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Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis.
JAMA. 2020 10 06; 324(13):1330-1341.JAMA

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.

Authors+Show Affiliations

No affiliation info availablePopulation Health Sciences, Bristol Medical School, University of Bristol, Bristol, England. NIHR Bristol Biomedical Research Centre, Bristol, England.Department of Pediatrics, University of British Columbia, Vancouver, Canada.Clinical Unit, Health Emergencies Programme, World Health Organization, Geneva, Switzerland.Applied Health Research Centre, Li Ka Shing Knowledge Institute of St Michael's Hospital, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.Research Unit, Hospital Universitario Dr Negrín, Las Palmas de Gran Canaria, Spain. CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.Department of Intensive Care, Raymond Poincaré Hospital (APHP), School of Medicine Simone Veil, University Paris Saclay-UVSQ, Paris, France.Hospital Sírio-Libanês, São Paulo, Brazil. Emergency Medicine Department, University of São Paulo School of Medicine, São Paulo, Brazil.Academic Research Organization, Hospital Israelita Albert Einstein, São Paulo, Brazil.HCor Research Insitute, São Paulo, Brazil.Médecine Intensive-Réanimation, INSERM CIC1415, CHRU de Tours, Tours, France. CRICS-TriGGERSep Network, Centre d'Etude des Pathologies Respiratoires, Université de Tours, Tours, France.Peking Union Medical College Hospital, Beijing, China.Nuffield Department of Population Health, University of Oxford, Oxford, England. MRC Population Health Research Unit, University of Oxford, Oxford, England.MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, Faculty of Population Health Sciences, University College London, London, England.CIC INSERM 1415-CHRU de Tours, Tours, France.Division of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, England.Department of Intensive Care, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.Australian and New Zealand Intensive Care Research Centre, School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia.Nuffield Department of Population Health, University of Oxford, Oxford, England. MRC Population Health Research Unit, University of Oxford, Oxford, England.Department of Intensive Care, Raymond Poincaré Hospital (APHP), School of Medicine Simone Veil, University Paris Saclay-UVSQ, Paris, France.Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, England. NIHR Bristol Biomedical Research Centre, Bristol, England. NIHR Applied Research Collaboration West, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, England.Nuffield Department of Medicine, University of Oxford, Oxford, England.Applied Health Research Centre, Li Ka Shing Knowledge Institute of St Michael's Hospital, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.Nuffield Department of Population Health, University of Oxford, Oxford, England. MRC Population Health Research Unit, University of Oxford, Oxford, England. NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, England.CIC INSERM 1415-CHRU de Tours, Tours, France.CIC INSERM 1415-CHRU de Tours, Tours, France.Respiratory Medicine Department, Nottingham University Hospitals NHS Trust, Nottingham, England.Anesthesiology, Pain, and Intensive Care Department, Federal University of São Paulo, São Paulo, Brazil.Australian and New Zealand Intensive Care Research Centre, School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia. Department of Critical Care Medicine, Auckland City Hospital, Auckland, New Zealand.Hôpitaux Universitaires de Strasbourg, Service de Médecine Intensive Réanimation, Nouvel Hôpital Civil, Strasbourg, France. INSERM UMR 1260, Regenerative Nanomedicine, FMTS, Strasbourg, France.Department of Intensive Care, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.Department of Intensive Care, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.Department of Intensive Care, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, England. NIHR Applied Research Collaboration West, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, England.Hospital Sírio-Libanês, São Paulo, Brazil. Department of Surgery, School of Medicine, University of São Paulo, São Paulo, Brazil.BP-A Beneficência Portuguesa de São Paulo, São Paulo, Brazil.Australian and New Zealand Intensive Care Research Centre, School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia. St John of God Healthcare, Subiaco, Australia.Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.

Pub Type(s)

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

Language

eng

PubMed ID

32876694

Citation

WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, et al. "Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: a Meta-analysis." JAMA, vol. 324, no. 13, 2020, pp. 1330-1341.
WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JAC, Murthy S, et al. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis. JAMA. 2020;324(13):1330-1341.
Sterne, J. A. C., Murthy, S., Diaz, J. V., Slutsky, A. S., Villar, J., Angus, D. C., Annane, D., Azevedo, L. C. P., Berwanger, O., Cavalcanti, A. B., Dequin, P. F., Du, B., Emberson, J., Fisher, D., Giraudeau, B., Gordon, A. C., Granholm, A., Green, C., Haynes, R., ... Marshall, J. C. (2020). Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis. JAMA, 324(13), 1330-1341. https://doi.org/10.1001/jama.2020.17023
WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, et al. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: a Meta-analysis. JAMA. 2020 10 6;324(13):1330-1341. PubMed PMID: 32876694.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis. AU - ,, AU - Sterne,Jonathan A C, AU - Murthy,Srinivas, AU - Diaz,Janet V, AU - Slutsky,Arthur S, AU - Villar,Jesús, AU - Angus,Derek C, AU - Annane,Djillali, AU - Azevedo,Luciano Cesar Pontes, AU - Berwanger,Otavio, AU - Cavalcanti,Alexandre B, AU - Dequin,Pierre-Francois, AU - Du,Bin, AU - Emberson,Jonathan, AU - Fisher,David, AU - Giraudeau,Bruno, AU - Gordon,Anthony C, AU - Granholm,Anders, AU - Green,Cameron, AU - Haynes,Richard, AU - Heming,Nicholas, AU - Higgins,Julian P T, AU - Horby,Peter, AU - Jüni,Peter, AU - Landray,Martin J, AU - Le Gouge,Amelie, AU - Leclerc,Marie, AU - Lim,Wei Shen, AU - Machado,Flávia R, AU - McArthur,Colin, AU - Meziani,Ferhat, AU - Møller,Morten Hylander, AU - Perner,Anders, AU - Petersen,Marie Warrer, AU - Savovic,Jelena, AU - Tomazini,Bruno, AU - Veiga,Viviane C, AU - Webb,Steve, AU - Marshall,John C, PY - 2020/9/3/pubmed PY - 2020/11/5/medline PY - 2020/9/3/entrez SP - 1330 EP - 1341 JF - JAMA JO - JAMA VL - 324 IS - 13 N2 - 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. SN - 1538-3598 UR - https://www.unboundmedicine.com/medline/citation/32876694/Association_Between_Administration_of_Systemic_Corticosteroids_and_Mortality_Among_Critically_Ill_Patients_With_COVID_19:_A_Meta_analysis_ L2 - https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2020.17023 DB - PRIME DP - Unbound Medicine ER -