Association between tocilizumab, sarilumab and all-cause mortality at 28 days in hospitalised patients with COVID-19: A network meta-analysis

  1. Peter J. Godolphin
  2. David J. Fisher
  3. Lindsay R. Berry
  4. Lennie P. G. Derde
  5. Janet V. Diaz
  6. Anthony C. Gordon
  7. Elizabeth Lorenzi
  8. John C. Marshall
  9. Srinivas Murthy
  10. Manu Shankar-Hari
  11. Jonathan A. C. Sterne
  12. Jayne F. Tierney
  13. Claire L. Vale

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Abstract

A recent prospective meta-analysis demonstrated that interleukin-6 antagonists are associated with lower all-cause mortality in hospitalised patients with COVID-19, compared with usual care or placebo. However, emerging evidence suggests that clinicians are favouring the use of tocilizumab over sarilumab. A new randomised comparison of these agents from the REMAP-CAP trial shows similar effects on in-hospital mortality. Therefore, we initiated a network meta-analysis, to estimate pairwise associations between tocilizumab, sarilumab and usual care or placebo with 28-day mortality, in COVID-19 patients receiving concomitant corticosteroids and ventilation, based on all available direct and indirect evidence.

Methods

Eligible trials randomised hospitalised patients with COVID-19 that compared tocilizumab or sarilumab with usual care or placebo in the prospective meta-analysis or that directly compared tocilizumab with sarilumab. Data were restricted to patients receiving corticosteroids and either non-invasive or invasive ventilation at randomisation.

Pairwise associations between tocilizumab, sarilumab and usual care or placebo for all-cause mortality 28 days after randomisation were estimated using a frequentist contrast-based network meta-analysis of odds ratios (ORs), implementing multivariate fixed-effects models that assume consistency between the direct and indirect evidence.

Findings

One trial (REMAP-CAP) was identified that directly compared tocilizumab with sarilumab and supplied results on all-cause mortality at 28-days. This network meta-analysis was based on 898 eligible patients (278 deaths) from REMAP-CAP and 3710 eligible patients from 18 trials (1278 deaths) from the prospective meta-analysis. Summary ORs were similar for tocilizumab [0·82 [0·71–0·95, p = 0·008]] and sarilumab [0·80 [0·61–1·04, p = 0·09]] compared with usual care or placebo. The summary OR for 28-day mortality comparing tocilizumab with sarilumab was 1·03 [95%CI 0·81–1·32, p = 0·80]. The p-value for the global test of inconsistency was 0·28.

Conclusions

Administration of either tocilizumab or sarilumab was associated with lower 28-day all-cause mortality compared with usual care or placebo. The association is not dependent on the choice of interleukin-6 receptor antagonist.

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  1. Version published to 10.1371/journal.pone.0270668
  2. ScreenIT

    SciScore for 10.1101/2021.08.26.21262523: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: All included trials secured institutional review board approval, and informed consent for participation in each trial was obtained, consistent with local institutional review board requirements.
    Consent: All included trials secured institutional review board approval, and informed consent for participation in each trial was obtained, consistent with local institutional review board requirements.
    Sex as a biological variablenot detected.
    RandomizationEligible randomized trials that aimed to compare tocilizumab or sarilumab with standard care in the treatment of hospitalized patients with COVID-19 were identified from the searches conducted by the same authors for a recently published systematic review and prospective meta-analysis1.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    All analyses were conducted in Stata statistical software version 16.1 [StataCorp, USA] using the ‘network’ user-written command suite14.
    Stata statistical
    suggested: None
    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:
    This study has a few limitations. First, these results are focused on patients treated with corticosteroids and NIV, IMV or ECMO alongside interleukin-6 receptor antagonists, and so may not generalize to less critically ill patients. Second, only five of the included trials have been published in peer-reviewed journals, with the remaining either currently available as pre-print publications or currently unpublished. Third, the direct evidence in each of the three comparisons included in this network meta-analysis came predominantly from a single trial (either RECOVERY, REGENERON-P3 or REMAP-CAP), with these three trials primarily conducted in high income countries. In conclusion, this network meta-analysis of clinical trials of hospitalized patients with COVID-19 receiving ventilation and corticosteroids at randomization, confirms that administration of tocilizumab or sarilumab, compared with usual care or placebo, is associated with similarly lower 28-day all-cause mortality.

    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

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  3. Version published to 10.1101/2021.08.26.21262523v1 on medRxiv