• Paul M Reynolds and Robert MacLaren.
• University of Colorado Skaggs School of Pharmacy, Aurora, Colorado.
• Pharmacotherapy. 2019 Mar 1; 39 (3): 408-420.

Study ObjectiveBecause recent studies have challenged the efficacy of stress ulcer prophylaxis (SUP) in the critically ill patient, our objective was to evaluate the efficacy of SUP with proton pump inhibitors (PPIs) or histamine2 -receptor antagonists (H2 RAs) against placebo, control, no therapy, or enteral nutrition alone in critically ill adults.DesignMeta-analysis with trial sequential analysis (TSA) of 34 randomized controlled trials.PatientsA total of 3220 critically ill adults who received PPIs or H2 RAs versus placebo, control, no therapy, or enteral nutrition.Measurements And Main ResultsA systematic review was performed using a random effects meta-analysis with TSA according to a predefined protocol. Randomized controlled trials comparing PPIs or H2 RAs with either placebo, control, no therapy, or enteral nutrition alone were identified through a comprehensive search of the literature. Two blinded reviewers independently assessed studies for inclusion, risk of bias, and extracted data using Cochrane Collaborative methodology. The predefined primary outcomes were clinically important, overt, and any (clinically important plus overt) gastrointestinal bleeding. Secondary outcomes included pneumonia, Clostridium difficile-associated diarrhea (CDAD), and mortality. Subgroup analyses were conducted for the primary outcome by PPI or H2 RA use, intensive care unit (ICU) subtype, studies published after early goal-directed therapy (EGDT), the presence of risk factors for stress ulceration, and enteral nutrition use. Of the 34 trials included, 33 were judged as high risk of bias and 1 was judged as low risk. Use of SUP significantly reduced clinically important bleeding (risk ratio [RR] 0.53, 95% confidence interval [CI] 0.37-0.76, p<0.001; I2  = 0%), overt bleeding (RR 0.55, 95% CI 0.39-0.76, p=0.0003; I2  = 53%), and any bleeding (RR 0.54, 95% CI 0.41-0.71, p<0.00001; I2  = 58%). TSA confirmed these findings. No significant differences in pneumonia, CDAD, or mortality were noted. Subgroup analyses revealed significant reductions in clinically important bleeding with SUP in neurosurgical patients (RR 0.37, p<0.05) but not in surgery/trauma or medical ICU patients with risk factors. SUP provided no benefit in studies published after EGDT. SUP significantly reduced clinically important bleeding regardless of the use of enteral nutrition (p<0.05).ConclusionThis meta-analysis demonstrated that SUP use was associated with significant reductions in bleeding but not mortality. SUP should not be abandoned until large randomized trials demonstrate the futility of this intervention.© 2018 Pharmacotherapy Publications, Inc.

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