Use of tocilizumab and sarilumab alone or in combination with corticosteroids for covid-19: systematic review and network meta-analysis

  1. Dena Zeraatkar
  2. Ellen Cusano
  3. Juan Pablo Díaz Martínez
  4. Anila Qasim
  5. Sophia Mangala
  6. Elena Kum
  7. Jessica Julia Bartoszko
  8. Tahira Devji
  9. Thomas Agoritsas
  10. Gordon Guyatt
  11. Ariel Izcovich
  12. Assem M Khamis
  13. Francois Lamontagne
  14. Bram Rochwerg
  15. Per Vandvik
  16. Romina Brignardello-Petersen
  17. Reed Alexander Cunningham Siemieniuk

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Abstract

To compare the effects of interleukin 6 receptor blockers, tocilizumab and sarilumab, with or without corticosteroids, on mortality in patients with covid-19.

Design

Systematic review and network meta-analysis.

Data sources

World Health Organization covid-19 database, a comprehensive multilingual source of global covid-19 literature, and two prospective meta-analyses (up to 9 June 2021).

Review methods

Trials in which people with suspected, probable, or confirmed covid-19 were randomised to interleukin 6 receptor blockers (with or without corticosteroids), corticosteroids, placebo, or standard care. The analysis used a bayesian framework and assessed the certainty of evidence using the GRADE approach. Results from the fixed effect meta-analysis were used for the primary analysis.

Results

Of 45 eligible trials (20 650 patients) identified, 36 (19 350 patients) could be included in the network meta-analysis. Of 36 trials, 27 were at high risk of bias, primarily due to lack of blinding. Tocilizumab, in combination with corticosteroids, suggested a reduction in the risk of death compared with corticosteroids alone (odds ratio 0.79, 95% credible interval 0.70 to 0.88; 35 fewer deaths per 1000 people, 95% credible interval 52 fewer to 18 fewer per 1000; moderate certainty of evidence), as did sarilumab in combination with corticosteroids, compared with corticosteroids alone (0.73, 0.58 to 0.92; 43 fewer per 1000, 73 fewer to 12 fewer; low certainty). Tocilizumab and sarilumab, each in combination with corticosteroids, appeared to have similar effects on mortality when compared with each other (1.07, 0.86 to 1.34; eight more per 1000, 20 fewer to 35 more; low certainty). The effects of tocilizumab (1.12, 0.91 to 1.38; 20 more per 1000, 16 fewer to 59 more; low certainty) and sarilumab (1.07, 0.81 to 1.40; 11 more per 1000, 38 fewer to 55 more; low certainty), when used alone, suggested an increase in the risk of death.

Conclusion

These findings suggest that in patients with severe or critical covid-19, tocilizumab, in combination with corticosteroids, probably reduces mortality, and that sarilumab, in combination with corticosteroids, might also reduce mortality. Tocilizumab and sarilumab, in combination with corticosteroids, could have similar effectiveness. Tocilizumab and sarilumab, when used alone, might not be beneficial.

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  1. Version published to 10.1136/bmjmed-2021-000036
  2. ScreenIT

    SciScore for 10.1101/2021.07.05.21259867: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    The database includes, but is not limited to the following bibliographic and grey literature sources: Medline (Ovid and PubMed), PubMed Central, Embase, CAB Abstracts, Global Health, PsycInfo, Cochrane Library, Scopus, Academic Search Complete, Africa Wide Information, CINAHL, ProQuest Central, SciFinder, the Virtual Health Library, LitCovid, WHO covid-19 website, CDC covid-19 website, Eurosurveillance, China CDC Weekly, Homeland Security Digital Library, ClinicalTrials.gov, bioRxiv (preprints), medRxiv (preprints), chemRxiv (preprints), and SSRN (preprints).
    Medline
    suggested: (MEDLINE, RRID:SCR_002185)
    PubMed
    suggested: (PubMed, RRID:SCR_004846)
    Embase
    suggested: (EMBASE, RRID:SCR_001650)
    PsycInfo
    suggested: (PsycINFO, RRID:SCR_014799)
    Cochrane Library
    suggested: (Cochrane Library, RRID:SCR_013000)
    bioRxiv
    suggested: (bioRxiv, RRID:SCR_003933)
    To assess risk of bias, reviewers, following training and calibration exercises, use a revision of the Cochrane tool for assessing risk of bias in randomized trials (RoB 2.0) (16).
    Cochrane tool
    suggested: None
    We produced network plots using the network map command of Stata version 17.0 (StataCorp, College Station, TX) with nodes weighted by the number of studies evaluating each treatment and edges weighted by the inverse variance of the direct estimate (18).
    StataCorp
    suggested: (Stata, RRID:SCR_012763)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Strengths and limitations: The strengths of this review include the comprehensive search and screening strategy. In addition to trials that we identified as part of our own search, we also included trials from two prospective meta-analyses that included an inception cohort of registered trials thereby minimizing the effects of publication bias (11, 15). Our findings are limited by the risk of bias of the trials, the majority of which were at high risk of bias due to lack of blinding. Lack of blinding may introduce bias through differences in co-interventions between randomized groups. We took a conservative approach and rated down the certainty of evidence for risk of bias. Some, including the linked WHO guideline panel, did not consider lack of blinding to be a serious concern for mortality, because it is an objective outcome (13). We only considered corticosteroid use at the time of randomization and some patients probably received corticosteroids after randomization, but were considered in this review not to have received concomitant corticosteroids. Whether or not IL-6 receptor blockers reduce mortality when not co-administered with corticosteroids remains uncertain. Four trials that we included in our systematic review were only available as preprint publications. Including preprints in meta-analyses may increase the precision of estimates, allow timely dissemination, and may minimize the effects of publication bias. It may, however, reduce the credibility of evidence sy...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2021.07.05.21259867v1 on medRxiv