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Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis.
Shankar-Hari, Manu; Vale, Claire L; Godolphin, Peter J; Fisher, David; Higgins, Julian P T; Spiga, Francesca; Savovic, Jelena; Tierney, Jayne; Baron, Gabriel; Benbenishty, Julie S; Berry, Lindsay R; Broman, Niklas; Cavalcanti, Alexandre Biasi; Colman, Roos; De Buyser, Stefanie L; Derde, Lennie P G; Domingo, Pere; Omar, Sharifah Faridah; Fernandez-Cruz, Ana; Feuth, Thijs; Garcia, Felipe; Garcia-Vicuna, Rosario; Gonzalez-Alvaro, Isidoro; Gordon, Anthony C; Haynes, Richard; Hermine, Olivier; Horby, Peter W; Horick, Nora K; Kumar, Kuldeep; Lambrecht, Bart N; Landray, Martin J; Leal, Lorna; Lederer, David J; Lorenzi, Elizabeth; Mariette, Xavier; Merchante, Nicolas; Misnan, Nor Arisah; Mohan, Shalini V; Nivens, Michael C; Oksi, Jarmo; Perez-Molina, Jose A; Pizov, Reuven; Porcher, Raphael; Postma, Simone; Rajasuriar, Reena; Ramanan, Athimalaipet V; Ravaud, Philippe; Reid, Pankti D; Rutgers, Abraham; Sancho-Lopez, Aranzazu.
  • Shankar-Hari M; Guy's and St Thomas' NHS Foundation Trust, ICU Support Offices, St Thomas' Hospital, London, England.
  • Vale CL; School of Immunology and Microbial Sciences, Kings College London, 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; University College London, MRC Clinical Trials Unit at UCL, London, England.
  • Spiga F; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, England.
  • Savovic J; NIHR Bristol Biomedical Research Centre, Bristol, England.
  • Tierney J; National Institute for Health Research Applied Research Collaboration West at University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, England.
  • Baron G; University of Bristol, Bristol, England.
  • Benbenishty JS; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, England.
  • Berry LR; National Institute for Health Research Applied Research Collaboration West at University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, England.
  • Broman N; University College London, MRC Clinical Trials Unit at UCL, London, England.
  • Cavalcanti AB; Assistance Publique-Hôpitaux de Paris, Centre for Clinical Epidemiology, Hôpital Hôtel-Dieu, Paris, France.
  • Colman R; INSERM UMRS-1153, Centre de Recherche Epidémiologie et Statistique Université de Paris, METHODS Team, Paris, France.
  • De Buyser SL; Department of Nursing, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
  • Derde LPG; Berry Consultants, Austin, Texas.
  • Domingo P; Turku University Hospital, Department of Infectious Diseases, Turku, Finland.
  • Omar SF; BP-A Beneficência Portuguesa de São Paulo, Rua Maestro Cardim, São Paulo, Brazil.
  • Fernandez-Cruz A; Department of Public Health and Primary Care, Ghent University, Ghent, Belgium.
  • Feuth T; Department of Public Health and Primary Care, Ghent University, Ghent, Belgium.
  • Garcia F; Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
  • Garcia-Vicuna R; Department of Infectious Diseases, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
  • Gonzalez-Alvaro I; Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
  • Gordon AC; Infectious Diseases Unit, Internal Medicine Department, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain.
  • Haynes R; Department of Pulmonary Diseases, Turku University Hospital, Turku, Finland.
  • Hermine O; Infectious Diseases Department, Hospital Clinic Barcelona-IDIBAPS, Barcelona, Spain.
  • Horby PW; Rheumatology, Hospital Universitario La Princesa IIS-IP, Madrid, Spain.
  • Horick NK; Rheumatology, Hospital Universitario La Princesa IIS-IP, Madrid, Spain.
  • Kumar K; Division of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, England.
  • Lambrecht BN; Nuffield Department of Population Health, University of Oxford, Oxford, England.
  • Landray MJ; MRC Population Health Research Unit, University of Oxford, Oxford, England.
  • Leal L; Department of Hematology, Necker Hospital, Paris, France.
  • Lederer DJ; Imagine Institute, University of Paris, INSERM U1153, Paris, France.
  • Lorenzi E; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, England.
  • Mariette X; International Severe Acute Respiratory and Emerging Infections Consortium, University of Oxford, Oxford, England.
  • Merchante N; Pandemic Sciences Centre, University of Oxford, Oxford, England.
  • Misnan NA; Department of Medicine, Massachusetts General Hospital, Boston.
  • Mohan SV; Medanta-The Medicity, Institute of Liver Transplantation and Regenerative Medicine, Gurugram, India.
  • Nivens MC; Research Department, Medanta Institute of Education and Research, Gurugram, India.
  • Oksi J; VIB Center for Inflammation Research, Ghent University, Ghent, Belgium.
  • Perez-Molina JA; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
  • Pizov R; Nuffield Department of Population Health, University of Oxford, Oxford, England.
  • Porcher R; MRC Population Health Research Unit, University of Oxford, Oxford, England.
  • Postma S; Infectious Diseases Department, Hospital Clinic Barcelona-IDIBAPS, Barcelona, Spain.
  • Rajasuriar R; Regeneron Pharmaceuticals Inc, Tarrytown, New York.
  • Ramanan AV; Berry Consultants, Austin, Texas.
  • Ravaud P; Centre for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Saclay, INSERM UMR1184, Le Kremlin-Bicêtre, Paris, France.
  • Reid PD; Department of Rheumatology, Assistance Publique-Hôpitaux de Paris, Le Le Kremlin-Bicêtre, Paris, France.
  • Rutgers A; Unit of Infectious Diseases and Microbiology, Valme University Hospital, Institute of Biomedicine of Sevilla, Seville, Spain.
  • Sancho-Lopez A; Hospital Sungai Buloh, Ministry of Health, Buloh, Malaysia.
JAMA ; 326(6): 499-518, 2021 08 10.
Article in English | MEDLINE | ID: covidwho-1413703
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.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: Interleukin-6 / Antibodies, Monoclonal, Humanized / COVID-19 Type of study: Controlled clinical trial / Observational study / Prognostic study / Randomized controlled trials / Reviews / Risk factors Limits: Aged / Female / Humans / Male / Middle aged Language: English Journal: JAMA Year: 2021 Document Type: Article Affiliation country: Jama.2021.11330

Full text: Available Collection: International databases Database: MEDLINE Main subject: Interleukin-6 / Antibodies, Monoclonal, Humanized / COVID-19 Type of study: Controlled clinical trial / Observational study / Prognostic study / Randomized controlled trials / Reviews / Risk factors Limits: Aged / Female / Humans / Male / Middle aged Language: English Journal: JAMA Year: 2021 Document Type: Article Affiliation country: Jama.2021.11330