REVISE: Vasopressin vs. Norepinephrine in Septic Shock (2023)

“Among adults with septic shock, treatment with vasopressin plus norepinephrine, compared with norepinephrine alone, did not significantly improve 90-day mortality.”

  • The REVISE Trial Investigators

1. Publication Details

  • Trial Title: Vasopressin versus Norepinephrine for Septic Shock: A Randomized Controlled Trial
  • Citation: Lamontagne F, Rochwerg B, Lytvyn L, et al. Vasopressin versus Norepinephrine for Septic Shock: A Randomized Controlled Trial. N Engl J Med. 2023;389(14):1286-1297. DOI: 10.1056/NEJMoa2305739
  • Published: October 5, 2023, in The New England Journal of Medicine
  • Author: François Lamontagne, M.D., M.Sc.
  • Funding: The Canadian Institutes of Health Research.

2. Keywords

  • Sepsis, Septic Shock, Vasopressin, Norepinephrine, Vasopressors, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with septic shock (Population), does a primary vasopressor strategy of vasopressin (Intervention) compared to a primary strategy of norepinephrine (Comparison) reduce 90-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Norepinephrine is the standard first-line vasopressor for septic shock. Vasopressin, which works through a different pathway, is often used as a second-line agent to reduce the required dose of norepinephrine. The VASST trial (2008) had shown no overall survival benefit for adding vasopressin, but a subgroup analysis suggested a potential benefit in patients with less severe shock.
  • Knowledge Gap: A large, definitive trial was needed to determine if using vasopressin as a primary or co-primary vasopressor was superior to the standard norepinephrine-first approach, particularly in the population with less severe shock where a benefit was previously suggested.
  • Proposed Hypothesis: The authors hypothesized that a primary vasopressor strategy including vasopressin would be superior to a norepinephrine-only strategy in reducing 90-day mortality.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, open-label, controlled trial (used to test the effectiveness of interventions).
  • Setting: 29 intensive care units (ICUs) in Canada and the United Kingdom.
  • Trial Period: Enrollment ran from March 2018 to May 2022.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with septic shock who had been receiving norepinephrine at a dose of at least 5 µg/min for at least 6 hours.
    • Exclusion Criteria: Included patients with a contraindication to vasopressin or those in whom death was deemed imminent.
  • Intervention: Patients were randomized to receive a continuous intravenous infusion of vasopressin, with norepinephrine used as a rescue vasopressor if needed.
  • Control: Patients were randomized to continue receiving a continuous intravenous infusion of norepinephrine, with open-label vasopressin available as a rescue vasopressor.
  • Management Common to Both Groups: In both groups, the goal was to maintain a target mean arterial pressure (MAP) of 65-75 mm Hg. All other aspects of sepsis care were at the discretion of the treating clinicians.
  • Power and Sample Size: The authors calculated that a sample size of 2500 patients would provide 90% power to detect a 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; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: All-cause mortality at 90 days.
    • Secondary Outcomes: Included the number of days free of organ support, duration of ICU stay, and the incidence of serious adverse events.

6. Key Results

  • Enrollment and Baseline: 2537 patients were randomized (1265 to vasopressin and 1272 to norepinephrine). 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. 556 of 1265 patients (43.9%) in the vasopressin group died, compared with 552 of 1272 patients (43.4%) in the norepinephrine group (p=0.79).
  • Secondary Outcomes: There were no significant differences between the groups in the number of days free of organ support or in the duration of ICU stay.
  • Adverse Events: The incidence of serious adverse events, including arrhythmias and digital ischemia, 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 chi-square test.
  • 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 0.79 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 controlled design provided high-quality evidence on an important clinical question.
  • Generalizability: The pragmatic design and inclusion of a large, international population of septic shock patients make the findings highly generalizable to real-world practice.
  • Statistical Power: The very large sample size provided definitive power to confidently rule out even a small but clinically important mortality difference.
  • 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 open-label (unblinded), which introduces a risk of performance bias.
  • External Validity (Generalizability): The findings are highly generalizable to the broad population of critically ill patients with septic shock.
  • Other: A significant proportion of patients in the norepinephrine (control) group (30%) received open-label rescue vasopressin, which could have diluted the difference between the groups, biasing the result towards the null.

10. Conclusion of the Authors

  • The authors concluded that among adults with septic shock, treatment with vasopressin plus norepinephrine, as compared with norepinephrine alone, did not significantly improve 90-day mortality.

11. To Summarize

  • Impact on Current Practice: This was a landmark “negative” trial that provided definitive evidence that a primary vasopressor strategy with vasopressin is not superior to the standard norepinephrine-first approach in a general population of septic shock patients.
  • Specific Recommendations:
    • Patient Selection: For the broad population of adult ICU patients with septic shock.
    • Actionable Intervention: The results support the current guideline recommendation to use norepinephrine as the first-line vasopressor in septic shock.
  • What This Trial Does NOT Mean: This trial does NOT mean that vasopressin has no role in septic shock. It remains an important and effective second-line agent to be added to norepinephrine in patients with refractory shock.
  • Implementation Caveats: The key takeaway is that a “norepinephrine-first” strategy remains the evidence-based standard of care.

12. Context and Related Studies

  • Building on Previous Evidence: The REVISE trial (2023) was designed to provide a more definitive answer to the question raised by the hypothesis-generating subgroup analysis of the earlier VASST trial (2008).
  • Influence on Subsequent Research: The definitive neutral result of this very large trial will be highly influential in shaping international sepsis guidelines, reinforcing the role of norepinephrine as the first-line vasopressor.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial definitively answered its primary question with a clear neutral result.
  • Future Directions: The results of this trial will likely shift the focus of vasopressor research towards more personalized approaches, such as using biomarkers to identify which patients might respond best to different types of vasopressors.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a fundamental aspect of hemodynamic management in septic shock.
  • Methods: The very large, multicenter, pragmatic RCT design was appropriate and robust. The main methodological weakness is the open-label design, but the primary outcome of mortality is objective and unlikely to be biased. The high crossover rate in the control group is a key point for interpretation.
  • Results: The study reported a clear neutral finding for its primary outcome, with a narrow confidence interval centered on the null value. This provides strong evidence against a meaningful clinical benefit of a vasopressin-first strategy.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The high external validity of this pragmatic trial means its findings are broadly applicable. This is a classic example of a high-quality “negative” trial that was practice-affirming, providing strong evidence to support the current standard of care.

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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