RENOVATE: High-Flow Nasal Oxygen vs. Noninvasive Ventilation in Acute Respiratory Failure (2024)

“Compared with NIV, HFNO met prespecified criteria for noninferiority for the primary outcome of endotracheal intubation or death within 7 days in 4 of the 5 patient groups with ARF.” — The RENOVATE Investigators

1. Publication Details

  • Trial Title: High-Flow Nasal Oxygen vs Noninvasive Ventilation in Patients With Acute Respiratory Failure: The RENOVATE Randomized Clinical Trial
  • Citation: Maia IS, Kawano-Dourado L, et al, for the RENOVATE Investigators and the BRICNet. High-Flow Nasal Oxygen vs Noninvasive Ventilation in Patients With Acute Respiratory Failure: The RENOVATE Randomized Clinical Trial. JAMA. 2024;333(10):875–890.
  • Published: December 10, 2024 (online), in JAMA
  • Author: Israel S. Maia, MD
  • Funding: Brazilian Ministry of Health

2. Keywords

  • Acute Respiratory Failure (ARF), High-Flow Nasal Oxygen (HFNO), Noninvasive Ventilation (NIV), Critical Care, Mechanical Ventilation, Hypoxemia

3. The Clinical Question

  • In adult patients with various types of acute respiratory failure (ARF) (Population), is initial treatment with high-flow nasal oxygen (HFNO) (Intervention) non-inferior to noninvasive ventilation (NIV) (Comparison) for preventing the composite outcome of endotracheal intubation or death within 7 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Both HFNO and NIV are commonly used as first-line noninvasive respiratory support to prevent the need for invasive mechanical ventilation in patients with ARF. While NIV is well-established for certain conditions like COPD exacerbations and cardiogenic pulmonary edema, the optimal initial strategy across the broad spectrum of ARF causes is unclear.
  • Knowledge Gap: There was a need for a large, robust trial directly comparing HFNO and NIV across different etiologies of ARF to determine if the simpler, more comfortable HFNO was a non-inferior alternative to NIV.
  • Proposed Hypothesis: The investigators hypothesized that HFNO would be non-inferior to NIV in reducing the rate of endotracheal intubation or death within 7 days across five distinct subgroups of patients with ARF.

5. Study Design and Methods

  • Design: Multicenter, adaptive, non-inferiority, randomized clinical trial.
  • Setting: 33 hospitals in Brazil.
  • Trial Period: November 2019 to November 2023.
  • Population:
    • Inclusion Criteria: Hospitalized adults (≥18 years) with ARF, classified into one of five predefined groups: (1) non-immunocompromised with hypoxemia, (2) immunocompromised with hypoxemia, (3) COPD exacerbation with respiratory acidosis, (4) acute cardiogenic pulmonary edema (ACPE), and (5) hypoxemic COVID-19.
    • Exclusion Criteria: Immediate need for intubation, Glasgow Coma Scale score ≤ 12, cardiorespiratory arrest, severe hemodynamic instability.
  • Intervention: High-flow nasal oxygen (HFNO).
  • Control: Noninvasive ventilation (NIV) delivered via facemask.
  • Management Common to Both Groups: Both interventions were managed according to a standardized protocol for settings, titration, and weaning. Clear criteria were established for treatment failure leading to intubation.
  • Outcomes:
    • Primary Outcome: A composite of endotracheal intubation or death within 7 days of randomization.
    • Secondary Outcomes: 28-day and 90-day mortality, ICU-free days, and mechanical ventilation-free days at 28 days.
    • Tertiary Outcomes: Patient comfort, hospital length of stay, and vasopressor-free days.

6. Key Results

  • Enrollment and Baseline: 1,766 patients were included in the final analysis (883 in the HFNO group, 883 in the NIV group). Baseline characteristics were well-matched between the groups.
  • Trial Status: The trial was completed. Enrollment was stopped early for futility in the immunocompromised group and for non-inferiority in several other groups as per the adaptive design.
  • Primary Outcome: Overall, the primary outcome occurred in 39% of the HFNO group and 38% of the NIV group. HFNO was found to be non-inferior to NIV in four of the five subgroups: non-immunocompromised hypoxemia, COPD with acidosis, ACPE, and hypoxemic COVID-19. The trial was stopped for futility in the immunocompromised hypoxemia group.
  • Secondary Outcomes: There were no significant differences in 28-day or 90-day mortality, or in ICU-free or ventilator-free days between the HFNO and NIV groups.
  • Adverse Events: The incidence of serious adverse events was similar in both groups. Patients reported significantly better comfort with HFNO compared to NIV.

7. Medical Statistics

  • Analysis Principle: The primary outcome was assessed using a Bayesian hierarchical model with dynamic borrowing of information across the five patient groups.
  • Statistical Tests Used: Bayesian hierarchical modeling.
  • Primary Outcome Analysis: Comparison of the composite of endotracheal intubation or death within 7 days.
  • Key Statistic(s) Reported: Non-inferiority was met if the posterior probability for an odds ratio (OR) < 1.55 was 0.992 or greater. This was achieved in 4 of the 5 groups. For example, in the non-immunocompromised hypoxemic group, the OR was 1.02 (95% Credible Interval, 0.81-1.26) with a non-inferiority posterior probability of 0.999.
  • Interpretation of Key Statistic(s):
    • Odds Ratio (OR) / Credible Interval (CrI):
      • Calculation: OR 1.02 (95% CrI, 0.81-1.26) for non-immunocompromised hypoxemia.
      • Clinical Meaning: The odds of intubation or death were essentially identical between the HFNO and NIV groups. The credible interval is narrow and centered around 1, indicating no significant difference.
  • Clinical Impact Measures: Not applicable in the traditional sense for a non-inferiority trial.
  • Subgroup Analyses: The trial was designed with five primary analysis groups. Non-inferiority was met in all except the immunocompromised group.

8. Strengths of the Study

  • Study Design and Conduct: This was a large, multicenter, randomized trial with a sophisticated adaptive design that allowed for efficient evaluation across multiple distinct patient populations.
  • Pragmatic Approach: The trial addressed a common and important clinical question, comparing two widely used therapies in a real-world setting.
  • Patient-Centered Outcomes: The inclusion of patient comfort as an outcome is a notable strength.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The open-label design is an inherent limitation when comparing two different interfaces, which could lead to performance bias.
  • Subgroup Power: Some of the subgroups (e.g., COPD and immunocompromised) had small sample sizes, which limits the certainty of the conclusions for those specific populations.
  • Other: A post-hoc analysis without the Bayesian dynamic borrowing showed some different results, highlighting the sensitivity of the findings to the statistical model chosen.

10. Conclusion of the Authors Compared with NIV, HFNO met the prespecified criteria for non-inferiority for the primary outcome of endotracheal intubation or death within 7 days in four of the five studied groups of patients with acute respiratory failure (non-immunocompromised hypoxemia, COPD, ACPE, and COVID-19).

11. To Summarize

  • Impact on Current Practice: This trial provides strong evidence that HFNO is a reasonable and effective first-line respiratory support strategy for most patients with ARF, and is not inferior to NIV. Given its superior comfort, it may be preferred as the initial approach.
  • Specific Recommendations:
    • Patient Selection: For patients with acute hypoxemic respiratory failure (including COVID-19), COPD exacerbation, or ACPE, initiating noninvasive support with HFNO is an acceptable alternative to NIV.
    • Actionable Intervention: Consider HFNO as a first-line therapy for most forms of ARF, with close monitoring for failure.
  • What This Trial Does NOT Mean: The results do not support the use of HFNO over NIV in immunocompromised patients with hypoxemic ARF, where the trial was stopped for futility. Clinical judgment is still required, and patients who fail to improve on HFNO should be escalated to NIV or intubation promptly.

12. Context and Related Studies

  • Building on Previous Evidence: This trial significantly expands on previous studies like the FLORALI trial by including a broader range of ARF etiologies and directly comparing HFNO to NIV, rather than just standard oxygen therapy. It provides the most comprehensive head-to-head comparison to date.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal strategy for immunocompromised patients with ARF remains uncertain. Further clarification is also needed for the COPD and ACPE subgroups, given their smaller sample sizes in this trial.
  • Future Directions: Future research could focus on identifying which patients are most likely to fail HFNO and require earlier escalation of support.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: A highly relevant and pragmatic question for clinicians in emergency medicine, hospital medicine, and critical care.
  • Methods: The adaptive randomized trial design was innovative and efficient. The primary outcome was patient-important and objective.
  • Results: The results clearly demonstrate non-inferiority in most major subgroups of ARF.
  • Conclusions and Applicability: The conclusions are well-supported by the data. The findings are broadly applicable to the initial management of undifferentiated respiratory failure in a variety of hospital settings.

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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