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Mortality Rates Among Hospitalized Patients With COVID-19 Infection Treated With Tocilizumab and CorticosteroidsA Bayesian Reanalysis of a Previous Meta-analysis

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To identify the key insights or developments described in this article
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Key Points

Question  Can bayesian methods clarify the uncertainty around tocilizumab’s association with mortality benefit in subgroups of hospitalized patients with COVID-19 receiving corticosteroids?

Findings  In this bayesian reanalysis of a previous meta-analysis of 15 randomized clinical trials comprising 5339 hospitalized patients with COVID-19 treated with tocilizumab and corticosteroids, those receiving simple oxygen only or noninvasive ventilation were associated with a clinically meaningful mortality benefit. In contrast, for those receiving invasive mechanical ventilation, an association with benefit was uncertain.

Meaning  This study’s findings indicate that further research is needed to assess the association between mortality benefit or risk in patients with COVID-19 receiving invasive mechanical ventilation and treated with tocilizumab and corticosteroids.


Importance  A World Health Organization (WHO) meta-analysis found that tocilizumab was associated with reduced mortality in hospitalized patients with COVID-19. However, uncertainty remains concerning the magnitude of tocilizumab’s benefits and whether its association with mortality benefit is similar across respiratory subgroups.

Objective  To use bayesian methods to assess the magnitude of mortality benefit associated with tocilizumab and the differences between respiratory support subgroups in hospitalized patients with COVID-19.

Design, Setting, and Participants  A bayesian hierarchical reanalysis of the WHO meta-analysis of tocilizumab studies published in 2020 and 2021 was performed. Main results were estimated using weakly informative priors to exert little influence on the observed data. The robustness of these results was evaluated using vague and informative priors. The studies featured in the meta-analysis were randomized clinical tocilizumab trials of hospitalized patients with COVID-19. Only patients receiving corticosteroids were included.

Interventions  Usual care plus tocilizumab in comparison with usual care or placebo.

Main Outcomes and Measures  All-cause mortality at 28 days after randomization.

Results  Among the 5339 patients included in this analysis, most were men, with mean ages between 56 and 66 years. There were 2117 patients receiving simple oxygen only, 2505 receiving noninvasive ventilation (NIV), and 717 receiving invasive mechanical ventilation (IMV) in 15 studies from multiple countries and continents. Assuming weakly informative priors, the overall odds ratios (ORs) for survival were 0.70 (95% credible interval [CrI], 0.50-0.91) for patients receiving simple oxygen only, 0.81 (95% CrI, 0.63-1.03) for patients receiving NIV, and 0.89 (95% CrI, 0.61-1.22) for patients receiving IMV, respectively. The posterior probabilities of any benefit (OR <1) were notably different between patients receiving simple oxygen only (98.9%), NIV (95.5%), and IMV (75.4%). The posterior probabilities of a clinically meaningful association (absolute mortality risk difference >1%) were greater than 95% in patients receiving simple oxygen only and greater than 90% in patients receiving NIV. In contrast, the posterior probability of this clinically meaningful association was only approximately 67% in patients receiving IMV. The probabilities of tocilizumab superiority in the simple oxygen only subgroup compared with the NIV and IMV subgroups were 85% and 90%, respectively. Predictive intervals highlighted that only 72.1% of future tocilizumab IMV studies would show benefit. The conclusions did not change with different prior distributions.

Conclusions and Relevance  In this bayesian reanalysis of a previous meta-analysis of 15 studies of hospitalized patients with COVID-19 treated with tocilizumab and corticosteroids, use of simple oxygen only and NIV was associated with a probability of a clinically meaningful mortality benefit from tocilizumab. Future research should clarify whether patients receiving IMV also benefit from tocilizumab.

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Article Information

Accepted for Publication: January 11, 2022.

Published: February 28, 2022. doi:10.1001/jamanetworkopen.2022.0548

Correction: This article was corrected on March 22, 2022, to delete “(95% CI)” from the x-axis labels of Figures 1B and 2B.

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Albuquerque AM et al. JAMA Network Open.

Corresponding Author: James M. Brophy, MD, PhD, McGill Health University Center, 5252 Boul de Maisonneuve W, Room 2B.37, Montreal, QC H4A 3S5, Canada (james.brophy@mcgill.ca).

Author Contributions: Mr Albuquerque and Dr Brophy had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Albuquerque, Tramujas, Williams, Brophy.

Acquisition, analysis, or interpretation of data: Albuquerque, Sewanan, Brophy.

Drafting of the manuscript: Albuquerque, Sewanan, Williams.

Critical revision of the manuscript for important intellectual content: Albuquerque, Tramujas, Sewanan, Brophy.

Statistical analysis: Albuquerque, Sewanan, Williams, Brophy.

Supervision: Tramujas, Brophy.

Conflict of Interest Disclosures: Dr Tramujas participated as a subinvestigator in TOCIBRAS, a randomized clinical trial included in this article. No other disclosures were reported.

Funding/Support: Dr Brophy is a research scholar supported by Les Fonds de Recherche Québec Santé.

Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Information: The complete analysis code is available at https://github.com/arthur-albuquerque/tocilizumab_reanalysis.

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