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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 , Shankar-Hari M 1 , Vale CL 2 , Godolphin PJ 2 , Fisher D 2 , Higgins JPT 3 Show all authors , Spiga F 4 , Savovic J 3 , Tierney J 2 , Baron G 5 , Benbenishty JS 6 , Berry LR 7 , Broman N 8 , Cavalcanti AB 9 , Colman R 10 , De Buyser SL 10 , Derde LPG 11 , Domingo P 12 , Omar SF 13 , Fernandez-Cruz A 14 , Feuth T 15 , Garcia F 16 , Garcia-Vicuna R 17 , Gonzalez-Alvaro I 17 , Gordon AC 18 , Haynes R 19 , Hermine O 20 , Horby PW 21 , Horick NK 22 , Kumar K 23 , Lambrecht BN 24 , Landray MJ 19 , Leal L 16 , Lederer DJ 25 , Lorenzi E 7 , Mariette X 26 , Merchante N 27 , Misnan NA 28 , Mohan SV 29 , Nivens MC 25 , Oksi J 8 , Perez-Molina JA 30 , Pizov R 31 , Porcher R 5 , Postma S 32 , Rajasuriar R 13 , Ramanan AV 33 , Ravaud P 5 , Reid PD 34 , Rutgers A 32 , Sancho-Lopez A 35 , Seto TB 36 , Sivapalasingam S 25 , Soin AS 23 , Staplin N 19 , Stone JH 37 , Strohbehn GW 38 , Sunden-Cullberg J 39 , Torre-Cisneros J 40 , Tsai LW 29 , van Hoogstraten H 41 , van Meerten T 42 , Veiga VC 9 , Westerweel PE 43 , Murthy S 44 , Diaz JV 45 , Marshall JC 46 , Sterne JAC 3

Affiliations 

  • 1 Guy's and St Thomas' NHS Foundation Trust, ICU Support Offices, St Thomas' Hospital, London, England
  • 2 University College London, MRC Clinical Trials Unit at UCL, London, England
  • 3 Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, England
  • 4 University of Bristol, Bristol, England
  • 5 Assistance Publique-Hôpitaux de Paris, Centre for Clinical Epidemiology, Hôpital Hôtel-Dieu, Paris, France
  • 6 Department of Nursing, Hadassah Hebrew University Medical Center, Jerusalem, Israel
  • 7 Berry Consultants, Austin, Texas
  • 8 Turku University Hospital, Department of Infectious Diseases, Turku, Finland
  • 9 BP-A Beneficência Portuguesa de São Paulo, Rua Maestro Cardim, São Paulo, Brazil
  • 10 Department of Public Health and Primary Care, Ghent University, Ghent, Belgium
  • 11 Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
  • 12 Department of Infectious Diseases, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
  • 13 Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 14 Infectious Diseases Unit, Internal Medicine Department, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain
  • 15 Department of Pulmonary Diseases, Turku University Hospital, Turku, Finland
  • 16 Infectious Diseases Department, Hospital Clinic Barcelona-IDIBAPS, Barcelona, Spain
  • 17 Rheumatology, Hospital Universitario La Princesa IIS-IP, Madrid, Spain
  • 18 Division of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, England
  • 19 Nuffield Department of Population Health, University of Oxford, Oxford, England
  • 20 Department of Hematology, Necker Hospital, Paris, France
  • 21 Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, England
  • 22 Department of Medicine, Massachusetts General Hospital, Boston
  • 23 Medanta-The Medicity, Institute of Liver Transplantation and Regenerative Medicine, Gurugram, India
  • 24 VIB Center for Inflammation Research, Ghent University, Ghent, Belgium
  • 25 Regeneron Pharmaceuticals Inc, Tarrytown, New York
  • 26 Centre for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Saclay, INSERM UMR1184, Le Kremlin-Bicêtre, Paris, France
  • 27 Unit of Infectious Diseases and Microbiology, Valme University Hospital, Institute of Biomedicine of Sevilla, Seville, Spain
  • 28 Hospital Sungai Buloh, Ministry of Health, Buloh, Malaysia
  • 29 Genentech, South San Francisco, California
  • 30 Hospital Universitario Ramón y Cajal IRYCIS, Infectious Diseases Department, Madrid, Spain
  • 31 Department of Anesthesilogy Critical Care and Pain Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel
  • 32 Department of Rheumatology and Clinical Immunology, University Hospital Groningen, University Medical Center Groningen, Groningen, the Netherlands
  • 33 Department of Paediatric Rheumatology, University Hospitals Bristol, NHS Foundation Trust, Bristol, England
  • 34 Department of Medicine (Rheumatology), University of Chicago Medical Center, Chicago, Illinois
  • 35 Department of Clinical Pharmacology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
  • 36 Center for Outcomes Research and Evaluation, Queen's Medical Center, Honolulu, Hawaii
  • 37 Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston
  • 38 VA Ann Arbor, Center for Clinical Management and Research, Ann Arbor, Michigan
  • 39 Department of Infectious Diseases, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden
  • 40 Maimonides Institute for Biomedical Research of Cordoba/Reina Sofia University Hospital/University of Córdoba, Córdoba, Spain
  • 41 Global Medical Affairs, Sanofi-Genzyme, Bridgewater, New Jersey
  • 42 Department of Hematology, University Medical Center Groningen, Groningen, the Netherlands
  • 43 Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, the Netherlands
  • 44 Department of Pediatrics, University of British Columbia, Vancouver, Canada
  • 45 Clinical Unit, Health Emergencies Programme, World Health Organization, Geneva, Switzerland
  • 46 Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
JAMA, 2021 Aug 10;326(6):499-518.
PMID: 34228774 DOI: 10.1001/jama.2021.11330

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 

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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