Dataset Information

Effect of Stress Ulcer Prophylaxis With Proton Pump Inhibitors vs Histamine-2 Receptor Blockers on In-Hospital Mortality Among ICU Patients Receiving Invasive Mechanical Ventilation: The PEPTIC Randomized Clinical Trial.

ABSTRACT:

Importance

Proton pump inhibitors (PPIs) or histamine-2 receptor blockers (H2RBs) are often prescribed for patients as stress ulcer prophylaxis drugs in the intensive care unit (ICU). The comparative effect of these drugs on mortality is unknown.

Objective

To compare in-hospital mortality rates using PPIs vs H2RBs for stress ulcer prophylaxis.

Design, setting, and participants

Cluster crossover randomized clinical trial conducted at 50 ICUs in 5 countries between August 2016 and January 2019. Patients requiring invasive mechanical ventilation within 24 hours of ICU admission were followed up for 90 days at the hospital.

Interventions

Two stress ulcer prophylaxis strategies were compared (preferential use with PPIs vs preferential use with H2RBs). Each ICU used each strategy sequentially for 6 months in random order; 25 ICUs were randomized to the sequence with use of PPIs and then use of H2RBs and 25 ICUs were randomized to the sequence with use of H2RBs and then use of PPIs (13 436 patients randomized by site to PPIs and 13 392 randomized by site to H2RBs).

Main outcomes and measures

The primary outcome was all-cause mortality within 90 days during index hospitalization. Secondary outcomes were clinically important upper gastrointestinal bleeding, Clostridioides difficile infection, and ICU and hospital lengths of stay.

Results

Among 26 982 patients who were randomized, 154 opted out, and 26 828 were analyzed (mean [SD] age, 58 [17.0] years; 9691 [36.1%] were women). There were 26 771 patients (99.2%) included in the mortality analysis; 2459 of 13 415 patients (18.3%) in the PPI group died at the hospital by day 90 and 2333 of 13 356 patients (17.5%) in the H2RB group died at the hospital by day 90 (risk ratio, 1.05 [95% CI, 1.00 to 1.10]; absolute risk difference, 0.93 percentage points [95% CI, -0.01 to 1.88] percentage points; P = .054). An estimated 4.1% of patients randomized by ICU site to PPIs actually received H2RBs and an estimated 20.1% of patients randomized by ICU site to H2RBs actually received PPIs. Clinically important upper gastrointestinal bleeding occurred in 1.3% of the PPI group and 1.8% of the H2RB group (risk ratio, 0.73 [95% CI, 0.57 to 0.92]; absolute risk difference, -0.51 percentage points [95% CI, -0.90 to -0.12 percentage points]; P = .009). Rates of Clostridioides difficile infection and ICU and hospital lengths of stay were not significantly different by treatment group. One adverse event (an allergic reaction) was reported in 1 patient in the PPI group.

Conclusions and relevance

Among ICU patients requiring mechanical ventilation, a strategy of stress ulcer prophylaxis with use of proton pump inhibitors vs histamine-2 receptor blockers resulted in hospital mortality rates of 18.3% vs 17.5%, respectively, a difference that did not reach the significance threshold. However, study interpretation may be limited by crossover in the use of the assigned medication.

Trial registration

anzctr.org.au Identifier: ACTRN12616000481471.

SUBMITTER: PEPTIC Investigators for the Australian and New Zealand Intensive Care Society Clinical Trials Group, Alberta Health Services Critical Care Strategic Clinical Network, and the Irish Critical Care Trials Group

PROVIDER: S-EPMC7029750 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundProton 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.MethodsLiterature 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.ResultsTwenty-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).ConclusionsSUP 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.

Project description:Histamine-2 receptor antagonists are commonly administered for stress ulcer prophylaxis in critically ill adults and may be associated with delirium development. We aimed to determine differential associations of histamine-2 receptor antagonist or proton-pump inhibitor administration with delirium development in patients admitted to a medical ICU.DesignRetrospective observational study using a deidentified database sourced from the University of North Carolina Health Care system. Participants were identified as having delirium utilizing an International Classification of Diseases-based algorithm. Associations among histamine-2 receptor antagonist, proton-pump inhibitor, or no medication administration and delirium were identified using relative risk. Multiple logistic regression was used to control for potential confounders including mechanical ventilation and age.SettingAcademic tertiary care medical ICU in the United States.PatientsAdults admitted to the University of North Carolina medical ICU from January 2015 to December 2019, excluding those on concurrent histamine-2 receptor antagonists and proton-pump inhibitors in the same encounter.InterventionsNone.Measurements and main resultsWe identified 6,645 critically ill patients, of whom 29% (n = 1,899) received mechanical ventilation, 45% (n = 3,022) were 65 or older, and 22% (n = 1,487) died during their medical ICU encounter. Of the 6,645 patients, 31% (n = 2,057) received an histamine-2 receptor antagonist and no proton-pump inhibitors, 40% (n = 2,648) received a proton-pump inhibitor and no histamine-2 receptor antagonists, and 46% (n = 3,076) had delirium. The histamine-2 receptor antagonist group had a greater association with delirium than the proton-pump inhibitor group compared with controls receiving neither medication, after controlling for mechanical ventilation and age (risk ratio, 1.36; 1.25-1.47; p < 0.001) and (risk ratio, 1.15; 1.07-1.24; p < 0.001, respectively).ConclusionsHistamine-2 receptor antagonists are more strongly associated with increased delirium than proton-pump inhibitors. Prospective studies are necessary to further elucidate this association and to determine if replacement of histamine-2 receptor antagonists with proton-pump inhibitors in ICUs decreases the burden of delirium in critically ill patients.