What was the rationale for the Reevaluating the Inhibition of Stress Erosions (REVISE) study regarding the use of Proton Pump Inhibitors (PPIs) in critically ill patients?

The Rationale for the REVISE Study: Concerns About PPI-Related Morbidity and Mortality

The primary rationale for the Reevaluating the Inhibition of Stress Erosions (REVISE) study by Cook and colleagues was concerns about the risk for morbidity and mortality from the use of proton pump inhibitors (PPIs) in critically ill patients undergoing invasive ventilation.

Background on Stress Ulcer Prophylaxis in Critical Care

Stress ulcer prophylaxis (SUP) has been a standard practice in intensive care units for decades, with PPIs and histamine-2 receptor antagonists (H2RAs) being the most commonly used agents. However, recent evidence has raised important questions about the risk-benefit profile of these medications, particularly PPIs.

Evolution of Evidence on SUP

The 2024 Society of Critical Care Medicine (SCCM) and American Society of Health-System Pharmacists (ASHP) guidelines highlight several key points that led to the need for the REVISE study:

• Despite reducing clinically important upper gastrointestinal bleeding (UGIB), there is uncertainty regarding the influence of PPIs on mortality in patients with high severity of illness in the ICU 1
• Recent subgroup assessments of randomized trials suggested an association between PPIs and increased mortality 1
• Network meta-analyses comparing PPIs to H2RAs found that PPIs were associated with reduced clinically important UGIB but potentially increased mortality (RR 1.05; 95% CI, 1-1.10) 1

Specific Concerns That Prompted REVISE

Mortality Concerns

The primary concern driving the REVISE study was emerging evidence suggesting that PPIs might increase mortality in critically ill patients, particularly those with high severity of illness. This concern is explicitly mentioned in the 2024 SCCM/ASHP guidelines, which note "uncertainty regarding the influence of PPIs on mortality in patients with high severity of illness in the ICU" 1.

Infectious Complications

Several studies raised concerns about infectious complications associated with PPI use:

• A 2014 study found that PPIs were associated with greater risks of pneumonia (OR 1.2; 95% CI, 1.03-1.41) and Clostridioides difficile infection (OR 1.29; 95% CI, 1.04-1.64) compared to H2RAs in mechanically ventilated patients 2
• A 2014 study identified PPIs as an independent risk factor for developing Clostridium difficile-associated diarrhea in ICU patients 3

Questioning Traditional Risk Factors

The 2024 guidelines also challenged traditional beliefs about risk factors for stress-related bleeding:

• There is no conclusive evidence for mechanical ventilation being an independent risk factor for UGIB 1
• The guidelines explicitly state: "Mechanical ventilation alone does not necessitate SUP" 1

This represents a significant shift from previous practice where mechanical ventilation was considered a primary indication for SUP.

Why This Matters for Clinical Practice

The REVISE study was designed to address these concerns by comparing pantoprazole to placebo specifically in invasively mechanically ventilated patients 4. This was critical because:

1. It would help determine if the mortality signal associated with PPIs was real
2. It would clarify whether mechanically ventilated patients truly benefit from SUP
3. It would provide high-quality evidence to guide clinical practice in an area with significant practice variation

Current Recommendations

The 2024 SCCM/ASHP guidelines now suggest:

• Using either PPIs or H2RAs as first-line agents for SUP in critically ill adults with risk factors for clinically important stress-related UGIB 1
• Risk factors that increase the likelihood of UGIB are coagulopathy, shock, and chronic liver disease - not mechanical ventilation alone 1
• SUP should be discontinued when risk factors are no longer present 1

The REVISE study was therefore designed to address a critical gap in our understanding of the risk-benefit profile of PPIs in mechanically ventilated patients, with particular concern about potential mortality risks that had been suggested in previous research.