Tocilizumab and Mortality in Hospitalised Patients with Covid-19. A Systematic Review Comparing Randomised Trials with Observational Studies

Background: Early observational studies suggested that tocilizumab might produce clinical improvement in covid-19 patients leading to the use of tocilizumab. Early underpowered randomised controlled trials (RCTs) however did not show benefit until the most recent largest trial. RECOVERY trial. We aimed to compare the evidence from RCTs and observational studies of the effect of tocilizumab on in-hospital mortality in patients with covid-19. Materials and Methods: Embase and PubMed were searched from July 2020 until 1 March 2021. Observational studies and RCTs assessing in-hospital mortality in patients receiving tocilizumab compared with standard care or placebo were included. The primary outcome was in-hospital mortality closest to 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 33 observational studies were identified. The RCTs showed an overall relative risk reduction in in-hospital mortality at 30 days of 0.86 (95% confidence interval (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.