• WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Manu Shankar-Hari, Claire L Vale, Peter J Godolphin, David Fisher, HigginsJulian P TJPTPopulation Health Sciences, Bristol Medical School, University of Bristol, Bristol, England.NIHR Bristol Biomedical Research Centre, Bristol, England.National Institute for Health Research Applied Research Collaboration West at Univers, Francesca Spiga, Jelena Savovic, Jayne Tierney, Gabriel Baron, Julie S Benbenishty, Lindsay R Berry, Niklas Broman, Alexandre Biasi Cavalcanti, Roos Colman, Stefanie L De Buyser, DerdeLennie P GLPGDepartment of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, the Netherlands., Pere Domingo, Sharifah Faridah Omar, Ana Fernandez-Cruz, Thijs Feuth, Felipe Garcia, Rosario Garcia-Vicuna, Isidoro Gonzalez-Alvaro, Anthony C Gordon, Richard Haynes, Olivier Hermine, Peter W Horby, Nora K Horick, Kuldeep Kumar, Bart N Lambrecht, Martin J Landray, Lorna Leal, David J Lederer, Elizabeth Lorenzi, Xavier Mariette, Nicolas Merchante, Nor Arisah Misnan, Shalini V Mohan, Michael C Nivens, Jarmo Oksi, Jose A Perez-Molina, Reuven Pizov, Raphael Porcher, Simone Postma, Reena Rajasuriar, Athimalaipet V Ramanan, Philippe Ravaud, Pankti D Reid, Abraham Rutgers, Aranzazu Sancho-Lopez, Todd B Seto, Sumathi Sivapalasingam, Arvinder Singh Soin, Natalie Staplin, John H Stone, Garth W Strohbehn, Jonas Sunden-Cullberg, Julian Torre-Cisneros, Larry W Tsai, Hubert van Hoogstraten, Tom van Meerten, Viviane Cordeiro Veiga, Peter E Westerweel, Srinivas Murthy, Janet V Diaz, John C Marshall, and SterneJonathan A CJACPopulation Health Sciences, Bristol Medical School, University of Bristol, Bristol, England.NIHR Bristol Biomedical Research Centre, Bristol, England.Health Data Research UK South-West, Bristol, England..
• Guy's and St Thomas' NHS Foundation Trust, ICU Support Offices, St Thomas' Hospital, London, England.
• JAMA. 2021 Aug 10; 326 (6): 499518499-518.

ImportanceClinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm.ObjectiveTo estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes.Data SourcesTrials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts.Study SelectionEligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria.Data Extraction And SynthesisIn this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality.Main Outcomes And MeasuresThe primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days.ResultsA total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16).Conclusions And RelevanceIn this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.Trial RegistrationPROSPERO Identifier: CRD42021230155.

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