High-flow nasal oxygen vs noninvasive ventilation in patients with Acute Respiratory Failure

High-flow nasal oxygen (HFNC) and noninvasive ventilation (NIV) are commonly used to manage acute respiratory failure in various clinical conditions. Strong evidence supports the efficacy of NIV in treating exacerbations of chronic obstructive pulmonary disease (COPD) and acute cardiogenic pulmonary edema (ACPE), while HFNC is encouraged for patients with hypoxemic acute respiratory failure. However, the comparative effectiveness of HFNC and NIV is still debated in this context.

RENOVATE is a large, multicenter, randomised trial that tested in the intensive care unit the noninferiority of first-line high-flow nasal oxygen compared to facemask noninvasive ventilation in acute respiratory failure of different etiologies: non-immunocompromised hypoxemic, immunocompromised hypoxemic, COPD exacerbation with respiratory acidosis, acute cardiogenic pulmonary oedema, and hypoxemic COVID-19.

This clinical trial was conducted in 33 hospitals in Brazil from November 2019 to November 2023. Adult patients admitted with acute respiratory failure were eligible, excluding those with urgent need for endotracheal intubation, contraindications to noninvasive ventilation or other forms of acute respiratory failure. Out of the 2731 patients assessed, 1800 were included in the analysis, categorised as 501 non-

immunocompromised hypoxemic, 51 immunocompromised hypoxemic, 79 with COPD exacerbation, 274 with ACPE, and 895 with COVID-19.

Before randomisation, the use of low-flow oxygen was permitted, and NIV could be used for up to 6 hours, except for patients with ACPE. Patients were then randomly assigned in a 1:1 ratio to receive either HFNC or NIV. In case of clinical worsening, endotracheal intubation was required, except for COPD and ACPE patients on HFNC, who were allowed NIV rescue therapy for up to 1 hour before considering intubation. If a response to treatment was observed, weaning could be started after 24 hours.

The primary outcome was a composite endpoint including endotracheal intubation or death within 7 days. The trial employed Bayesian adaptive statistical methods to evaluate the primary outcome, using hierarchical modelling with dynamic borrowing across the five groups. The noninferiority margin was based on a meta-analysis showing a 36% absolute effect of NIV compared to low-flow oxygen in reducing intubation rates. An absolute difference of 10% was chosen for the margin, converted to the Odds Ratio based on a 30% event rate. Noninferiority and/or superiority were established if the posterior probability exceeded 0.992, with an OR < 1.55 for noninferiority and OR < 1 for superiority. Interim analyses allowed stopping of groups based on futility, noninferiority, or superiority.

Noninferiority was reached in the non-immunocompromised hypoxemic (OR 1.02, [95%CrI, 0.81-1.26]; noninferiority posterior probability 0.999), COPD (OR 1.05, [95%CrI, 0.79-1.36]; noninferiority posterior probability 0.992), ACPE (OR 0.97, [95%CrI, 0.73-1.23]; noninferiority posterior probability 0.997), and COVID-19 groups (OR 1.13, [95%CrI, 0.94-1.38]; noninferiority posterior probability 0.997) with Bayesian analysis. However, noninferiority was not confirmed for the COPD group in the post hoc analysis without dynamic borrowing (OR 1.48, [95%CrI, 0.67-3.09]; noninferiority posterior probability 0.549). In the immunocompromised hypoxemic group, enrollment was stopped in April 2021 for evidence of futility.

None of the secondary outcomes (28-day mortality, 90-day mortality, mechanical ventilation-free days at 28 days, ICU-free days at 28 days) showed significant differences across the groups.
For tertiary outcomes, comfort was superior with HFNC. At the same time, no differences were observed for hospital LOS and ICU LOS within 90 days, vasopressor-free days within 28 days, and the proportion of patients receiving a do-not-intubate order within 7 days.

STUDY STRENGTHS & LIMITATIONS

Strengths

• Large-scale, randomised multicenter design: The involvement of multiple hospitals enhances the external validity and applicability across several clinical settings.
• Randomised design: This ensured well-matched baseline characteristics between the treatment groups, minimising potential confounding factors and allowing for a robust comparison of the two interventions.
• Well-defined protocol: A comprehensive protocol and strict monitoring of patients, including specific guidelines for setting, titration and weaning criteria, ensured consistency in treatment.
• Comprehensive outcomes: A broad range of outcomes were examined, providing important insights into the long-term implications of the treatments.

Limitations

• Open-label design: The trial was unblinded for both patients and clinicians, which could introduce bias, as varying expertise among personnel from different hospitals may lead to differences in the treatment provided. This is unavoidable in trials assessing noninvasive support.
• Comparator choice: The trial compared HFNC to facemask NIV, which represents the optimal treatment exclusively for patients with COPD and ACPE. However, these subgroups were underpowered in this study, limiting the generalizability of the findings for these patients. This is further highlighted by post hoc analyses without dynamic borrowing, which failed to demonstrate noninferiority in the two groups.
• Intubation criteria: Endotracheal intubation could be considered according to criteria which are not universally accepted, potentially introducing subjectivity in the decision-making process. This lack of standardisation may have limited the ability to draw definitive conclusions on the impact of the interventions.
• Composite primary outcome: The primary outcome of intubation or death within 7 days carries differing significance. Initial calculations of the noninferiority margin were based exclusively on intubation rates, but the primary outcome was revised in April 2021 (fifth version of the protocol) to include mortality. Hence, alternative calculations might have provided a clearer comparison between HFNC and NIV.
  Furthermore, the association of mortality and intubation in a composite outcome may divert attention from the clinical benefits in practice. For instance, enrolment of immunocompromised hypoxemic patients was stopped early due to demonstration of futility. However, separate analysis of intubation and death revealed a higher intubation rate with HFNC, but comparable mortality rates.
• Different sample sizes: While the larger sample size in the hypoxemic and COVID-19 groups supports the noninferiority of HFNC, results for the smaller COPD and ACPE groups should be interpreted with prudency. The adaptive design and Bayesian borrowing did not provide definitive conclusions for the smaller groups, and post hoc analysis without dynamic borrowing did not confirm noninferiority in COPD.
• Exclusion of ACPE cases: Patients with ACPE who received NIV prior to randomisation were not included. This may raise concerns that patients with more severe forms of ACPE have been excluded from the study. Thus, characterizing the clinical severity of the enrolled patients would have been useful in this context.
• Late separation of COVID-19 Cases: During the fifth interim analysis patients with COVID-19 were moved to a specific subgroup that that was not present in the initial protocol. This also required a retrospective re-analysis of cases that had previously been included in other subgroups.

TAKE-HOME MESSAGES

The RENOVATE Trial demonstrates the noninferiority of HFNC to facemask NIV in preventing intubation and death within 7 days, particularly in non-immunocompromised hypoxemic and COVID-19 patients in the intensive care unit, where strict monitoring and prompt intubation are feasible.

This article review was prepared and submitted by Dr Gaia Tempo and Dr Domenico Luca Grieco, Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, Rome (Italy), on behalf of ESICM Review Club.