PPIs vs. Histamine-2 Receptor Blockers for ICU Stress Ulcer Prophylaxis

Study Questions:

What are the comparative rates of mortality and upper gastrointestinal bleeding (UGIB) among intensive care unit (ICU) patients receiving proton-pump inhibitors (PPIs) versus histamine-2 receptor blockers (H2RBs) for stress ulcer prophylaxis in the PEPTIC trial?


In a crossover study design, 50 ICUs adopted 6-month preferential use of PPIs versus H2RBs, followed by 6 months of the alternate therapy. The primary outcome was 90-day mortality, and secondary outcomes were rates of UGIB and Clostridioides difficile infection, and lengths of ICU and hospital stay. Tertiary outcomes were duration of mechanical ventilation and incidence of ventilator-associated conditions.


Among 26,828 patients who enrolled and participated, mortality rates differed only modestly between patients randomized to PPIs versus H2RBs (18.3% vs. 17.5%, relative risk [RR], 1.05; 95% confidence interval [CI], 1.00-1.10; absolute risk difference, 0.93 percentage points; 95% CI, -0.01 to 1.88). Significant UGIB occurred less frequently in the PPI compared to H2RB group (1.3% vs. 1.8%, RR, 0.73; 95% CI, 0.57-0.92). However, rates of Clostridioides difficile and hospital/ICU lengths of stay did not differ significantly by assignment. The analyses were conducted by intention-to-treat; after randomization, 4.1% of subjects in the PPI arm received Clostridioides difficile, and 20.1% in the Clostridioides difficile arm received PPIs. Post hoc analysis revealed that patients in higher risk strata had significantly greater mortality after assignment to PPIs compared to H2RBs.


ICU patients assigned to PPIs versus H2RBs for ulcer prophylaxis had marginally higher 90-day mortality that just missed statistical significance. Significantly fewer UGIB events occurred among those assigned to PPIs compared to H2RBs.


The sizable, unbalanced rate of protocol nonadherence (five-fold greater crossover from H2RB to PPI) hinders interpretation of the relatively small outcome differences between drug treatments. Whether full protocol adherence would have increased or further minimized outcome differences between PPIs versus H2RBs cannot be determined based on the published findings.

Clinical Topics: Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure

Keywords: Duodenal Ulcer, Gastrointestinal Hemorrhage, Heart Failure, Histamine, Histamine H2 Antagonists, Hospital Mortality, Intensive Care Units, Peptic Ulcer, Primary Prevention, Proton Pump Inhibitors, Respiration, Artificial, Risk, Ulcer, Ventilators, Mechanical

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