Tocilizumab and mortality in hospitalised patients with covid-19. A systematic review comparing randomised trials with observational studies

  1. Bélène Podmore
  2. Nawab Qizilbash
  3. Alessandra Lacetera
  4. Itziar Ubillos
  5. Kirsty Andresen
  6. Ana Roncero Martín
  7. Jara Majuelos-Melguizo
  8. Ana Cuñado Moral
  9. Marina Hinojosa Campos
  10. Jeffrey K Aronson
  11. Stuart Pocock
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Abstract

Objective

To summarise and compare evidence from randomised controlled trials and observational studies of the effect of tocilizumab on in-hospital mortality in patients with covid-19.

Design

Systematic review and meta-analysis.

Data sources

Searches conducted in Embase and PubMed from July 2020 until 1 March 2021.

Study Selection

Observational studies and randomised controlled trials (RCTs) assessing in-hospital mortality in patients receiving tocilizumab compared with standard care or placebo.

Data extraction

The primary outcome was in-hospital mortality at 30 days. The risk of bias in observational studies was assessed using the ROBINS-I tool. A fixed effect meta-analysis was used to combine relative risks, with random effects and risk of bias as a sensitivity analysis.

Results

Of 5,792 publications screened for inclusion, eight RCTs and 35 observational studies were identified. The RCTs showed an overall relative risk reduction in in-hospital mortality at 30 days of 0.86 (95% CI 0.78 to 0.96) with no statistically significant heterogeneity. 23 of the observational studies had a severe risk of bias, 10 of which did not adjust for potential confounders. The 10 observational studies with moderate risk of bias reported a larger reduction in mortality at 30-days (relative risk 0.72, 95% CI 0.64 to 0.81) but with significant heterogeneity (P<0.01).

Conclusion

This meta-analysis provides strong evidence from RCTs that tocilizumab reduces the risk of mortality in hospitalised covid-19 patients. Observational studies with moderate risk of bias exaggerated the benefits on mortality two-fold and showed heterogeneity. Collectively observational studies provide a less reliable evidence base for evaluating treatments for covid-19.

Summary box

What is already known on this topic

  • Early case reports suggested that tocilizumab might produce clinical and biochemical improvement in covid-19. This was followed by observational studies using retrospective data, largely supporting clinicians’ impressions of benefit.

  • This led to wider use of tocilizumab, despite failure to show benefit on all-cause mortality from early underpowered randomised controlled trials (RCTs) in severe covid-19. The RECOVERY trial, the largest trial, has recently shown clear overall benefit in hospitalised patients with covid-19.

What this study adds

  • This meta-analysis provides strong evidence from RCTs that tocilizumab reduces the risk of mortality in hospitalised covid-19 patients.

  • Observational studies with moderate risk of bias exaggerated the benefits on mortality by two-fold.

  • Collectively observational studies provide a less reliable evidence base for evaluating treatments for covid-19.

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