PREVENT: Pantoprazole vs. Placebo for Stress Ulcer Prophylaxis (2019)

“Among adult patients in the ICU who were at risk for gastrointestinal bleeding, mortality at 90 days and the incidence of clinically important events were not significantly lower with pantoprazole than with placebo.”

  • The PREVENT Investigators

1. Publication Details

  • Trial Title: Pantoprazole in Patients at Risk for Gastrointestinal Bleeding in the ICU
  • Citation: Krag M, Marker S, Perner A, et al. Pantoprazole in Patients at Risk for Gastrointestinal Bleeding in the ICU. N Engl J Med. 2018;379(23):2199-2208. DOI: 10.1056/NEJMoa1714919
  • Published: December 6, 2018, in The New England Journal of Medicine
  • Author: Mette Krag, M.D., Ph.D.
  • Funding: The Innovation Fund of Denmark and others.

2. Keywords

  • Stress Ulcer Prophylaxis, Proton-Pump Inhibitor (PPI), Pantoprazole, Gastrointestinal Bleeding, Critical Care, Randomized Controlled Trial

3. The Clinical Question

  • In adult ICU patients at risk for clinically important gastrointestinal (GI) bleeding (Population), does prophylactic treatment with intravenous pantoprazole (Intervention) compared to placebo (Comparison) reduce 90-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Stress ulcer prophylaxis with acid-suppressive drugs, particularly proton-pump inhibitors (PPIs), was a routine and widespread practice in ICUs worldwide to prevent GI bleeding in critically ill patients.
  • Knowledge Gap: This practice was based on older evidence from an era before modern ICU care, and it was largely unproven in large, high-quality trials. There were growing concerns that routine acid suppression could be harmful by increasing the risk of pneumonia and Clostridium difficile infection. A large, definitive trial was needed to assess the true risk-benefit balance.
  • Proposed Hypothesis: The authors hypothesized that prophylactic pantoprazole would be superior to placebo in reducing 90-day mortality in at-risk ICU patients.

5. Study Design and Methods

  • Design: A large, international, multicenter, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 33 intensive care units (ICUs) in 6 countries.
  • Trial Period: Enrollment ran from January 2016 to October 2017.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) acutely admitted to the ICU with at least one risk factor for clinically important GI bleeding (e.g., shock, mechanical ventilation, coagulopathy, renal-replacement therapy).
    • Exclusion Criteria: Included patients with active GI bleeding on admission or those already taking high-dose acid-suppressive therapy.
  • Intervention: Patients received intravenous pantoprazole (40 mg) once daily.
  • Control: Patients received a matching intravenous placebo (0.9% saline).
  • Management Common to Both Groups: All other aspects of ICU care were at the discretion of the treating clinicians according to local guidelines.
  • Power and Sample Size: The authors calculated that a sample size of 3350 patients would provide 80% power to detect a 3.5% absolute risk reduction in 90-day mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: All-cause mortality at 90 days.
    • Secondary Outcomes: Included the incidence of clinically important GI bleeding, new infections (pneumonia and C. difficile), and the composite of mortality or any clinically important event.

6. Key Results

  • Enrollment and Baseline: 3298 patients were randomized (1645 to pantoprazole and 1653 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. 510 of 1642 patients (31.1%) in the pantoprazole group died, compared with 499 of 1645 patients (30.4%) in the placebo group (p=0.76).
  • Secondary Outcomes: There was no significant difference in the incidence of clinically important GI bleeding (2.5% in the pantoprazole group vs. 4.2% in the placebo group). There were also no significant differences in the rates of pneumonia or C. difficile infection.
  • Adverse Events: The incidence of serious adverse events was similar in both groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a logistic regression model.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute mortality rates and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.76 for the primary outcome is much higher than the 0.05 threshold, indicating that the result was not statistically significant and very likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral, ARR and NNT are not applicable.
  • Subgroup Analyses: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The very large, multicenter, randomized, double-blind, placebo-controlled design is the gold standard and provided a massive amount of high-quality data.
  • Generalizability: The pragmatic design and inclusion of a very large, heterogeneous population of at-risk ICU patients make the findings highly generalizable to real-world practice.
  • Statistical Power: The enormous sample size provided definitive power to confidently rule out even a small but clinically important mortality benefit.
  • Patient-Centered Outcomes: The primary outcome of 90-day mortality is a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a very low risk of bias.
  • External Validity (Generalizability): The findings are highly generalizable to the broad population of critically ill patients.
  • Other: The overall rate of clinically important GI bleeding was lower than anticipated in the placebo group (4.2%), which may have made it more difficult to show a benefit from prophylaxis.

10. Conclusion of the Authors

  • The authors concluded that among adult patients in the ICU who were at risk for gastrointestinal bleeding, 90-day mortality and the incidence of clinically important events were not significantly lower with pantoprazole than with placebo.

11. To Summarize

  • Impact on Current Practice: This was a profoundly practice-changing trial. It provided definitive evidence that the routine, “one-size-fits-all” use of PPIs for stress ulcer prophylaxis in a general ICU population does not improve survival and provides only a small, non-significant reduction in GI bleeding, without the feared increase in infections.
  • Specific Recommendations:
    • Patient Selection: For the broad population of adult ICU patients.
    • Actionable Intervention: The results do not support the routine, universal use of proton-pump inhibitors for stress ulcer prophylaxis.
  • What This Trial Does NOT Mean: This trial does NOT mean that stress ulcer prophylaxis is never indicated. It may still be considered for very high-risk patients (e.g., those with coagulopathy and mechanical ventilation), but the threshold for its use should be much higher.
  • Implementation Caveats: The key takeaway is that for the majority of ICU patients, the benefit of routine PPI prophylaxis is negligible. This supports a more restrictive, targeted approach to this common intervention.

12. Context and Related Studies

  • Building on Previous Evidence: The PREVENT trial (2018) was designed to provide a definitive, high-quality answer to a question that was based on decades of dogma and older, less robust evidence.
  • Influence on Subsequent Research: The definitive neutral result of this trial, along with the subsequent SUP-ICU trial (2020), has been highly influential in shaping international guidelines, which now recommend a more restrictive and targeted approach to stress ulcer prophylaxis.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question is how to best identify the small subgroup of very high-risk patients who might still derive a net benefit from stress ulcer prophylaxis.
  • Future Directions: Future research is focused on developing better risk-stratification tools to guide a more personalized approach to stress ulcer prophylaxis in the ICU.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was of the highest relevance, testing a ubiquitous, routine clinical practice that lacked high-quality, modern evidence.
  • Methods: The very large, multicenter, double-blind RCT design was of the highest quality and was essential for providing a definitive answer. The pragmatic design ensured high external validity.
  • Results: The study reported a clear neutral finding for its primary outcome of mortality. It also found no significant difference in the key secondary outcomes of GI bleeding or infections.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The trial is a landmark in evidence-based critical care and a classic example of how a high-quality trial can be profoundly practice-changing by providing strong evidence to de-adopt a long-standing but ultimately ineffective routine therapy.

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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