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Study Authors: The 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; Todd W. Rice, Sunil Kripalani, Christopher J. Lindsell

Target Audience and Goal Statement: Critical care specialists, pulmonologists, gastroenterologists, hospitalists

The goal of this study was to compare in-hospital mortality rates for critically ill patients using proton pump inhibitors (PPIs) versus histamine-2 receptor blockers (H2RBs) for stress ulcer prophylaxis.

Question Addressed:

What was the comparative effect on in-hospital mortality of using PPIs versus H2RBs for stress ulcer prophylaxis among adults requiring invasive mechanical ventilation in the intensive care unit (ICU)?

Action Points Among critically ill patients requiring mechanical ventilation, stress ulcer prophylaxis with proton pump inhibitors resulted in a hospital mortality rate of 18.3% versus 17.5% with the use of histamine-2 receptor blockers, which did not reach the significance threshold, according to results from the large, international PEPTIC trial.

Note that study interpretation may be limited by crossover in medication use, since physicians were able to override study drug assignment.

Study Synopsis and Perspective:

Complications, including stress ulcers in the upper gastrointestinal tract, are frequent among critically ill ICU patients. Antagonism of gastric acid (historically with antacids) or suppression of acid production (more recently with H2RBs) are part of routine clinical care. While PPIs are commonly prescribed and reportedly reduce bleeding risks, as demonstrated in prior studies, some physicians still prescribe H2RBs.

Practice variations rely on physician preference or hospital policy. Each year, an estimated 2.5 million critically ill patients (in high-income countries alone) are affected by uncertainty about which drug class to use for stress ulcers. Associations between the use of PPIs and adverse events, including Clostridioides difficile infection, cognitive decline, and nosocomial pneumonia, further complicate treatment decisions.

No randomized clinical trials directly compared H2RBs to PPIs in critically ill patients. Accordingly, Paul Young, PhD, of Wellington Hospital in Wellington South, New Zealand, and colleagues compared two strategies of stress ulcer prophylaxis in mechanically ventilated adults in ICUs. Their results were presented at the Critical Care Reviews Meeting 2020 in Belfast, Northern Ireland and published in JAMA.

Comparisons were performed as part of the international open-label, cluster crossover, registry-embedded randomized PEPTIC (Proton Pump Inhibitors vs Histamine-2 Receptor Blockers for Ulcer Prophylaxis Treatment in the Intensive Care Unit) trial.

"One approach was to use PPIs as the default treatment and the other was to use H2RBs as the default treatment when stress ulcer prophylaxis was prescribed. Irrespective of the treatment being implemented in the ICU, clinicians could use either a PPI or an H2RB for individual patients where they considered this indicated," Young told MedicalResearch.com.

The primary outcome was in-hospital all-cause mortality up to 90 days. Clinically important upper gastrointestinal bleeding, C. difficile infection, and ICU and hospital lengths of stay were listed as secondary outcomes.

PEPTIC included 26,828 participants from ICUs in Australia, New Zealand, Canada, Ireland, and England. All patients required invasive mechanical ventilation within 24 hours of ICU admission. A total of 13,436 patients were randomized by site to PPIs and 13,392 randomized by site to H2RBs. The mean age in both treatment groups was just over 58, about 64% of both groups were men, and the burden of comorbidities at baseline was comparable.

The findings showed that 18.3% of PPI-treated patients died at the hospital by day 90 versus 17.5% in the H2RB group (risk ratio 1.05, 95% CI 1.00-1.10, P=0.05). However, fewer patients assigned to receive the PPI strategy experienced clinically important upper gastrointestinal bleeding (1.3% vs 1.8% in the H2RB group, risk ratio 0.73, P=0.009). C. difficile infection was reported in 0.3% of patients in the PPI group and 0.43% of patients in the H2RB group.

One patient in the PPI group had an allergic reaction to omeprazole and was switched to ranitidine.

There were no statistically significant between-group differences for ICU and hospital lengths of stay. Duration of mechanical ventilation and ventilator-associated conditions were also not significantly different as a function of treatment group.

The researchers acknowledged that some patients with a diagnosis of upper GI bleeding at ICU admission might actually have been lower GI bleeding; in addition, some diagnosed with upper GI bleeding in the ICU may have already been bleeding at admission. Other study limitations included investigator knowledge of treatment assignments, an inability to distinguish which individual patients received the other medication based on physician preference, and the possibility that a trial using different combinations of drugs or varying routes of administration could have yielded different results.

Source References: JAMA 2020; DOI: 10.1001/jama.2019.22190

Editorial: JAMA 2020; DOI: 10.1001/jama.2019.22436

Study Highlights and Explanation of Findings:

Among ICU patients requiring mechanical ventilation, stress ulcer prophylaxis with PPIs resulted in a hospital mortality rate of 18.3% versus 17.5% with the use of H2RBs, which did not reach the significance threshold. However, the researchers cautioned that study interpretation might have been limited by crossover in the use of assigned medications.

Though the PEPTIC trial design enabled rapid enrollment of many patients, it complicated an understanding of PPI versus H2RB drug effects, noted Todd Rice, MD, MSc, of Vanderbilt University Medical Center in Nashville, and colleagues in an accompanying editorial.

In the study, 20% of patients in the H2RB group also received PPIs for stress ulcer prophylaxis. "Although this may be presumed to bias the results toward finding no between-group differences, the likely nonrandom override of the recommended prevention strategy could have several effects," they wrote.

"If patients at greatest risk of benefit or harm from one strategy had the recommended approach overridden in such a way that they all ended up receiving the same drug, any signal of either benefit or harm of the drug would be attenuated," they added.

Additionally, the motivation for the trial was based on the safety concerns surrounding PPIs, not the hypothesized benefit of H2RBs. "The potential indication bias introduced by clinicians lacking equipoise and treating higher-risk patients with proton pump inhibitors, even in the histamine-2 receptor blocker group, might have masked higher mortality from proton pump inhibitors and attenuated the benefit of a proton pump inhibitor strategy on clinically important upper gastrointestinal bleeding," the editorialists wrote.

While post hoc analyses by treatment adherence refuted this hypothesis, they contended that "the true effects of the specific drugs, as opposed to treatment strategies, in this trial cannot be disentangled due to the significant rate of override."

Nevertheless, they lauded the study investigators' enrollment of more than 25,000 patients in 30 months in a randomized clinical trial, calling it "a remarkable accomplishment."

"Overall, the results do not preclude the possibility of a small increase in hospital mortality with the proton pump inhibitor prophylaxis strategy despite showing a small, statistically significant reduction in clinically important gastrointestinal bleeding," they wrote.