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Meta-Analysis
. 2021 May;82(5):178-185.
doi: 10.1016/j.jinf.2021.03.008. Epub 2021 Mar 18.

IL-6 inhibition in the treatment of COVID-19: A meta-analysis and meta-regression

Emmanuel Tharmarajah  1 , April Buazon  1 , Vishit Patel  1 , Jennifer R Hannah  1 , Maryam Adas  1 , Victoria B Allen  1 , Katie Bechman  1 , Benjamin D Clarke  1 , Deepak Nagra  1 , Sam Norton  1 , Mark D Russell  2 , Andrew I Rutherford  1 , Mark Yates  1 , James B Galloway  1
Affiliations
Meta-Analysis

IL-6 inhibition in the treatment of COVID-19: A meta-analysis and meta-regression

Emmanuel Tharmarajah et al. J Infect. 2021 May.

Abstract

Objectives: Multiple RCTs of interleukin-6 (IL-6) inhibitors in COVID-19 have been published, with conflicting conclusions. We performed a meta-analysis to assess the impact of IL-6 inhibition on mortality from COVID-19, utilising meta-regression to explore differences in study results.

Methods: Systematic database searches were performed to identify RCTs comparing IL-6 inhibitors (tocilizumab and sarilumab) to placebo or standard of care in adults with COVID-19. Meta-analysis was used to estimate the relative risk of mortality at 28 days between arms, expressed as a risk ratio. Within-study mortality rates were compared, and meta-regression was used to investigate treatment effect modification.

Results: Data from nine RCTs were included. The combined mortality rate across studies was 19% (95% CI: 18, 20%), ranging from 2% to 31%. The overall risk ratio for 28-day mortality was 0.90 (95% CI: 0.81, 0.99), in favour of benefit for IL-6 inhibition over placebo or standard of care, with low treatment effect heterogeneity: I2 0% (95% CI: 0, 53%). Meta-regression showed no evidence of treatment effect modification by patient characteristics. Trial-specific mortality rates were explained by known patient-level predictors of COVID-19 outcome (male sex, CRP, hypertension), and country-level COVID-19 incidence.

Conclusions: IL-6 inhibition is associated with clinically meaningful improvements in outcomes for patients admitted with COVID-19. Long-term benefits of IL-6 inhibition, its effectiveness across healthcare systems, and implications for differing standards of care are currently unknown.

Keywords: COVID-19; IL-6; Meta-analysis; Sarilumab; Tocilizumab.

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Conflict of interest statement

Declaration of Competing Interest JG receives speaker fees from Abbvie, Biovitrum, BMS, Celgene, Chugai, Gilead, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, Sobi and UCB. MDR has received honoraria from Pfizer and UCB. BDC has received honoraria from Abbvie. MY has received honoraria from Abbvie and UCB. All other authors have nothing to declare. JG, MDR, BDC, KB, MY, DN, ADB, JRH were investigators for the RECOVERY trial.

Figures

Fig. 1
Fig. 1
PRISMA flowchart of studies identified from the systematic literature search. Adapted from: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097.
Fig. 2
Fig. 2
Forest plot of the 28-day mortality risk ratios between intervention and control arms. Meta-analysis of the relative risk of mortality between intervention and control arms of included studies, expressed as risk ratios with 95% confidence intervals (CI), depicted graphically as a forest plot. The majority of studies reported mortality at 28 days; RCT-TCZ-COVID-19 reported at day 30, TOCIBRAS and Lescure et al. at day 29, and REMAP-CAP at day 21. The relative weighting of each study from a random effects model is shown. For studies comparing two interventions (either different doses or different IL-6 inhibitors), the intervention arms are included separately, whilst the number of patients contributing to the control arms were divided equally for use as a comparator. Heterogeneity between studies was assessed using I² statistics. TCZ: Tocilizumab; SARI: Sarilumab.
Fig. 3
Fig. 3
Comparison of incidence rate for mortality at day 28 in the combined intervention and control arms of each study. Meta-analysis of overall mortality rate, with 95% confidence intervals (CI), for the combined intervention and control arms of each individual study, depicted graphically as a forest plot. The relative weighting of each study is shown. Heterogeneity between studies was assessed using I² statistics.
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