High-Flow Nasal Oxygen vs Noninvasive Ventilation in Patients With Acute Respiratory Failure: The RENOVATE Randomized Clinical Trial

Abstract

Importance: High-flow nasal oxygen (HFNO) and noninvasive ventilation (NIV) are commonly used respiratory support therapies for patients with acute respiratory failure (ARF).

Objective: To assess whether HFNO is noninferior to NIV on the rates of endotracheal intubation or death at 7 days in 5 patient groups with ARF.

Design, setting, and participants: This noninferiority, randomized clinical trial enrolled hospitalized adults (aged ≥18 years; classified as 5 patient groups with ARF: nonimmunocompromised with hypoxemia, immunocompromised with hypoxemia, chronic obstructive pulmonary disease [COPD] exacerbation with respiratory acidosis, acute cardiogenic pulmonary edema [ACPE], or hypoxemic COVID-19, which was added as a separate group on June 26, 2023) at 33 hospitals in Brazil between November 2019 and November 2023 (final follow-up: April 26, 2024).

Interventions: High-flow nasal oxygen (n = 883) or NIV (n = 883).

Main outcomes and measures: The primary outcome was endotracheal intubation or death within 7 days assessed using a bayesian hierarchical model with dynamic borrowing across patient groups. Noninferiority was defined by a posterior probability of 0.992 or greater for an odds ratio (OR) less than 1.55.

Results: Among 1800 patients, 1766 completed the study (mean age, 64 [SD, 17] years; 707 [40%] were women). The primary outcome of endotracheal intubation or death at 7 days occurred in 39% (344/883) in the HFNO group vs 38% (336/883) in the NIV group. In the immunocompromised with hypoxemia patient group, the primary outcome occurred in 57.1% (16/28) in the HFNO group vs 36.4% (8/22) in the NIV group; enrollment was stopped for futility (final OR, 1.07; 95% credible interval [CrI], 0.81-1.39; noninferiority posterior probability [NPP], 0.989). In the nonimmunocompromised with hypoxemia group, the primary outcome occurred in 32.5% (81/249) in the HFNO group vs 33.1% (78/236) in the NIV group (OR, 1.02 [95% CrI, 0.81-1.26]; NPP, 0.999). In the ACPE group, the primary outcome occurred in 10.3% (14/136) in the HFNO group vs 21.3% (29/136) in the NIV group (OR, 0.97 [95% CrI, 0.73-1.23]; NPP, 0.997). In the hypoxemic COVID-19 group, the primary outcome occurred in 51.3% (223/435) in the HFNO group vs 47.0% (210/447) in the NIV group (OR, 1.13 [95% CrI, 0.94-1.38]; NPP, 0.997). In the COPD exacerbation with respiratory acidosis group, the primary outcome occurred in 28.6% (10/35) in the HFNO group vs 26.2% (11/42) in the NIV group (OR, 1.05 [95% CrI, 0.79-1.36]; NPP, 0.992). However, a post hoc analysis without dynamic borrowing across the 5 ARF patient groups revealed some qualitatively different results in patients with COPD, immunocompromised patients, and patients with ACPE. The incidence of serious adverse events was similar (9.4% of patients in HFNO group vs 9.9% in NIV group).

Conclusions and relevance: 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. However, the small sample sizes in some patient groups and the sensitivity of the findings to the choice of analysis model suggests the need for further study in patients with COPD, immunocompromised patients, and patients with ACPE.

Trial registration: ClinicalTrials.gov Identifier: NCT03643939.

Figure 1.. Enrollment, Randomization, and Follow-Up in the Study

^aInvestigators registered all patients assessed for eligibility during the trial period; however, they did not collect data on the total number of potentially eligible patients. ^bPatients may have met more than 1 reason for exclusion. Detailed counts of individual exclusions stratified by the selected patient groups with acute respiratory failure appear in the eMethods and in eFigures 2-5 in Supplement 1. ^cPatients or next of kin were asked to provide consent after randomization. The reason for postrandomization exclusion was death before their next of kin could provide consent and lack of authorization from the ethics committee to include the data. ^dDelivered through a nasal cannula with larger-bore tubing. ^eNoninvasive positive-pressure ventilation delivered through a face mask using either a ventilator in the intensive care unit or a bilevel device.

Figure 2.. Primary Outcome of Endotracheal Intubation or Death Within 7 Days

^aIncludes all randomized patients with informed consent. The primary outcome was analyzed with a bayesian hierarchical modeling with dynamic borrowing across the 5 patient groups with acute respiratory failure. More borrowing occurs when the groups are consistent, and less borrowing occurs when the groups differ. Borrowing via a hierarchical model is a type of shrinkage estimation (it provides a formal mechanism by which extreme observations are shrunk toward the mean). The model is a compromise between the extremes of a completely pooled analysis as opposed to a separate analysis in each group. ^bOdds of requiring endotracheal intubation or dying within 7 days in the high-flow nasal oxygen group vs the noninvasive ventilation group. ^cA bayesian approach based on posterior probabilities was used to test the noninferiority and superiority hypotheses with predefined thresholds. ^dDefined as a posterior probability greater than 0.992 that the odds ratio was less than 1.55. For each patient group with acute respiratory failure, noninferiority was declared if the posterior probability was greater than 0.992. If noninferiority was not demonstrated, the final result was futility. ^eDefined as a posterior probability greater than 0.992 that the odds ratio was less than 1. If noninferiority was demonstrated, then superiority was declared if the superiority posterior probability was also higher than 0.992. ^fThe same bayesian model structure was used as in the primary analysis, but without borrowing. Although borrowing can improve precision under the assumption of similar treatment effects, it could also produce biased estimates when there is heterogeneity across groups.