JAMA OCTOBER 03, 2020

PEPTIC (Proton Pump Inhibitors vs Histamine-2 Receptor Blockers for Ulcer Prophylaxis Treatment in the Intensive Care Unit)

Young, P., et al. (The PEPTIC Investigators)

Bottom Line

The PEPTIC trial was a large, multicenter, randomized clinical trial demonstrating no significant difference in in-hospital mortality between proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) for stress ulcer prophylaxis in critically ill patients.

Key Findings

1. The primary outcome of in-hospital mortality occurred in 18.3% of the PPI group compared to 17.5% in the H2RA group, showing no statistically significant difference (adjusted odds ratio, 1.05; 95% CI, 0.91–1.20).

2. There was no significant difference in the composite of clinically important gastrointestinal bleeding, which was rare in both groups (1.3% in the PPI group vs 1.8% in the H2RA group).

3. Incidences of secondary safety outcomes, including hospital-acquired infections like C. difficile, were comparable between the two cohorts.

Study Design

Design

Cluster-randomized, crossover trial

Open-label

Sample

26,982

Patients

Duration

In-hospital

Median

Setting

Multicenter, international

Population Adult patients admitted to the ICU who required stress ulcer prophylaxis

Intervention Proton pump inhibitors

Comparator Histamine-2 receptor antagonists

Outcome In-hospital mortality

Study Limitations

• As an open-label trial, there was potential for bias in the administration of prophylaxis and the reporting of outcomes.

• The trial was conducted in a real-world setting with varying clinical practices across centers, which may have introduced heterogeneity.

• The study design focused on mortality as a primary endpoint, which may be influenced by many factors beyond the choice of gastrointestinal prophylaxis.

Clinical Significance

The results suggest that either PPIs or H2RAs can be used for stress ulcer prophylaxis in critically ill adults without a meaningful difference in mortality, allowing clinicians to choose based on local protocols, drug availability, and cost.

Historical Context

The PEPTIC trial sought to address the long-standing clinical uncertainty regarding the relative safety and efficacy of PPIs versus H2RAs for stress ulcer prophylaxis, particularly given previous concerns that PPIs might increase the risk of infections or mortality in critically ill patients compared to H2 blockers.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Compare the pharmacological mechanisms of action between proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) and explain the physiological basis for 'stress ulcers' in critically ill patients.

Key Response

PPIs (like pantoprazole) irreversibly inhibit the H+/K+ ATPase pump, the final common pathway for gastric acid secretion. H2RAs (like famotidine) competitively block histamine receptors on parietal cells, which is only one pathway for acid production. Stress ulcers in the ICU typically result from splanchnic hypoperfusion leading to mucosal ischemia (Curling's ulcers) or increased intracranial pressure leading to vagal-mediated hyperacidity (Cushing's ulcers).

Resident

In the context of the PEPTIC trial findings, how should a clinician weigh the choice of stress ulcer prophylaxis (SUP) for a patient at high risk for both gastrointestinal bleeding and Clostridioides difficile infection?

Key Response

While PEPTIC showed no significant difference in in-hospital mortality between PPIs and H2RAs, previous observational data and some meta-analyses suggest PPIs may be associated with higher rates of C. difficile and ventilator-associated pneumonia due to more profound gastric acid suppression. Clinicians must balance the lower rate of clinically significant GI bleeding often associated with PPIs against the potential infectious risks of H2RAs, though PEPTIC suggests these differences do not ultimately translate to a mortality benefit.

Fellow

The PEPTIC trial observed a potential signal for increased mortality in the PPI group within the cardiac surgery subgroup. How does this finding challenge the 'one-size-fits-all' approach to SUP in a mixed medical-surgical ICU?

Key Response

The cardiac surgery subgroup analysis (OR 1.27) suggested PPIs might be less favorable than H2RAs in this specific population. This highlights that physiological stressors differ by admission type; cardiac surgery patients may have different risks regarding gut perfusion or inflammatory responses to acid suppression compared to general medical or trauma patients, suggesting that protocolized 'unit-wide' SUP choices may ignore important subspecialty nuances.

Attending

The PEPTIC trial utilized a cluster-randomized crossover design involving over 26,000 patients. How should this high-level evidence influence your teaching of 'default bias' in electronic health record (EHR) order sets?

Key Response

PEPTIC demonstrates that at a population level, the choice of SUP (PPI vs H2RA) is largely equivalent regarding mortality. This provides an opportunity to teach that 'default' choices in order sets drive massive resource utilization and potential side-effect profiles across thousands of patients. Since mortality is unaffected, the 'default' should perhaps be driven by secondary factors like cost or the specific unit's baseline rate of C. difficile.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Analyze the strengths and limitations of using a cluster-randomized crossover design versus a standard individual-level randomized controlled trial (RCT) for a study of the scale and scope of PEPTIC.

Key Response

Cluster-randomization allows for the study of 'real-world' implementation and minimizes treatment contamination within an ICU. The crossover design helps control for unit-specific variables. However, it introduces the risk of period effects and requires complex statistical accounting for the intra-cluster correlation coefficient (ICC). The sheer size (n=26,859) provides immense power, but the 'average' effect across clusters can mask individual-level heterogeneity of treatment effect (HTE).

Journal Editor

The 95% confidence interval for the primary outcome (mortality) in PEPTIC was 1.00 to 1.10 for PPIs compared to H2RAs. As an editor, how do you interpret a result where the point estimate is exactly on the line of unity but the interval is entirely on the side of potential harm?

Key Response

This is a classic 'near-miss' for statistical significance. While the p-value (0.054) was technically non-significant, the fact that the entire 95% CI rests at or above 1.00 suggests a potential, albeit small, increase in mortality with PPIs. A tough reviewer would flag that the study cannot definitively claim 'equivalence' or 'non-inferiority' but rather only 'no statistically significant difference,' which are distinct statistical assertions.

Guideline Committee

The Surviving Sepsis Campaign (SSC) guidelines currently suggest using SUP in patients with risk factors for GI bleeding. How does PEPTIC influence the level of evidence for choosing between PPIs and H2RAs, and should the recommendations be updated to favor one class?

Key Response

Current guidelines (like SSC 2021) generally recommend SUP for patients with risk factors (e.g., mechanical ventilation >48h) but often remain neutral on the specific agent. PEPTIC provides 'high-quality' evidence that neither class is superior for mortality. However, because it did not show a clear benefit of PPIs over H2RAs even in high-risk patients, it supports a 'weak' or 'conditional' recommendation where the choice remains at the clinician's discretion based on local cost and side-effect profiles.

Clinical Landscape

Noteworthy Related Trials

2004

Canadian Critical Care Trials Group Trial

n = 1,238 · NEJM

Tested

Ranitidine 50 mg IV every 8 hours

Population

Critically ill patients receiving mechanical ventilation

Comparator

Sucralfate 1 g suspension every 6 hours

Endpoint

Clinically important gastrointestinal bleeding

Key result: Ranitidine was associated with a lower rate of clinically important GI bleeding compared to sucralfate, but rates of ventilator-associated pneumonia were similar.

2018

SUP-ICU Trial

n = 3,298 · NEJM

Tested

Pantoprazole 40 mg daily

Population

Adult ICU patients at risk for gastrointestinal bleeding

Comparator

Placebo

Endpoint

90-day mortality

Key result: Pantoprazole did not result in a lower 90-day mortality rate compared to placebo in ICU patients.

2022

REVISE Trial

n = 3,805 · NEJM

Tested

Pantoprazole 40 mg daily

Population

Critically ill adults receiving invasive mechanical ventilation

Comparator

Placebo

Endpoint

Clinically important upper gastrointestinal bleeding at 90 days

Key result: Pantoprazole reduced clinically important upper GI bleeding compared to placebo but did not affect mortality.

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