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Tocilizumab in COVID-19: a meta-analysis, trial sequential analysis, and meta-regression of randomized-controlled trials.
Intensive Care Med. 2021 06; 47(6):641-652.IC

Abstract

PURPOSE

Interleukin-6 (IL-6) levels discriminate between patients with mild and severe COVID-19, making IL-6 inhibition an attractive therapeutic strategy. We conducted a systematic review, meta-analysis, trial sequential analysis (TSA), and meta-regression of randomized-controlled trials to ascertain the benefit of IL-6 blockade with tocilizumab for COVID-19.

METHODS

We included randomized-controlled trials (RCTs) allocating patients with COVID-19 to tocilizumab. Our control group included standard care or placebo. Trials co-administering other pharmacological interventions for COVID-19 were not excluded. Primary outcome was 28-30 day mortality. Secondary outcomes included progression-to-severe disease defined as need for mechanical ventilation, intensive-care unit (ICU) admission, or a composite.

RESULTS

We identified 10 RCTs using tocilizumab, 9 of which reported primary outcome data (mortality), recruiting 6493 patients with 3358 (52.2%) allocated to tocilizumab. Tocilizumab may be associated with an improvement in mortality (24.4% vs. 29.0%; OR 0.87 [0.74-1.01]; p = 0.07; I2 = 10%; TSA adjusted CI 0.66-1.14). Meta-regression suggested a relationship between treatment effect and mortality risk, with benefit at higher levels of risk (logOR vs %risk beta = -0.018 [-0.037 to -0.002]; p = 0.07). Tocilizumab did reduce the need for mechanical ventilation and was associated with a benefit in the composite secondary outcome but did not reduce ICU admission.

CONCLUSIONS

For hospitalized COVID-19 patients, there is some evidence that tocilizumab use may be associated with a short-term mortality benefit, but further high-quality data are required. Its benefits may also lie in reducing the need for mechanical ventilation.

Authors+Show Affiliations

Bloomsbury Institute of Intensive Care Medicine, University College London, Gower St, London, WC1E 6BT, UK. timothy.snow@doctors.net.uk.Bloomsbury Institute of Intensive Care Medicine, University College London, Gower St, London, WC1E 6BT, UK.Department of Statistical Science, University College London, London, UK.Department of Clinical Virology, University College London Hospital, London, UK. Department of Infection, Immunity and Inflammation, UCL Great Ormond Street Institute of Child Health, London, UK.Bloomsbury Institute of Intensive Care Medicine, University College London, Gower St, London, WC1E 6BT, UK.Bloomsbury Institute of Intensive Care Medicine, University College London, Gower St, London, WC1E 6BT, UK.

Pub Type(s)

Meta-Analysis
Systematic Review

Language

eng

PubMed ID

34019122

Citation

Snow, Timothy Arthur Chandos, et al. "Tocilizumab in COVID-19: a Meta-analysis, Trial Sequential Analysis, and Meta-regression of Randomized-controlled Trials." Intensive Care Medicine, vol. 47, no. 6, 2021, pp. 641-652.
Snow TAC, Saleem N, Ambler G, et al. Tocilizumab in COVID-19: a meta-analysis, trial sequential analysis, and meta-regression of randomized-controlled trials. Intensive Care Med. 2021;47(6):641-652.
Snow, T. A. C., Saleem, N., Ambler, G., Nastouli, E., Singer, M., & Arulkumaran, N. (2021). Tocilizumab in COVID-19: a meta-analysis, trial sequential analysis, and meta-regression of randomized-controlled trials. Intensive Care Medicine, 47(6), 641-652. https://doi.org/10.1007/s00134-021-06416-z
Snow TAC, et al. Tocilizumab in COVID-19: a Meta-analysis, Trial Sequential Analysis, and Meta-regression of Randomized-controlled Trials. Intensive Care Med. 2021;47(6):641-652. PubMed PMID: 34019122.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tocilizumab in COVID-19: a meta-analysis, trial sequential analysis, and meta-regression of randomized-controlled trials. AU - Snow,Timothy Arthur Chandos, AU - Saleem,Naveed, AU - Ambler,Gareth, AU - Nastouli,Eleni, AU - Singer,Mervyn, AU - Arulkumaran,Nishkantha, Y1 - 2021/05/21/ PY - 2021/02/10/received PY - 2021/04/20/accepted PY - 2021/5/22/pubmed PY - 2021/6/22/medline PY - 2021/5/21/entrez KW - COVID-19 KW - Immunologic factors KW - Interleukin-6 KW - Meta-analysis SP - 641 EP - 652 JF - Intensive care medicine JO - Intensive Care Med VL - 47 IS - 6 N2 - PURPOSE: Interleukin-6 (IL-6) levels discriminate between patients with mild and severe COVID-19, making IL-6 inhibition an attractive therapeutic strategy. We conducted a systematic review, meta-analysis, trial sequential analysis (TSA), and meta-regression of randomized-controlled trials to ascertain the benefit of IL-6 blockade with tocilizumab for COVID-19. METHODS: We included randomized-controlled trials (RCTs) allocating patients with COVID-19 to tocilizumab. Our control group included standard care or placebo. Trials co-administering other pharmacological interventions for COVID-19 were not excluded. Primary outcome was 28-30 day mortality. Secondary outcomes included progression-to-severe disease defined as need for mechanical ventilation, intensive-care unit (ICU) admission, or a composite. RESULTS: We identified 10 RCTs using tocilizumab, 9 of which reported primary outcome data (mortality), recruiting 6493 patients with 3358 (52.2%) allocated to tocilizumab. Tocilizumab may be associated with an improvement in mortality (24.4% vs. 29.0%; OR 0.87 [0.74-1.01]; p = 0.07; I2 = 10%; TSA adjusted CI 0.66-1.14). Meta-regression suggested a relationship between treatment effect and mortality risk, with benefit at higher levels of risk (logOR vs %risk beta = -0.018 [-0.037 to -0.002]; p = 0.07). Tocilizumab did reduce the need for mechanical ventilation and was associated with a benefit in the composite secondary outcome but did not reduce ICU admission. CONCLUSIONS: For hospitalized COVID-19 patients, there is some evidence that tocilizumab use may be associated with a short-term mortality benefit, but further high-quality data are required. Its benefits may also lie in reducing the need for mechanical ventilation. SN - 1432-1238 UR - https://www.unboundmedicine.com/medline/citation/34019122/Tocilizumab_in_COVID_19:_a_meta_analysis_trial_sequential_analysis_and_meta_regression_of_randomized_controlled_trials_ DB - PRIME DP - Unbound Medicine ER -