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Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19A Meta-analysis

Educational Objective
To understand the association between administration of systemic Corticosteroids And mortality among critically ill patients with COVID-19
1 Credit CME
Key Points

Question  Is administration of systemic corticosteroids associated with reduced 28-day mortality in critically ill patients with coronavirus disease 2019 (COVID-19)?

Findings  In this prospective meta-analysis of 7 randomized trials that included 1703 patients of whom 647 died, 28-day all-cause mortality was lower among patients who received corticosteroids compared with those who received usual care or placebo (summary odds ratio, 0.66).

Meaning  Administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality in critically ill patients with COVID-19.

Abstract

Importance  Effective therapies for patients with coronavirus disease 2019 (COVID-19) are needed, and clinical trial data have demonstrated that low-dose dexamethasone reduced mortality in hospitalized patients with COVID-19 who required respiratory support.

Objective  To estimate the association between administration of corticosteroids compared with usual care or placebo and 28-day all-cause mortality.

Design, Setting, and Participants  Prospective meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19. The trials were conducted in 12 countries from February 26, 2020, to June 9, 2020, and the date of final follow-up was July 6, 2020. Pooled data were aggregated from the individual trials, overall, and in predefined subgroups. 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-effect meta-analysis of overall mortality, with the association between the intervention and mortality quantified using odds ratios (ORs). Random-effects meta-analyses also were conducted (with the Paule-Mandel estimate of heterogeneity and the Hartung-Knapp adjustment) and an inverse variance–weighted fixed-effect analysis using risk ratios.

Exposures  Patients had been randomized to receive systemic dexamethasone, hydrocortisone, or methylprednisolone (678 patients) or to receive usual care or placebo (1025 patients).

Main Outcomes and Measures  The primary outcome measure was all-cause mortality at 28 days after randomization. A secondary outcome was investigator-defined serious adverse events.

Results  A total of 1703 patients (median age, 60 years [interquartile range, 52-68 years]; 488 [29%] women) were included in the analysis. Risk of bias was assessed as “low” for 6 of the 7 mortality results and as “some concerns” in 1 trial because of the randomization method. Five trials reported mortality at 28 days, 1 trial at 21 days, and 1 trial at 30 days. There were 222 deaths among the 678 patients randomized to corticosteroids and 425 deaths among the 1025 patients randomized to usual care or placebo (summary OR, 0.66 [95% CI, 0.53-0.82]; P < .001 based on a fixed-effect meta-analysis). There was little inconsistency between the trial results (I2 = 15.6%; P = .31 for heterogeneity) and the summary OR was 0.70 (95% CI, 0.48-1.01; P = .053) based on the random-effects meta-analysis. The fixed-effect summary OR for the association with mortality was 0.64 (95% CI, 0.50-0.82; P < .001) for dexamethasone compared with usual care or placebo (3 trials, 1282 patients, and 527 deaths), the OR was 0.69 (95% CI, 0.43-1.12; P = .13) for hydrocortisone (3 trials, 374 patients, and 94 deaths), and the OR was 0.91 (95% CI, 0.29-2.87; P = .87) for methylprednisolone (1 trial, 47 patients, and 26 deaths). Among the 6 trials that reported serious adverse events, 64 events occurred among 354 patients randomized to corticosteroids and 80 events occurred among 342 patients randomized to usual care or placebo.

Conclusions and Relevance  In this prospective meta-analysis of clinical trials of critically ill patients with COVID-19, administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.

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Article Information

Accepted for Publication: August 21, 2020.

Corresponding Author: Jonathan A. C. Sterne, MA, MSc, PhD, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, England (jonathan.sterne@bristol.ac.uk).

Published Online: September 2, 2020. doi:10.1001/jama.2020.17023

The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group Authors and Members of the Writing Committee: Jonathan A. C. Sterne, MA, MSc, PhD; Srinivas Murthy, MD, MSc; Janet V. Diaz, MD; Arthur S. Slutsky, CM, MD; Jesús Villar, MD, PhD; Derek C. Angus, MD, MPH; Djillali Annane, MD, PhD; Luciano Cesar Pontes Azevedo, MD, PhD; Otavio Berwanger, MD, PhD; Alexandre B. Cavalcanti, MD, PhD; Pierre-Francois Dequin, MD, PhD; Bin Du, MD; Jonathan Emberson, PhD; David Fisher, MSc; Bruno Giraudeau, PhD; Anthony C. Gordon, MBBS, MD; Anders Granholm, MD; Cameron Green, MSc; Richard Haynes, DM; Nicholas Heming, MD, PhD; Julian P. T. Higgins, BA, PhD; Peter Horby, PhD; Peter Jüni, MD; Martin J. Landray, PhD; Amelie Le Gouge, MSc; Marie Leclerc, MSc; Wei Shen Lim, BMedSci, BMBS, DM; Flávia R. Machado, MD, PhD; Colin McArthur, MBChB; Ferhat Meziani, MD, PhD; Morten Hylander Møller, MD, PhD; Anders Perner, MD, PhD; Marie Warrer Petersen, MD; Jelena Savović, BPharm, MSc, PhD; Bruno Tomazini, MD; Viviane C. Veiga, MD, PhD; Steve Webb, MBBS, MPH, PhD; John C. Marshall, MD.

Affiliations of The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group Authors and Members of the Writing Committee: Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, England (Sterne, Higgins, Savović); NIHR Bristol Biomedical Research Centre, Bristol, England (Sterne, Higgins); Department of Pediatrics, University of British Columbia, Vancouver, Canada (Murthy); Clinical Unit, Health Emergencies Programme, World Health Organization, Geneva, Switzerland (Diaz); Applied Health Research Centre, Li Ka Shing Knowledge Institute of St Michael’s Hospital, Department of Medicine, University of Toronto, Toronto, Ontario, Canada (Slutsky, Jüni); Research Unit, Hospital Universitario Dr Negrín, Las Palmas de Gran Canaria, Spain (Villar); CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain (Villar); Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (Angus); Department of Intensive Care, Raymond Poincaré Hospital (APHP), School of Medicine Simone Veil, University Paris Saclay-UVSQ, Paris, France (Annane, Heming); Hospital Sírio-Libanês, São Paulo, Brazil (Azevedo, Tomazini); Emergency Medicine Department, University of São Paulo School of Medicine, São Paulo, Brazil (Azevedo); Academic Research Organization, Hospital Israelita Albert Einstein, São Paulo, Brazil (Berwanger); HCor Research Insitute, São Paulo, Brazil (Cavalcanti); Médecine Intensive-Réanimation, INSERM CIC1415, CHRU de Tours, Tours, France (Dequin); CRICS-TriGGERSep Network, Centre d’Etude des Pathologies Respiratoires, Université de Tours, Tours, France (Dequin); Peking Union Medical College Hospital, Beijing, China (Du); Nuffield Department of Population Health, University of Oxford, Oxford, England (Emberson, Haynes, Landray); MRC Population Health Research Unit, University of Oxford, Oxford, England (Emberson, Haynes, Landray); MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, Faculty of Population Health Sciences, University College London, London, England (Fisher); CIC INSERM 1415-CHRU de Tours, Tours, France (Giraudeau, Le Gouge, Leclerc); Division of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, England (Gordon); Department of Intensive Care, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark (Granholm, Møller, Perner, Petersen); Australian and New Zealand Intensive Care Research Centre, School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia (Green, McArthur, Webb); NIHR Applied Research Collaboration West, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, England (Higgins, Savović); Nuffield Department of Medicine, University of Oxford, Oxford, England (Horby); NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, England (Landray); Respiratory Medicine Department, Nottingham University Hospitals NHS Trust, Nottingham, England (Lim); Anesthesiology, Pain, and Intensive Care Department, Federal University of São Paulo, São Paulo, Brazil (Machado); Department of Critical Care Medicine, Auckland City Hospital, Auckland, New Zealand (McArthur); Hôpitaux Universitaires de Strasbourg, Service de Médecine Intensive Réanimation, Nouvel Hôpital Civil, Strasbourg, France (Meziani); INSERM UMR 1260, Regenerative Nanomedicine, FMTS, Strasbourg, France (Meziani); Department of Surgery, School of Medicine, University of São Paulo, São Paulo, Brazil (Tomazini); BP-A Beneficência Portuguesa de São Paulo, São Paulo, Brazil (Veiga); St John of God Healthcare, Subiaco, Australia (Webb); Li Ka Shing Knowledge Institute, St Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada (Marshall).

Author Contributions: Dr Sterne had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Sterne, Murthy, Diaz, Slutsky, Villar, Angus, Annane, Du, Gordon, Higgins, Jüni, Le Gouge, Leclerc, Machado, Møller, Perner, Tomazini, Veiga, Marshall.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Sterne, Murthy, Diaz, Villar, Angus, Fisher, Higgins, Machado, Møller, Veiga, Marshall.

Critical revision of the manuscript for important intellectual content: Sterne, Murthy, Diaz, Slutsky, Villar, Angus, Annane, Azevedo, Berwanger, Du, Cavalcanti, Dequin, Emberson, Giraudeau, Gordon, Granholm, Green, Haynes, Heming, Higgins, Horby, Jüni, Landray, Le Gouge, Leclerc, Lim, Machado, McArthur, Meziani, Møller, Perner, Petersen, Savovic, Tomazini, Veiga, Webb, Marshall.

Statistical analysis: Sterne, Murthy, Angus, Du, Emberson, Fisher, Higgins, Jüni, Møller, Perner.

Obtained funding: Gordon, McArthur, Perner, Webb.

Administrative, technical, or material support: Sterne, Murthy, Diaz, Slutsky, Villar, Angus, Du, Gordon, McArthur, Perner, Tomazini, Veiga, Webb, Marshall.

Supervision: Sterne, Murthy, Diaz, Villar, Angus, Azevedo, Machado, Meziani, Veiga, Marshall.

Conflict of Interest Disclosures: Dr Sterne reported receiving grants from the UK National Institute for Health Research (NIHR). Dr Murthy reported receiving grants from the Canadian Institutes of Health Research. Dr Slutsky reported being a co-primary investigator of one of the trials that is included in the meta-analysis. Dr Angus reported receiving personal fees from Ferring Pharmaceuticals Inc, Bristol-Myers Squibb, Bayer AG, and Alung Technologies Inc; and having patents pending for Selepressin (compounds, compositions, and methods for treating sepsis) and for proteomic biomarkers of sepsis in elderly patients. Dr Annane reported receiving grants from the French Ministry of Health; and being on the steering committees for 2 of the trials (CAPE COVID and REMAP-CAP) included in this meta-analysis. Dr Azevedo reported receiving grants from Ache Pharma; and receiving personal fees from Pfizer and Halex-Istar. Dr Berwanger reported receiving grants from AstraZeneca, Servier, Novartis, Bayer, Boehringer-Ingelheim, and Amgen. Dr Cavalcanti reported receiving grants from Bayer, Bactiguard, Johnson & Johnson do Brasil, Hemaclear, Hillrom, and Pfizer. Dr Dequin reported receiving grants from the French Ministry of Health, Abionic, Atox Bio, Sphingotec Gmbh, Adrenomed, Medspace, Aridis, Merck, Combioxin, GlaxoSmithKline, Medimmune, Genentech, Revimmune, Faron, Kenta, and Tigenix. Dr Du reported receiving grants from Peking Union Medical College, the Chinese Academy of Medical Sciences, and the Chinese Ministry of Science and Technology. Dr Emberson reported receiving grants from Boehringer Ingelheim. Dr Gordon reported receiving grants from the NIHR; receiving a research professorship from the NIHR; receiving nonfinancial support from the NIHR Clinical Research Network and the NIHR Imperial Biomedical Research Centre; receiving personal fees from GlaxoSmithKline and Bristol-Myers Squibb; and being the UK chief investigator and a member of the international trial steering committee for the REMAP-CAP trial. Dr Granholm reported receiving grants from the Novo Nordisk Foundation, Pfizer, the Rigshospitalet Research Council, Ferring Pharmaceuticals, and Fresenius Kabi; and being a member of the management committee of one of the trials (COVID STEROID) included in this meta-analysis. Dr Jüni reported receiving personal fees from Amgen, Ava, and Fresenius; receiving grants from the Canadian Institutes of Health Research and Appili Therapeutics; and serving as an unpaid member of the steering group of trials funded by Abbott Vascular, AstraZeneca, Biotronik, Biosensors, St Jude Medical, Terumo, and the Medicines Company. Dr Landray reported receiving grants from UK Research and Innovation, the UK NIHR, Health Data Research UK, the NIHR Oxford Biomedical Research Centre, MRC Population Health Research Unit, Merck, Sharp & Dohme, Novartis, Boehringer Ingelheim, the Medicines Company, and UK Biobank Ltd; and receiving nonfinancial support from Roche and AbbVie. Dr Lim reported receiving grants from Pfizer. Dr Machado reported receiving personal fees from ACHE. Dr McArthur reported receiving grants from the Health Research Council of New Zealand. Dr Perner reported receiving grants from the Novo Nordisk Foundation and Pfizer. Dr Petersen reported receiving grants from the Novo Nordisk Foundation and Pfizer. Dr Savović reported receiving grants from the UK NIHR. Dr Webb reported receiving grants from the National Health and Medical Research Council and the Minderoo Foundation. Dr Marshall reported receiving personal fees from AM Pharma; and serving as co-chair on the WHO Working Group on Clinical Characterization and as management chair for the International Forum for Acute Care Trialists. No other disclosures were reported.

Funding/Support: Funding for administrative and communications support was provided by the World Health Organization.

Role of the Funder/Sponsor: The World Health Organization (WHO) contributed to the design and conduct of the study by convening the WHO COVID-19 Clinical Management and Characterization Working Group. This group assembled information on ongoing trials and invited trial investigators to participate in this prospective meta-analysis. The WHO chief scientist invited trial investigators to participate and provided a secure portal for submission of data. Other than the contributions of Dr Diaz as a coauthor, the WHO had no role in the preparation, review, or approval of the manuscript. The WHO had no role in the decision to submit the manuscript for publication.

Disclaimer: The views expressed in this article are those of the authors and not necessarily those of the UK National Institute for Health Research or the UK Department of Health and Social Care. Dr Angus is Associate Editor, JAMA, but was not involved in any of the decisions regarding review of the manuscript or its acceptance.

Additional Contributions: We gratefully acknowledge the efforts of all trial investigators (the lists of names appear in the Supplement) and the patients who provided consent for participation. We thank Agnes Sagfors, PhD, and other staff at the W2O Group for searches of trial registries and for administrative and communications support. We thank Kerry Barot, BA (University of Bristol), for administrative support. We thank Vanderson de Souza Sampaio, PhD (Fundação de Medicina Tropical Dr Heitor Vieira Dourado-FMT-HVD, Manaus, Amazonas, Brazil; Universidade do Estado do Amazonas, Manaus, Amazonas, Brazil; and Fundação de Vigilância em Saúde, Manaus, Amazonas, Brazil), and colleagues for providing additional data from the Metcovid trial. None of these persons received compensation beyond their usual salaries.

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