Stress ulcer prophylaxis with proton pump inhibitors or histamine 2 receptor antagonists in critically ill adults-a meta-analysis of randomized controlled trials with trial sequential analysis

Background Proton pump inhibitors (PPI) and histamine 2 receptor antagonists (H2RA) have been widely used as stress ulcer prophylaxis (SUP) in critically ill patients, however, its efficacy and safety remain unclear. This study aimed to assess the effect of SUP on clinical outcomes in critically ill adults. Methods Literature search was conducted in PubMed, EMBASE, Web of Science, and the Cochrane database of clinical trials for randomized controlled trials (RCTs) that investigated SUP, with PPI or H2RA, versus placebo or no prophylaxis in critically ill patients from database inception through 1 June 2019. Study selection, data extraction and quality assessment were performed in duplicate. The primary outcomes were clinically important gastrointestinal (GI) bleeding and overt GI bleeding. Conventional meta-analysis with random-effects model and trial sequential analysis (TSA) were performed. Results Twenty-nine RCTs were identified, of which four RCTs were judged as low risk of bias. Overall, SUP could reduce the incident of clinically important GI bleeding [relative risk (RR) = 0.58; 95% confidence intervals (CI): 0.42-0.81] and overt GI bleeding (RR = 0.48; 95% CI: 0.36-0.63), these results were confirmed by the sub-analysis of trials with low risk of bias, TSA indicated a firm evidence on its beneficial effects on the overt GI bleeding (TSA-adjusted CI: 0.31-0.75), but lack of sufficient evidence on the clinically important GI bleeding (TSA-adjusted CI: 0.23-1.51). Among patients who received enteral nutrition (EN), SUP was associated with a decreased risk of clinically important GI bleeding (RR = 0.61; 95% CI: 0.44-0.85; TSA-adjusted CI: 0.16-2.38) and overt GI bleeding (RR = 0.64; 95% CI: 0.42-0.96; TSA-adjusted CI: 0.12-3.35), but these benefits disappeared after adjustment with TSA. Among patients who did not receive EN, SUP had only benefits in reducing the risk of overt GI bleeding (RR = 0.37; 95% CI: 0.25-0.55; TSA-adjusted CI: 0.22-0.63), but not the clinically important GI bleeding (RR = 0.27; 95% CI: 0.04-2.09). Conclusions SUP has benefits on the overt GI bleeding in critically ill patients who did not receive EN, however, its benefits on clinically important GI bleeding still needs more evidence to confirm.