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Proton Pump Inhibitors Versus Histamine 2 Receptor Antagonists for Stress Ulcer Prophylaxis in Critically Ill Patients: A Systematic Review and Meta-Analysis*

Alhazzani, Waleed MD1; Alenezi, Farhan MD1; Jaeschke, Roman Z. MD1,2; Moayyedi, Paul MD1,2; Cook, Deborah J. MD1,2

doi: 10.1097/CCM.0b013e3182758734
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Background: Critically ill patients may develop bleeding caused by stress ulceration. Acid suppression is commonly prescribed for patients at risk of stress ulcer bleeding. Whether proton pump inhibitors are more effective than histamine 2 receptor antagonists is unclear.

Objectives: To determine the efficacy and safety of proton pump inhibitors vs. histamine 2 receptor antagonists for the prevention of upper gastrointestinal bleeding in the ICU.

Search Methods: We searched Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, ACPJC, CINHAL, online trials registries (, ISRCTN Register, WHO ICTRP), conference proceedings databases, and reference lists of relevant articles.

Selection Criteria Randomized controlled parallel group trials comparing proton pump inhibitors to histamine 2 receptor antagonists for the prevention of upper gastrointestinal bleeding in critically ill patients, published before March 2012.

Data Collection and Analysis: Two reviewers independently applied eligibility criteria, assessed quality, and extracted data. The primary outcomes were clinically important upper gastrointestinal bleeding and overt upper gastrointestinal bleeding; secondary outcomes were nosocomial pneumonia, ICU mortality, ICU length of stay, and Clostridium difficile infection. Trial authors were contacted for additional or clarifying information.

Results: Fourteen trials enrolling a total of 1,720 patients were included. Proton pump inhibitors were more effective than histamine 2 receptor antagonists at reducing clinically important upper gastrointestinal bleeding (relative risk 0.36; 95% confidence interval 0.19–0.68; p = 0.002; I2 = 0%) and overt upper gastrointestinal bleeding (relative risk 0.35; 95% confidence interval 0.21–0.59; p < 0.0001; I2 = 15%). There were no differences between proton pump inhibitors and histamine 2 receptor antagonists in the risk of nosocomial pneumonia (relative risk 1.06; 95% confidence interval 0.73–1.52; p = 0.76; I2 = 0%), ICU mortality (relative risk 1.01; 95% confidence interval 0.83–1.24; p = 0.91; I2 = 0%), or ICU length of stay (mean difference −0.54 days; 95% confidence interval −2.20 to 1.13; p = 0.53; I2 = 39%). No trials reported on C. difficile infection.

Conclusions: In critically ill patients, proton pump inhibitors seem to be more effective than histamine 2 receptor antagonists in preventing clinically important and overt upper gastrointestinal bleeding. The robustness of this conclusion is limited by the trial methodology, differences between lower and higher quality trials, sparse data, and possible publication bias. We observed no differences between drugs in the risk of pneumonia, death, or ICU length of stay.

Supplemental Digital Content is available in the text.

1 Department of Medicine, McMaster University, Hamilton, Canada.

2 Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Canada.

* See also p. 906.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (

Dr. Moayyedi has accepted speakers fees from AstraZeneca, Nycomed, and Abbott and has received research support from AstraZeneca and Aptlalis over the last 5 years. His chair is supported in part by an unrestricted donation to McMaster University. Dr. Cook holds a Research Chair funded by the Canadian Institutes for Health Research. The remaining authors have not disclosed any potential conflicts of interest.

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© 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins