Corticosteroids reduce the risk of death among critically ill COVID-19 patients by 20%, an analysis of seven trials has found. The results of three of the trials included in the meta-analysis are also published. The study by an international team of scientists of the WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group and the WHO COVID-19 Clinical Management and Characterisation Working Group, which was co-ordinated by the World Health Organisation (WHO) with analyses led by National Institute for Health Research (NIHR) researchers at the University of Bristol, looked at mortality over a 28-day period after the start of treatment.
They found that treatment with one of the three corticosteroids dexamethasone, hydrocortisone or methylprednisolone led to an estimated 20% reduction in the risk of death. This is equivalent to around 68% of patients surviving after treatment with corticosteroids, compared to around 60% surviving in the absence of corticosteroids.
The dexamethasone finding is mainly based on results from the RECOVERY trial, which were included in the analysis.
The analysis is the result of unprecedented co-operation between study teams, guideline developers and journals in response to the global pandemic. This ground-breaking collaboration saw results shared between research teams and with guideline developers before they were published, and papers reporting individual trials, the meta-analysis and international treatment guidelines published simultaneously.
The seven randomised control trials (the best type of study to examine the effect of a medical intervention) recruited 1,703 critically ill patients in total, spanning five continents and including some of the countries hardest hit by COVID-19. The analysis included critically ill patients from the RECOVERY trial, which reported its findings in June 2020.
The mortality results were consistent across the seven trials with two types of corticosteroid, dexamethasone and hydrocortisone, giving similar effects. Too few patients were included in trials of methylprednisolone to allow its effect to be estimated with precision.
There was evidence of benefit from corticosteroids regardless of whether patients were receiving invasive mechanical ventilation at the time they started treatment. The benefit appeared greater among patients who were not so sick that they needed medicine to support their blood pressure, although the results were not definitive in this regard. The effect of corticosteroids appeared similar regardless of age, sex or how long patients had been ill.
Jonathan Sterne, professor of medical statistics and epidemiology, University of Bristol and deputy director of the NIHR Bristol Biomedical Research Centre (NIHR Bristol BRC), said: “Our review is good news in the effort to treat COVID-19, and provides important new information that builds on the findings of the RECOVERY trial. Steroids are a cheap and readily available medication, and our analysis has confirmed that they are effective in reducing deaths amongst the people most severely affected by COVID-19. The results were consistent across the trials and show benefit regardless of age or sex.”
The team behind the review includes the lead researchers for all of the seven trials and scientists from Brazil, Canada, China, France, Spain, the UK and the US. The work is part of the WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) initiative.
John Marshall, professor of surgery at the University of Toronto, senior scientist at the Li Ka Shing Knowledge Institute at St Michael’s Hospital of Unity Health Toronto, and co-chair of the WHO Working Group on Clinical Characterisation and Management, added: “Even beyond the clear evidence of benefit for an inexpensive and widely available medication, the process of this work – pooling data across seven trials conducted over a period of only three months – highlights the willingness of researchers around the world to share data in a new research model that can bring reliable evidence rapidly to improve the care of patients with COVID-19.”
Janet Diaz, lead, clinical response for COVID-19, WHO Emergency Programme, said: “WHO is committed to transforming science to policy in order to save lives. The COVID-19 pandemic has challenged us to work faster, but not to sacrifice quality and standards. The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group demonstrates how, in solidarity, science and public health can come together quickly for a common cause. The milestone of pooling of trial data before publication, using that data to inform clinical guidance development and then simultaneous publication of the evidence, evidence synthesis and guidance is unprecedented. I am privileged to have been part of this tremendous collaboration.”
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
Jonathan AC Sterne, Srinivas Murthy, Janet Diaz, Arthur S Slutsky, Jesús Villar, Derek C Angus, Djillali Annane, Luciano Cesar Pontes Azevedo, Otavio Berwanger, Du Bin, Alexandre B Cavalcanti, Pierre-Francois Dequin, Jonathan Emberson, David Fisher, Bruno Giraudeau, Anthony C Gordon, Anders Granholm, Cameron Green, Richard Haynes, Nicholas Heming, Julian P T Higgins, Peter Horby, Peter Jüni, Martin J Landray, Amelie Le Gouge, Marie Leclerc, Wei Shen Lim, Flávia R. Machado, Colin McArthur, Ferhat Meziani, Morten Hylander Møller, Anders Perner, Marie W Petersen, Jelena Savovic, Bruno Tomazini, Viviane C Veiga, Steve Webb, John C Marshall
[link url="https://www.bristol.ac.uk/news/2020/september/corticosteroids-study.html"]University of Bristol material[/link]
[link url="https://jamanetwork.com/journals/jama/fullarticle/2770279?guestAccessKey=ec87204d-c42d-4d34-bef5-077a40bc86b0&utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_content=tfl&utm_term=090220"]JAMA abstract[/link]