Rationale for the REVISE Study by Cook and Colleagues
The primary rationale for the Reevaluating the Inhibition of Stress Erosions (REVISE) study was concerns about the risk for morbidity and mortality from the use of proton pump inhibitors (PPIs) in critically ill patients undergoing invasive ventilation. 1
Background on PPI Concerns in Critical Care
The Society of Critical Care Medicine (SCCM) and American Society of Health-System Pharmacists (ASHP) guidelines highlight significant concerns regarding PPI use in critically ill patients:
- Emerging evidence suggested that PPIs might increase mortality in critically ill patients, particularly those with high severity of illness 1
- Subgroup analyses from randomized trials indicated an association between PPI use and increased mortality 1
- Network meta-analyses comparing PPIs to histamine-2 receptor antagonists (H2RAs) found that while PPIs reduced clinically important upper gastrointestinal bleeding (UGIB), they potentially increased mortality (RR 1.05; 95% CI, 1-1.10) 1
Specific Safety Concerns with PPIs
The REVISE study was designed to address several specific concerns about PPI use:
- Increased risk of pneumonia in mechanically ventilated patients 2, 3
- Higher rates of Clostridioides difficile infection 4, 3
- Most critically, increased mortality risk in severely ill ICU patients 1, 2
A 2021 retrospective study found that the PPI group had a significantly higher 90-day mortality than the H2RA group (relative risk: 1.28; P = 0.01), contradicting current recommendations that prefer PPIs for gastrointestinal bleeding prophylaxis in the ICU 2.
Mechanical Ventilation as a Risk Factor
It's important to note that contrary to traditional belief, there is no conclusive evidence that mechanical ventilation alone is an independent risk factor for UGIB. The guidelines explicitly state "Mechanical ventilation alone does not necessitate SUP" 1. This challenges the conventional practice of routine stress ulcer prophylaxis in all mechanically ventilated patients.
Balancing Benefits and Risks
The REVISE study aimed to address the critical balance between:
- The established benefit of PPIs in reducing clinically important UGIB 5
- The potential increased risk of mortality and infectious complications 1, 4, 2, 3
This balance is particularly important given that gastrointestinal bleeding events are relatively rare in modern ICU practice, with one study showing only 0.9% of 3,286 patients developing GI bleeds during ICU treatment 4.
Clinical Implications
The uncertainty around PPI safety in critically ill patients has significant implications for clinical practice:
- Current guidelines 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
- The REVISE trial was designed to provide definitive evidence regarding the efficacy and safety of PPIs versus placebo in invasively mechanically ventilated patients 6
- The study results would help determine whether the benefits of routine PPI prophylaxis outweigh the potential risks in this patient population 6