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

Abstract

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.

Figure 1.. Posterior Distributions and Probabilities Assuming Weakly Informative Priors

Results of the meta-analysis assuming weakly informative priors: posterior distributions and probabilities of each subgroup. An odds ratio (OR) lower than 1 indicates reduced mortality owing to tocilizumab in comparison with control treatment. A, Posterior distributions, in which point estimates (black solid-circle data markers) depict the median and interval bars represent the 95% credible (highest-density) intervals (CrIs). B, Cumulative posterior probabilities, which correspond to the probabilities that the OR is lower than or equal to the effect size on the x-axis (X). C through E, Posterior distributions in the risk difference scale (control minus tocilizumab risk) across plausible ranges of mortality risk under control treatment for each subgroup (solid lines represent the median, and shaded areas represent the 95% CrIs). Vertical dashed lines represent the assumed mean risk under control treatment in each subgroup (eMethods in the Supplement). A risk difference greater than 0 indicates reduced mortality owing to tocilizumab in comparison with control treatment. Underlying weakly informative priors are normal, mean (SD) of 0 (0.82) for coefficients and half-normal of 0.5 for the between-study standard deviation.

Figure 2.. Posterior Predictive Distributions and Probabilities Assuming Weakly Informative Priors

Posterior predictive distributions and probabilities of each subgroup. A, Posterior predictive distributions, in which point estimates (black solid-circle data markers) depict the median, and interval bars represent the 95% credible (highest-density) intervals (CrIs). B, Cumulative posterior probabilities, which correspond to the probabilities that future studies (specific to each subgroup) will find a point estimate lower than or equal to the effect size on the x-axis (X). Underlying weakly informative priors are normal, mean (SD) of 0 (0.82) for coefficients and half-normal of 0.5 for the between-study standard deviation. OR indicates odds ratio.

Figure 3.. Posterior Distributions and Probabilities From Normal Conjugate Analyses on the Invasive Mechanical Ventilation Subgroup

Results for the invasive mechanical ventilation subgroup from meta-analyses using an informative prior based on simulated randomized clinical trials (eTable 5 in the Supplement). “(Current) 717” depicts the results previously shown in Figure 1A and B for this subgroup. A, Posterior distributions for each separate meta-analysis. The y-axis depicts the number of total patients receiving invasive mechanical ventilation included in each respective model (current plus simulated patients). Point estimates (black solid-circle data markers) depict the median, and interval bars represent the 95% credible (highest-density) intervals (CrIs). The vertical dashed line represents a 0.77 odds ratio (OR; World Health Organization Rapid Evidence Appraisal for COVID-19 Therapies Working Group mean result for tocilizumab- and corticosteroid-treated patients). This value is the mean OR underlying the generated randomized clinical trials (eTable 5 in the Supplement). B, Posterior probability of benefit for different thresholds (OR <1.0 and <0.9). Underlying weakly informative priors are normal, mean (SD) of 0 (1.5) for coefficients and half-normal of 0.5 for the between-study standard deviation.