Effect of tocilizumab, sarilumab, and baricitinib on mortality among patients hospitalized for COVID-19 treated with corticosteroids: a systematic review and meta-analysis

Abstract

Background: Randomized controlled trials (RCT) established the mortality reduction by tocilizumab (Actemra), baricitinib (Olumiant), and sarilumab (Kevzara) in hospitalized COVID-19 patients. However, uncertainty remains about which treatment performs best in patients receiving corticosteroids.

Objectives: To estimate probabilities of noninferiority between baricitinib and sarilumab compared to tocilizumab in patients treated with corticosteroids.

Data sources: PubMed, Embase, Cochrane Library, and MedRxiv.

Study eligibility criteria: Eligible RCTs assigning hospitalized adults with COVID-19 treated with corticosteroids to tocilizumab or baricitinib or sarilumab versus standard of care or placebo (control).

Methods: Reviewers independently abstracted published data and assessed study quality with the Risk of Bias 2 tool. Unpublished data, if required, were requested from authors of included studies. The outcome of interest was all-cause mortality at 28 days.

Participants: Twenty-seven RCTs with 13 549 patients were included. Overall, the risk of bias was low. Bayesian pairwise meta-analyses were used to aggregate results of each treatment versus control. The average odds ratio for mortality was 0.78 (95% credible interval [CrI]: 0.65, 0.94) for tocilizumab; 0.78 (95% CrI: 0.56, 1.03) for baricitinib; and 0.91 (95% CrI: 0.60, 1.40) for sarilumab. The certainty of evidence (GRADE) ranged from moderate to low. Bayesian meta-regressions with multiple priors were used to estimate probabilities of noninferiority (margin of 13% greater effect by tocilizumab). Compared to tocilizumab, there were ≤94% and 90% probabilities of noninferiority with baricitinib and sarilumab, respectively.

Results: All but two studies included data with only indirect evidence for the comparison of interest.

Conclusions: Among hospitalized COVID-19 treated with corticosteroids, there are high probabilities that both baricitinib and sarilumab are associated with similar mortality reductions in comparison to tocilizumab.

Keywords: Baricitinib; COVID-19; Corticosteroids; Mortality; Sarilumab; Tocilizumab.

Fig. 1

Preferred Items for Systematic Reviews and Meta-analyses 2020 flow diagram.

Fig. 2

Meta-analyses: Forest plots of Bayesian random-effect meta-analyses of tocilizumab, baricitinib, or sarilumab versus control (three separate models). Black diamonds represent median and 95% credible intervals of posterior overall results. Purple diamonds represent the 95% prediction intervals of posterior predictive distributions. The median and 95% credible intervals of the between-study SD parameter (tau) are displayed on the left bottom corner of each forest plot. RE, random effect; CrI, credible interval; PI, prediction interval. Underlying prior distributions: average effect parameter, Normal (0, 0.75²); between-study standard deviation parameter, Log-Normal (-1.975, 0.67²).

Fig. 3

Meta-regressions: Indirect comparisons of therapy effects: Ratio of odds ratios between tocilizumab and baricitinib (left panel) or tocilizumab and sarilumab (right panel). Colour-filled curves represent the posterior distributions. Colour-filled areas represent the posterior probability of noninferiority (Pr < 1.14), as the percentages on top of each figure. Interval bars depict the posterior median and 95% credible intervals. Solid gray lines represent underlying prior distributions. Each belief is labeled on top of each figure. Underlying prior distributions for baricitinib versus tocilizumab results: “skeptical,” normal (0, 0.354²); “optimistic for baricitinib (Karampitsakos et al.)," normal (-0.335, 0.264²); “optimistic for tocilizumab (inverse Karampitsakos et al.)," normal (0.335, 0.264²); “vague,” normal(0, 4²); Underlying prior distributions for sarilumab versus tocilizumab results: “skeptical,” normal (0, 0.354²); “optimistic for sarilumab (REMAP-CAP)," normal (-0.049, 0.118²); “optimistic for tocilizumab (inverse REMAP-CAP)," normal (0.049, 0.118²); “vague,” normal (0, 4²).