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Meta-Analysis
. 2021 Aug 10;326(6):499-518.
doi: 10.1001/jama.2021.11330.

Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis

WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group; Manu Shankar-Hari  1   2 , Claire L Vale  3 , Peter J Godolphin  3 , David Fisher  3 , Julian P T Higgins  4   5   6 , Francesca Spiga  7 , Jelena Savovic  4   6 , Jayne Tierney  3 , Gabriel Baron  8   9 , Julie S Benbenishty  10 , Lindsay R Berry  11 , Niklas Broman  12 , Alexandre Biasi Cavalcanti  13 , Roos Colman  14 , Stefanie L De Buyser  14 , Lennie P G Derde  15 , Pere Domingo  16 , Sharifah Faridah Omar  17 , Ana Fernandez-Cruz  18 , Thijs Feuth  19 , Felipe Garcia  20 , Rosario Garcia-Vicuna  21 , Isidoro Gonzalez-Alvaro  21 , Anthony C Gordon  22 , Richard Haynes  23   24 , Olivier Hermine  25   26 , Peter W Horby  27   28   29 , Nora K Horick  30 , Kuldeep Kumar  31   32 , Bart N Lambrecht  33   34 , Martin J Landray  23   24 , Lorna Leal  20 , David J Lederer  35 , Elizabeth Lorenzi  11 , Xavier Mariette  36   37 , Nicolas Merchante  38 , Nor Arisah Misnan  39 , Shalini V Mohan  40 , Michael C Nivens  35 , Jarmo Oksi  12 , Jose A Perez-Molina  41 , Reuven Pizov  42 , Raphael Porcher  8   9   43 , Simone Postma  44 , Reena Rajasuriar  17   45 , Athimalaipet V Ramanan  46 , Philippe Ravaud  8   9   43 , Pankti D Reid  47 , Abraham Rutgers  44 , Aranzazu Sancho-Lopez  48 , Todd B Seto  49 , Sumathi Sivapalasingam  35 , Arvinder Singh Soin  31 , Natalie Staplin  23   24 , John H Stone  50   51 , Garth W Strohbehn  52 , Jonas Sunden-Cullberg  53 , Julian Torre-Cisneros  54 , Larry W Tsai  40 , Hubert van Hoogstraten  55 , Tom van Meerten  56 , Viviane Cordeiro Veiga  13 , Peter E Westerweel  57 , Srinivas Murthy  58 , Janet V Diaz  59 , John C Marshall  60 , Jonathan A C Sterne  4   5   61
Collaborators, Affiliations
Meta-Analysis

Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis

WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group et al. JAMA. .

Abstract

Importance: Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm.

Objective: To 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 sources: Trials 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 selection: Eligible 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 synthesis: In 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 measures: The 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.

Results: A 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 relevance: In 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 registration: PROSPERO Identifier: CRD42021230155.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Shankar-Hari reported being supported by clinician scientist award NIHR-CS-2016-16-011 from the UK National Institute for Health Research. Dr Vale, Mr Fisher, and Dr Tierney reported being supported by grant MC_UU_12023/24 from the UK Medical Research Council. Dr Godolphin reported being fully supported and Mr Fisher was partially supported by grant RIA 16-ST2-020 from Prostate Cancer UK. Dr Higgins reported being supported by senior investigator award NF-SI-0617-10145 from the UK National Institute for Health Research. Drs Higgins and Savović were supported by grants from the UK National Institute for Health Research Applied Research Collaboration West. Drs Higgins and Sterne reported being supported by grants from the UK National Institute for Health Research Bristol Biomedical Research Centre, Weston NHS Foundation Trust, and the University of Bristol. Dr Berry reported receiving grants from Berry Consultants. Dr Derde reported being a member of the COVID-19 guideline committee for the Society of Critical Care Medicine/European Society of Intensive Care Medicine/Surviving Sepsis Campaign. Drs De Buyser and Lambrecht reported being supported by grants from Belgian Health Care Knowledge Centre. Dr Domingo reported receiving support from the General Subdirectorate of Networks and Cooperative Research Centres, Ministry of Science and Innovation, Spanish Network for Research in Infectious Diseases; being co-financed by the European Regional Development Fund; receiving grant support from the Instituto de Salud Carlos III for the TOCOVID clinical trial; and receiving honoraria from Merck Sharp & Dohme, Gilead Sciences, ViiV Healthcare, Janssen, Cilag, Theratechnologies, and Roche. Dr Omar reported being supported by grants from the University of Malaya. Dr Garcia-Vicuna reported receiving grants and personal fees from Sanofi and Lilly. Dr Gonzalez-Alvaro reported receiving grants from Sanofi, Biohope, and Gebro; serving on advisory boards for Lilly and Sanofi; receiving personal fees from Lilly, Sanofi, Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Abbvie, Pfizer, and Novartis; and owning stock in PharmaMar. Dr Gordon reported being supported by grants from the UK National Institute for Health Research and the European Union and receiving personal fees from Thirty Respiratory Ltd and GlaxoSmithKline. Dr Haynes reported receiving study drugs from Roche and receiving grants from Novartis and Boehringer Ingelheim. Dr Hermine reported receiving grants from Celgene, Bristol Myers Squibb, Alexion, Inatherys, and AB Science. Dr Horby reported receiving study drugs from Roche. Dr Horby reported being supported by grants from UK Research and Innovation–National Institute for Health Research. Dr Lambrecht reported receiving consultancy fees from GlaxoSmithKline, Sanofi, Argenx, Oncoarendi, and Novartis. Dr Landray reported receiving nonfinancial support from Roche and Regeneron and receiving grants from Boehringer Ingelheim, Novartis, and Janssen. Drs Lederer, Nivens, and Sivapalasingam reported being employees of and owning stock in Regeneron. Dr Lorenzi reported receiving personal fees from Berry Consultants. Dr Mariette reported receiving personal fees from Bristol Myers Squibb, Gilead, GlaxoSmithKline, Janssen, Novartis, Pfizer, UCB, and Sanofi and receiving grants from Biogen, Ose Pharmaceutical, and Pfizer. Dr Merchante reported receiving grants from Merck Sharp & Dome and personal fees from Gilead, Merck Sharp & Dome, and Shionogi for providing expert testimony. Drs Mohan and Tsai reported being employees of Genetech. Dr Nivens also reported receiving grants from the Biomedical Advanced Research and Development Authority. Dr Perez-Molina reported receiving grants from Roche Spain. Dr Ramanan reported receiving personal fees from Roche, Abbvie, Eli Lilly, Novartis, UCB, and the Swedish Orphan Biovitrum AB. Dr Ravaud reported being the primary investigator of the Corimmuno platform funded by the Ministry of Health in France. Drs Reid and Strohbehn reported being co-inventors of a filed patent (held by the University of Chicago) covering the use of low-dose tocilizumab for treatment of viral infections. Dr Staplin reported receiving study drugs from Roche and Regeneron and receiving grants from Boehringer Ingelheim. Dr Stone reported receiving grants from Roche/Genentech. Dr Strohbehn also reported being an employee of the US government. Dr Sunden-Cullberg reported receiving grants from the Swedish Research Council and the Center for Innovative Medicine. Dr Torre-Cisneros reported being supported by General Sub-Directorate of Networks and Cooperative Research Centres, Ministry of Science and Innovation, Spanish Network for Research in Infectious Diseases; and being co-financed by the European Regional Development Fund. Dr Tsai also reported being involved with 2 patents pending that were filed and are owned by Genentech/Roche (one for a method to treating pneumonia, including COVID-19 pneumonia with an IL-6 antagonist, and another for tocilizumab and remdesivir combination therapy for COVID-19 pneumonia). Dr van Hoogstraten reported being an employee of and owning stock in Sanofi Genzyme. Dr Veiga reported receiving personal fees from Aspen Pharmacare, Cristália, and Pfizer for speaking and serving on advisory boards. Dr Murthy reported receiving grants from the Canadian Institutes of Health Research, Innovative Medicines Canada, and the Canadian Health Research Foundation. Dr Marshall reported receiving personal fees from AM Pharma (for serving as the chair of a data and safety monitoring board), Gilead (for serving as a consultant), and Critical Care Medicine (for serving as associate editor). Dr Sterne also reported being supported by grants from Health Data Research UK. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Association Between IL-6 Antagonists vs Usual Care or Placebo and Primary Outcome of 28-Day All-Cause Mortality
The area of the data marker for each trial is proportional to its weight in the fixed-effects meta-analysis. aCommon control group across both treatment comparisons of the COV-AID trial. bNA indicates not available; there were insufficient data to estimate odds ratio. cThe data for the PreToVid trial are based on events up until 30 days after randomization. dThere were 21 patients in the control group for both treatment comparisons. The analyses have been adjusted to correct for this.
Figure 2.
Figure 2.. Subgroup Analysis of 3 Outcomes by Treatment Group and Corticosteroid Use
For the outcome of progression to invasive mechanical ventilation (IMV), extracorporeal membrane oxygenation (ECMO), or death at 28 days, only patients not receiving IMV or ECMO at randomization were included in the analyses. All trials supplied data until 28 days after randomization, except for the PreToVid trial for which data are based on events up until 30 days after randomization. The ratios of odds ratios (ROR) compare the associations of anti–IL-6 agents with outcomes between patients receiving and not receiving corticosteroids within each trial. The displayed summary ROR for each comparison is based on a meta-analysis of trial-specific RORs. Only the trials that recruited patients receiving and not receiving corticosteroids at randomization contribute to these meta-analyses. The estimated RORs are not necessarily consistent with the ratios of the subgroup ORs (left panel), which were calculated from meta-analyses within subgroups defined by receipt or no receipt of corticosteroids at randomization. aThe odds ratios are based on raw percentages while the ratios of odds ratios account for pooling trials of different sizes.
Figure 3.
Figure 3.. Association Between IL-6 Antagonists vs Usual Care or Placebo and Secondary Outcome of Progression to Invasive Mechanical Ventilation, Extracorporeal Membrane Oxygenation, or Death
The area of the data marker for each trial is proportional to its weight in the fixed-effects meta-analysis. Progression to requiring invasive mechanical ventilation or extracorporeal membrane oxygenation or death among patients not receiving invasive mechanical ventilation at randomization. aNA indicates not available; there were insufficient data to estimate odds ratio or the trial did not supply data for this outcome. bCommon control group across both treatment comparisons of the COV-AID trial. cThe data for the PreToVid trial are based on events up until 30 days after randomization. dThere were 21 patients in the control group for both treatment comparisons. The analyses have been adjusted to correct for this.
Figure 4.
Figure 4.. Association Between IL-6 Antagonists vs Usual Care or Placebo and Secondary Infections
The area of the data marker for each trial is proportional to its weight in the fixed-effects meta-analysis. aCommon control group across both treatment comparisons of the COV-AID trial. bNA indicates not available; the trial did not supply data for this outcome. cThe data for the PreToVid trial are based on events up until 30 days after randomization.
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