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Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis.
JAMA. 2021 08 10; 326(6):499-518.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.

Links

PMC Free PDF

Authors+Show Affiliations

WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group
No affiliation info available
Shankar-Hari M
Guy's and St Thomas' NHS Foundation Trust, ICU Support Offices, St Thomas' Hospital, London, England. School of Immunology and Microbial Sciences, Kings College London, London, England.
Vale CL
University College London, MRC Clinical Trials Unit at UCL, London, England.
Godolphin PJ
University College London, MRC Clinical Trials Unit at UCL, London, England.
Fisher D
University College London, MRC Clinical Trials Unit at UCL, London, England.
Higgins JPT
Population 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 University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, England.
Spiga F
University of Bristol, Bristol, England.
Savovic J
Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, England. National Institute for Health Research Applied Research Collaboration West at University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, England.
Tierney J
University College London, MRC Clinical Trials Unit at UCL, London, England.
Baron G
Assistance Publique-Hôpitaux de Paris, Centre for Clinical Epidemiology, Hôpital Hôtel-Dieu, Paris, France. INSERM UMRS-1153, Centre de Recherche Epidémiologie et Statistique Université de Paris, METHODS Team, Paris, France.
Benbenishty JS
Department of Nursing, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
Berry LR
Berry Consultants, Austin, Texas.
Broman N
Turku University Hospital, Department of Infectious Diseases, Turku, Finland.
Cavalcanti AB
BP-A Beneficência Portuguesa de São Paulo, Rua Maestro Cardim, São Paulo, Brazil.
Colman R
Department of Public Health and Primary Care, Ghent University, Ghent, Belgium.
De Buyser SL
Department of Public Health and Primary Care, Ghent University, Ghent, Belgium.
Derde LPG
Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
Domingo P
Department of Infectious Diseases, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Omar SF
Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
Fernandez-Cruz A
Infectious Diseases Unit, Internal Medicine Department, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain.
Feuth T
Department of Pulmonary Diseases, Turku University Hospital, Turku, Finland.
Garcia F
Infectious Diseases Department, Hospital Clinic Barcelona-IDIBAPS, Barcelona, Spain.
Garcia-Vicuna R
Rheumatology, Hospital Universitario La Princesa IIS-IP, Madrid, Spain.
Gonzalez-Alvaro I
Rheumatology, Hospital Universitario La Princesa IIS-IP, Madrid, Spain.
Gordon AC
Division of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, England.
Haynes R
Nuffield Department of Population Health, University of Oxford, Oxford, England. MRC Population Health Research Unit, University of Oxford, Oxford, England.
Hermine O
Department of Hematology, Necker Hospital, Paris, France. Imagine Institute, University of Paris, INSERM U1153, Paris, France.
Horby PW
Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, England. International Severe Acute Respiratory and Emerging Infections Consortium, University of Oxford, Oxford, England. Pandemic Sciences Centre, University of Oxford, Oxford, England.
Horick NK
Department of Medicine, Massachusetts General Hospital, Boston.
Kumar K
Medanta-The Medicity, Institute of Liver Transplantation and Regenerative Medicine, Gurugram, India. Research Department, Medanta Institute of Education and Research, Gurugram, India.
Lambrecht BN
VIB Center for Inflammation Research, Ghent University, Ghent, Belgium. Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
Landray MJ
Nuffield Department of Population Health, University of Oxford, Oxford, England. MRC Population Health Research Unit, University of Oxford, Oxford, England.
Leal L
Infectious Diseases Department, Hospital Clinic Barcelona-IDIBAPS, Barcelona, Spain.
Lederer DJ
Regeneron Pharmaceuticals Inc, Tarrytown, New York.
Lorenzi E
Berry Consultants, Austin, Texas.
Mariette X
Centre for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Saclay, INSERM UMR1184, Le Kremlin-Bicêtre, Paris, France. Department of Rheumatology, Assistance Publique-Hôpitaux de Paris, Le Le Kremlin-Bicêtre, Paris, France.
Merchante N
Unit of Infectious Diseases and Microbiology, Valme University Hospital, Institute of Biomedicine of Sevilla, Seville, Spain.
Misnan NA
Hospital Sungai Buloh, Ministry of Health, Buloh, Malaysia.
Mohan SV
Genentech, South San Francisco, California.
Nivens MC
Regeneron Pharmaceuticals Inc, Tarrytown, New York.
Oksi J
Turku University Hospital, Department of Infectious Diseases, Turku, Finland.
Perez-Molina JA
Hospital Universitario Ramón y Cajal IRYCIS, Infectious Diseases Department, Madrid, Spain.
Pizov R
Department of Anesthesilogy Critical Care and Pain Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel.
Porcher R
Assistance Publique-Hôpitaux de Paris, Centre for Clinical Epidemiology, Hôpital Hôtel-Dieu, Paris, France. INSERM UMRS-1153, Centre de Recherche Epidémiologie et Statistique Université de Paris, METHODS Team, Paris, France. University de Paris, CRESS UMR1153, INSERM, INRA, Paris, France.
Postma S
Department of Rheumatology and Clinical Immunology, University Hospital Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Rajasuriar R
Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia. Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia.
Ramanan AV
Department of Paediatric Rheumatology, University Hospitals Bristol, NHS Foundation Trust, Bristol, England.
Ravaud P
Assistance Publique-Hôpitaux de Paris, Centre for Clinical Epidemiology, Hôpital Hôtel-Dieu, Paris, France. INSERM UMRS-1153, Centre de Recherche Epidémiologie et Statistique Université de Paris, METHODS Team, Paris, France. University de Paris, CRESS UMR1153, INSERM, INRA, Paris, France.
Reid PD
Department of Medicine (Rheumatology), University of Chicago Medical Center, Chicago, Illinois.
Rutgers A
Department of Rheumatology and Clinical Immunology, University Hospital Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Sancho-Lopez A
Department of Clinical Pharmacology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.
Seto TB
Center for Outcomes Research and Evaluation, Queen's Medical Center, Honolulu, Hawaii.
Sivapalasingam S
Regeneron Pharmaceuticals Inc, Tarrytown, New York.
Soin AS
Medanta-The Medicity, Institute of Liver Transplantation and Regenerative Medicine, Gurugram, India.
Staplin N
Nuffield Department of Population Health, University of Oxford, Oxford, England. MRC Population Health Research Unit, University of Oxford, Oxford, England.
Stone JH
Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston. Department of Medicine (Rheumatology), Massachusetts General Hospital, Boston.
Strohbehn GW
VA Ann Arbor, Center for Clinical Management and Research, Ann Arbor, Michigan.
Sunden-Cullberg J
Department of Infectious Diseases, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden.
Torre-Cisneros J
Maimonides Institute for Biomedical Research of Cordoba/Reina Sofia University Hospital/University of Córdoba, Córdoba, Spain.
Tsai LW
Genentech, South San Francisco, California.
van Hoogstraten H
Global Medical Affairs, Sanofi-Genzyme, Bridgewater, New Jersey.
van Meerten T
Department of Hematology, University Medical Center Groningen, Groningen, the Netherlands.
Veiga VC
BP-A Beneficência Portuguesa de São Paulo, Rua Maestro Cardim, São Paulo, Brazil.
Westerweel PE
Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, the Netherlands.
Murthy S
Department of Pediatrics, University of British Columbia, Vancouver, Canada.
Diaz JV
Clinical Unit, Health Emergencies Programme, World Health Organization, Geneva, Switzerland.
Marshall JC
Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
Sterne JAC
Population 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.

MeSH

AgedAntibodies, Monoclonal, HumanizedCOVID-19Cause of DeathCoinfectionDisease ProgressionDrug Therapy, CombinationFemaleGlucocorticoidsHospitalizationHumansInterleukin-6MaleMiddle AgedProspective StudiesRandomized Controlled Trials as TopicRespiration, ArtificialCOVID-19 Drug Treatment

Pub Type(s)

Comparative Study
Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

34228774

Citation

WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, et al. "Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: a Meta-analysis." JAMA, vol. 326, no. 6, 2021, pp. 499-518.
WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Shankar-Hari M, Vale CL, et al. Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis. JAMA. 2021;326(6):499-518.
Shankar-Hari, M., Vale, C. L., Godolphin, P. J., Fisher, D., Higgins, J. P. T., Spiga, F., Savovic, J., Tierney, J., Baron, G., Benbenishty, J. S., Berry, L. R., Broman, N., Cavalcanti, A. B., Colman, R., De Buyser, S. L., Derde, L. P. G., Domingo, P., Omar, S. F., Fernandez-Cruz, A., ... Sterne, J. A. C. (2021). Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis. JAMA, 326(6), 499-518. https://doi.org/10.1001/jama.2021.11330
WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, et al. Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: a Meta-analysis. JAMA. 2021 08 10;326(6):499-518. PubMed PMID: 34228774.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis. AU - ,, AU - Shankar-Hari,Manu, AU - Vale,Claire L, AU - Godolphin,Peter J, AU - Fisher,David, AU - Higgins,Julian P T, AU - Spiga,Francesca, AU - Savovic,Jelena, AU - Tierney,Jayne, AU - Baron,Gabriel, AU - Benbenishty,Julie S, AU - Berry,Lindsay R, AU - Broman,Niklas, AU - Cavalcanti,Alexandre Biasi, AU - Colman,Roos, AU - De Buyser,Stefanie L, AU - Derde,Lennie P G, AU - Domingo,Pere, AU - Omar,Sharifah Faridah, AU - Fernandez-Cruz,Ana, AU - Feuth,Thijs, AU - Garcia,Felipe, AU - Garcia-Vicuna,Rosario, AU - Gonzalez-Alvaro,Isidoro, AU - Gordon,Anthony C, AU - Haynes,Richard, AU - Hermine,Olivier, AU - Horby,Peter W, AU - Horick,Nora K, AU - Kumar,Kuldeep, AU - Lambrecht,Bart N, AU - Landray,Martin J, AU - Leal,Lorna, AU - Lederer,David J, AU - Lorenzi,Elizabeth, AU - Mariette,Xavier, AU - Merchante,Nicolas, AU - Misnan,Nor Arisah, AU - Mohan,Shalini V, AU - Nivens,Michael C, AU - Oksi,Jarmo, AU - Perez-Molina,Jose A, AU - Pizov,Reuven, AU - Porcher,Raphael, AU - Postma,Simone, AU - Rajasuriar,Reena, AU - Ramanan,Athimalaipet V, AU - Ravaud,Philippe, AU - Reid,Pankti D, AU - Rutgers,Abraham, AU - Sancho-Lopez,Aranzazu, AU - Seto,Todd B, AU - Sivapalasingam,Sumathi, AU - Soin,Arvinder Singh, AU - Staplin,Natalie, AU - Stone,John H, AU - Strohbehn,Garth W, AU - Sunden-Cullberg,Jonas, AU - Torre-Cisneros,Julian, AU - Tsai,Larry W, AU - van Hoogstraten,Hubert, AU - van Meerten,Tom, AU - Veiga,Viviane Cordeiro, AU - Westerweel,Peter E, AU - Murthy,Srinivas, AU - Diaz,Janet V, AU - Marshall,John C, AU - Sterne,Jonathan A C, PY - 2021/7/7/pubmed PY - 2021/8/17/medline PY - 2021/7/6/entrez SP - 499 EP - 518 JF - JAMA JO - JAMA VL - 326 IS - 6 N2 - 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. SN - 1538-3598 UR - https://www.unboundmedicine.com/medline/citation/34228774/Association_Between_Administration_of_IL_6_Antagonists_and_Mortality_Among_Patients_Hospitalized_for_COVID_19:_A_Meta_analysis_ DB - PRIME DP - Unbound Medicine ER -