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

Podmore, B.; Qizilbash, N.; Lacetera, A.; Ubillos, I.; Andresen, K.; Roncero Martin, A.; Majuelos-Melguizo, J.; Cunado Moral, A.; Hinojosa Campos, M.; Aronson, J. K.; Pocock, S.

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.