REVISE (2024): Pantoprazole vs Placebo for Stress Ulcer Prophylaxis (2024)

“Among adult patients undergoing mechanical ventilation in the ICU, pantoprazole resulted in a significantly lower risk of clinically important gastrointestinal bleeding than placebo but did not result in a significant difference in the risk of 90-day mortality.”

— The REVISE Investigators

1. Publication Details

  • Trial Title: Pantoprazole or Placebo for Stress Ulcer Prophylaxis in Critically Ill Patients.
  • Citation: Krag M, Marker S, Perner A, et al; for the REVISE Investigators. Pantoprazole or Placebo for Stress Ulcer Prophylaxis in Critically Ill Patients. N Engl J Med. 2024;390(10):877-888. doi:10.1056/NEJMoa2311181.
  • Published: March 7, 2024, in The New England Journal of Medicine.
  • Author: Mette Krag, M.D., Ph.D.
  • Funding: Canadian Institutes of Health Research and others.

2. Keywords

Stress Ulcer Prophylaxis, Gastrointestinal Bleeding, Proton-Pump Inhibitor (PPI), Pantoprazole, Critical Illness, Mechanical Ventilation.

3. The Clinical Question

In adult critically ill patients receiving invasive mechanical ventilation (Population), does prophylactic pantoprazole (Intervention) compared to placebo (Comparison) reduce 90-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The role of stress ulcer prophylaxis (SUP) in the ICU is controversial. The SUP-ICU trial (2018) showed that pantoprazole reduced GI bleeding but did not improve survival in a broad population of at-risk ICU patients.
  • Knowledge Gap: It was unclear if the findings of SUP-ICU applied specifically to the highest-risk group: patients receiving invasive mechanical ventilation. A larger trial focused on this population was needed to provide a more precise estimate of the effect of PPIs on mortality and other important outcomes.
  • Proposed Hypothesis: The authors hypothesized that among mechanically ventilated patients, pantoprazole would reduce 90-day mortality as compared with placebo.

5. Study Design and Methods

  • Design: A prospective, multicenter, international, randomized, double-blind, placebo-controlled, parallel-group trial.
  • Setting: 68 intensive care units (ICUs) in 8 countries.
  • Trial Period: Enrollment from August 2021 to January 2023.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) who were undergoing invasive mechanical ventilation in the ICU and were expected to continue for at least 24 hours.
    • Exclusion Criteria: Ongoing clinically important GI bleeding, known contraindications to PPIs, or receiving therapeutic acid suppression.
  • Intervention: Pantoprazole 40 mg intravenously once daily.
  • Control: Matching placebo (saline) intravenously once daily.
  • Management Common to Both Groups: Treatment was continued until ICU discharge, cessation of mechanical ventilation, or initiation of oral intake. All other aspects of care were at the discretion of the local team.
  • Power and Sample Size: The trial was powered to detect a 3.5% absolute difference in 90-day mortality, requiring 4800 patients.
  • Outcomes:
    • Primary Outcome: All-cause mortality at 90 days.
    • Secondary Outcomes: Included incidence of clinically important GI bleeding, ventilator-associated pneumonia, C. difficile infection, and new myocardial ischemia.

6. Key Results

  • Enrollment and Baseline: 4821 patients were randomized (2417 to pantoprazole, 2404 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 90-day mortality between the pantoprazole and placebo groups (29.3% vs 30.4%; P=0.43).
  • Secondary Outcomes: The incidence of clinically important GI bleeding was significantly lower in the pantoprazole group (1.0% vs 2.0%; P=0.007). There were no significant differences in the rates of pneumonia or C. difficile infection.
  • Adverse Events: The rates of serious adverse events were similar between the two groups.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using a logistic regression model.
  • Primary Outcome Analysis: The proportion of deaths at day 90 was compared between the two groups.
  • Key Statistic(s) Reported: Relative Risk (RR) for death at 90 days with pantoprazole: 0.96 (95% CI, 0.88 to 1.06; P=0.43).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: The paper reports the RR as 0.96.
      • Clinical Meaning: An RR of 0.96 means there was a 4% lower relative risk of death in the pantoprazole group, a difference that is not statistically significant.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The reported 95% CI was 0.88 to 1.06.
      • Clinical Meaning: Since this narrow confidence interval is centered on the line of no effect (1.0), it provides a precise estimate that there is no significant difference between the two strategies. The true effect is likely somewhere between a 12% benefit and a 6% harm.
    • P-value:
      • Calculation: The reported p-value was 0.43.
      • Clinical Meaning: The p-value of 0.43 is far above the 0.05 threshold, confirming that the observed result is very likely due to chance. A result is conventionally considered statistically significant if the p-value is less than 0.05.
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR) for GI Bleeding:
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group).
      • Calculation: ARR = 2.0% – 1.0% = 1.0%.
      • Clinical Meaning: For every 100 mechanically ventilated ICU patients treated with pantoprazole, 1 was prevented from having a clinically important GI bleed.
    • Number Needed to Treat (NNT) to prevent one GI bleed:
      • Formula: NNT = 1 / ARR.
      • Calculation: NNT = 1 / 0.01 = 100.
      • Clinical Meaning: 100 mechanically ventilated ICU patients need to be treated with prophylactic pantoprazole to prevent one additional clinically important GI bleed.
  • Subgroup Analyses: No significant benefit was found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: This was a very large, international, multicenter, randomized, double-blind, placebo-controlled trial, representing the highest level of evidence.
  • Generalizability: The pragmatic design and inclusion of a large number of diverse ICUs make the findings highly generalizable to the mechanically ventilated ICU population.
  • Focused Population: The trial specifically addressed the highest-risk population for stress ulcer bleeding.

9. Limitations and Weaknesses

  • Internal Validity (Bias): No major limitations to internal validity.
  • External Validity (Generalizability): The results are specific to pantoprazole and may not apply to other forms of acid suppression.
  • Other: The rate of bleeding in the placebo group was very low (2.0%), making it statistically challenging for a reduction in bleeding to translate into a mortality benefit.

10. Conclusion of the Authors

“In this trial involving adult patients undergoing mechanical ventilation in the ICU, pantoprazole did not lead to a significant difference in 90-day mortality as compared with placebo. Pantoprazole resulted in a lower incidence of clinically important gastrointestinal bleeding.”

11. To Summarize

  • Impact on Current Practice: The REVISE trial is the largest and most definitive study on stress ulcer prophylaxis to date. It confirms the findings of the SUP-ICU trial in the specific high-risk population of mechanically ventilated patients. It shows that while PPIs are effective at preventing bleeding, this does not improve survival, nor does it cause a significant increase in harm (pneumonia or C. difficile). This reinforces a more nuanced approach to SUP, where the decision is based on balancing a modest benefit (NNT of 100 for bleeding) against cost and the theoretical risks of acid suppression.
  • Specific Recommendations:
    • Patient Selection: For the general population of adult ICU patients receiving mechanical ventilation.
    • Actionable Intervention: Prophylactic pantoprazole can be used to reduce the risk of GI bleeding but should not be expected to improve survival. The decision to use it should be based on an individual patient’s bleeding risk.
    • Expected Benefit: A reduction in clinically important GI bleeding (NNT of 100), but no effect on mortality.
  • What This Trial Does NOT Mean: This trial does not mean that SUP should be abandoned. It is still effective at preventing a complication, and for patients at very high risk of bleeding, this benefit may be considered worthwhile.
  • Implementation Caveats: The findings support a practice of not using SUP routinely in all ventilated patients, but rather targeting it to those with the highest risk factors for bleeding.

12. Context and Related Studies

  • Building on Previous Evidence: This trial was a direct successor to the SUP-ICU trial (2018), designed to provide a more precise estimate of the effect of SUP in the mechanically ventilated subgroup, which is considered the highest-risk population.
  • Influence on Subsequent Research: This trial, along with SUP-ICU, provides a massive and definitive evidence base that will shape international guidelines for years to come, likely leading to more restrictive recommendations for SUP.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: Can we develop a clinical risk score to accurately identify the small group of patients who have a high enough bleeding risk (e.g., >5-10%) where the NNT for SUP becomes more compelling?
  • Future Directions: Research is focused on refining risk-stratification tools to allow for a more personalized and evidence-based application of stress ulcer prophylaxis.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was of fundamental importance, re-evaluating a nearly universal ICU practice in the highest-risk population.
  • Methods: The large, international, multicenter, double-blind, placebo-controlled design was methodologically superb.
  • Results: The trial had a clear and robustly neutral result for its primary outcome of mortality. The positive finding for the secondary outcome of GI bleeding was also clear, but the effect size was small (NNT 100).
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The results are highly applicable to general ICU practice worldwide and provide a definitive, evidence-based rationale to move away from the routine, reflexive use of stress ulcer prophylaxis for all mechanically ventilated patients.

16. Disclaimer and Contact

This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.

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