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.

Figure 1.. Screening, Randomization, and Follow-up of Participants in the PEPTIC Randomized Trial

One intensive care unit (ICU) randomized to the sequence of proton pump inhibitors (PPIs) first and then histamine-2 receptor blockers (H₂RBs) contributed 46 patients to the H₂RB group but did not contribute patients to the PPI group because it did not contribute to the registry for treatment period 1. As shown in eFigure 2 in Supplement 2, patients in a small number of sites received both PPIs and H₂RBs, and a small number of patients distributed across multiple sites received no stress ulcer prophylaxis. ^aDefined by the presence of a registry ICU admission code indicating that the patient was admitted to the ICU with upper gastrointestinal bleeding.

Figure 2.. Cumulative Incidence of In-Hospital Mortality

A total of 2459 of 13 415 patients (18.3%) in the proton pump inhibitor (PPI) group and 2333 of 13 356 patients (17.5%) in the histamine-2 receptor blocker (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 [95% CI, −0.01 to 1.88] percentage points; P = .054). The median observation time was 7.99 days (interquartile range, 4.79 to 17.0 days) in the PPI group vs 8.03 days (interquartile range, 4.82 to 17.0 days) in the H₂RB group. Curve truncated at 40 days beyond which less than 10% of the study population remained at risk.