included 201834 participants were analyzed. Studies were performed in 6 countries and nine of them were multicenter. Most studies did not specify the type or duration of H2RAs therapy. The pooled effect estimate was 1.44, 95% CI (1.22-1.7), I(2) = 70.5%. This association was consistent across different subgroups (by study design and country) and there was no evidence of publication bias. The pooled effect estimate for high quality studies was 1.39 (1.15-1.68), I2 = 72.3%. Meta-regression analysis of 10 study-level variables did not identify sources of heterogeneity. In a speculative analysis, the number needed to harm (NNH) with H2RAs at 14 days after hospital admission in patients receiving antibiotics or not was 58, 95% CI (37, 115) and 425, 95% CI (267, 848), respectively. For the general population, the NNH at 1 year was 4549, 95% CI (2860, 9097).

Conclusion: In this rigorous systematic review and meta-analysis, we observed an association between H2RAs and CDI. The absolute risk of CDI associated with H2RAs is highest in hospitalized patients receiving antibiotics.

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-random effect model meta-analysis of the association between CDI and H2RAs based on 35 observations stratified by country.
Error bars indicate confidence interval.
Figure 3
Figure 3. Forest plot of the pooled proportion of Clostridium difficile cases that were exposed to antibiotics.
Figure 4
Figure 4. Contour-enhanced funnel plot
of the association between the estimated effect size and its standard error in all studies comparing those exposed and unexposed to H2RA displays areas of statistical significance on a funnel plot. Contours represent conventional “milestone” levels of statistical significance (e.g., <0.01, <0.05, <0.1). This funnel plot is symmetrical as it is not missing studies in the white area excluding the possibility of publication bias (Egger's test, p = 0.905).
Figure 5
Figure 5. Influence of a hypothetical dichotomous confounder present in 20% (panel A) and 40% (panel B) of the study population, unaccounted for in prior adjustments performed in individual studies.
The graphs depict what combinations of OREC and RR would be necessary for the confounder to fully account for the observed association between H2RA use and CDI acquisition. Abbreviations: OREC, odds ratio of exposure to the confounder in H2RA non-users vs. H2RA users; RRCD, relative risk of CDAD in individuals exposed to the confounder vs. non-exposed.

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