Clinical and methodological considerations from the RENOVATE trial

We thank the editorialists for their insightful appraisal of the RENOVATE trial (1). We provide the following clarifications to ensure accurate interpretation of our findings.

Interpretation of chronic obstructive pulmonary disease (COPD) exacerbation with respiratory acidosis results

We agree that the COPD exacerbation with respiratory acidosis cohort in RENOVATE was small, and as stated in our manuscript, definitive phenotype-specific conclusions cannot be drawn for this subgroup. However, the editorial’s suggestion that the COPD results were “unexpected” or inconsistent with prior evidence requires additional context. Non-invasive ventilation failure rates of 20–30% in hypercapnic COPD are not unprecedented in Brazil. In the multicenter study by Azevedo et al. (2), 54% of patients treated with non-invasive ventilation (NIV) required intubation, with a median Simplified Acute Physiology Score (SAPS) 3 of 62, corresponding to an estimated mortality of 52% in South American settings. This reflects the severity of disease and the high baseline risk of treatment failure in real-world cohorts.

In RENOVATE, baseline severity was substantial: median SAPS 3 was 58 [interquartile range (IQR), 51–63.8], 14.3% required vasopressors, and 19% had heart failure. Within 7 days, 23.4% required vasopressors and 21.4% required sedatives such as dexmedetomidine and propofol (9.5%), markers of treatment intolerance that were largely absent in older COPD trials (3). Furthermore, some patients were enrolled during the coronavirus disease 2019 (COVID-19) pandemic, a period characterized by delayed hospital presentation and higher severity. These factors, combined with an NIV intolerance rate of 31%, help explain the higher NIV failure rate observed in RENOVATE.

The editorial also highlights the “unequal dose” of respiratory support. However, this reflects established practice rather than imbalance: high-flow nasal cannula (HFNC) is typically continuous, whereas NIV is delivered in intermittent, time-limited sessions. In RENOVATE, although NIV was recommended continuously in the first 24 hours, only a minority of patients tolerated the therapy as planned. In Plant et al. (3), NIV exposure was 8 hours on day 1, 7 hours on day 2, and 5 hours on day 3, values virtually very similar to our cohort. Thus, the shorter “dose” of NIV in RENOVATE is not a design artifact but a known feature of real-world NIV administration.

Escalation from HFNC to NIV (23%) should likewise not be interpreted as protocol weakness. Actually, we avoid using the term cross-over, which suggests protocol violation, because among COPD patients who did not improve with initial HFNC, our protocol suggested a trial of NIV before moving to tracheal intubation. Comparable crossover rates were seen in previous COPD trials and reflect standard rescue practice (4,5).

We acknowledge the single-center randomized controlled trial (RCT) by Tan et al. reporting higher intubation with HFNC in COPD with moderate acidosis. However, its monocentric design and limited sample size constrain generalizability. Two other RCTs did not show increased treatment failure with HFNC, aligning more closely with the neutral signal observed in RENOVATE (4,5). Taken together, current evidence does not support a consistent harm signal for HFNC in COPD and highlights the need for larger, multicenter, phenotype-specific trials.

Dynamic borrowing and exchangeability

The editorial appropriately notes that dynamic borrowing assumes approximate exchangeability among subgroups (1,6). We acknowledged this as an assumption and, for that reason, the RENOVATE design incorporated explicit safeguards against over-borrowing in the presence of heterogeneity.

First, the hierarchical Bayesian model did not enforce full exchangeability. Instead, it used a mixture-model structure that averages across several possible clustering configurations, including the possibility that groups behave differently. This allows information to be shared adaptively rather than uniformly, mitigating the risk that truly distinct subgroups (such as hypercapnic vs. hypoxemic patients) are forced toward a common effect.

Second, posterior-probability thresholds for non-inferiority and superiority were made deliberately more conservative at all interim analyses. These stricter thresholds were selected to preserve type I error when exchangeability is imperfect, reducing the likelihood of premature or inappropriate non-inferiority declarations due to shrinkage toward the overall mean.

The borrowing model underwent extensive simulation, showing type I error consistently controlled below 0.025 across all acute respiratory failure (ARF) phenotypes. In contrast, no-borrowing analyses are known to be underpowered and imprecise in small strata once no pre-specified simulation was done specifically for this purpose. Applying the same stopping criteria without borrowing would likely increase type I error and increase the probability of stopping on random extremes (benefit or futility), especially in the COPD subgroup.

In summary, the RENOVATE statistical design was specifically engineered to be robust to partial violations of exchangeability, combining adaptive clustering and conservative decision thresholds. Given the extensive simulation and the instability of subgroup estimates without borrowing, we believe the borrowing-based analysis provides the most reliable overall estimate in this heterogeneous context.

Justification for the non-inferiority margin

The 10% absolute non-inferiority margin was selected using a fixed-margin approach grounded in prior evidence showing an absolute 36% effect of NIV on intubation (7,8). Following established methodological guidance that margins should not exceed half the established effect, we selected 10% (9). This aligns with margins used in other high-stakes ARF or intubation-related trials (5,10-13), all of which used margins of 7–10%.

To ensure comparability across groups with different baseline risks, this absolute margin was translated into a relative margin [odds ratio (OR) =1.55], preserving proportionality in lower-risk groups such as acute cardiogenic pulmonary edema or COPD. Evidence from orotracheal intubation-focused non-inferiority trials and survey of clinician acceptability further supports 10% as a reasonable and clinically accepted threshold (14,15).

Generalizability to obesity hypoventilation syndrome and do-not-intubate (DNI) patients

RENOVATE aimed to assess the comparative effectiveness of HFNC versus NIV in a broad range of patients with ARF while simultaneously being able to offer valid estimates of effect for specific subtypes of patients. Nevertheless, as the editorialists point out, not every possible type of ARF patient was enrolled. Thus, generalizability is limited for obesity hypoventilation syndrome, and patients with do not intubate orders, who were not a target population of the trial.

When is HFNC an appropriate first-line option?

RENOVATE provides strong evidence supporting HFNC as a safe first-line option for de novo hypoxemic ARF, including patients with COVID-19 and those with mild and moderate acute cardiogenic pulmonary edema. For phenotypes requiring substantial ventilatory unloading, such as COPD, obesity hypoventilation, and other hypercapnic states, evidence remains limited. Larger, dedicated studies are needed to define the optimal role of HFNC in acute-on-chronic hypercapnic respiratory failure.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Thoracic Disease. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2681/coif). I.S.M. has received grant for the Renovate trial from Brazilian Ministry of Health PROADI-SUS; and received fees for lectures, support for meetings, sites devices distribution and travel from Fisher&Paykel Healthcare, and participation in the Brazilian Intensive Care Research Network as a Scientific Director. A.B.C. declares that his institution has received grant for the Renovate Trial from Brazilian Ministry of Health. Fisher&Paykel Healthcare has provided all the HFNC devices for the Renovate Trial which he is part of the Steering Committee. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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