Findings from a study published today [6 July] in the Journal of the American Medical Association (JAMA) have prompted new World Health Organization (WHO) recommendations to use interleukin-6 antagonists in patients with severe or critical COVID-19 along with corticosteroids.
A new analysis of 27 randomised trials involving nearly 11,000 patients found that treating hospitalised COVID-19 patients with drugs that block the effects of interleukin-6 (the interleukin-6 antagonists tocilizumab and sarilumab) reduces the risk of death and the need for mechanical ventilation.
The study, which was coordinated by WHO in partnership with King's College London, University of Bristol, University College London and Guy's and St Thomas' NHS Foundation Trust, found that interleukin-6 antagonists were most effective when administered with corticosteroids. In hospitalised patients, administering one of these drugs in addition to corticosteroids reduces the risk of death by 17%, compared to the use of corticosteroids alone. In patients not on mechanical ventilation, the risk of mechanical ventilation or death is reduced by 21%, compared to the use of corticosteroids alone.
In severely ill COVID-19 patients, the immune system overreacts, generating cytokines such as interleukin-6. Clinical trials have been testing whether drugs that inhibit the effects of interleukin-6, such as tocilizumab and sarilumab, benefit hospitalised patients with COVID-19. These trials have variously reported benefit, no effect and harm.
This prompted researchers from WHO's Rapid Evidence Appraisal for COVID-19 Therapies [REACT] Working Group, to examine the clinical benefit of treating hospitalised COVID-19 patients with interleukin-6 antagonists, compared with either a placebo or usual care. They combined data from 27 randomised trials that were conducted in 28 countries.
This analysis included information on 10,930 patients, of whom 6,449 were randomly assigned to receive interleukin-6 antagonists and 4,481 to receive usual care or placebo.
Results showed that the risk of dying within 28 days is lower in patients receiving interleukin-6 antagonists. In this group, the risk of death is 22% compared with an assumed risk of 25% in those receiving only usual care.
Importantly, improvements in outcomes were greater in patients who also received corticosteroids. In these patients, the risk of dying within 28 days is 21% in patients receiving interleukin-6 antagonists compared with an assumed 25% in patients receiving usual care. This means that for every 100 such patients, four more will survive.
The study also looked at the effect of these drugs on whether patients progressed to mechanical ventilation or death. Among patients also treated with corticosteroids, the risk was found to be 26% for those receiving interleukin-6 antagonists compared with an assumed 33% in those receiving usual care. This means that for every 100 such patients, 7 more will survive and avoid mechanical ventilation.
Commenting on the results of the analysis Dr Janet Diaz, Lead for Clinical management, WHO Health Emergencies, said: "Bringing together the results of trials conducted around the world is one of the best ways to find treatments that will help more people survive COVID-19. We have updated our clinical care treatment guidance to reflect this latest development. While science has delivered, we must now turn our attention to access. Given the extent of global vaccine inequity, people in the lowest income countries will be the ones most at risk of severe and critical COVID-19. Those are the people these drugs need to reach."
Prof Manu Shankar-Hari, Critical Care Consultant at Guy's and St Thomas' Hospital NHS Foundation Trust, Professor of Critical Care Medicine at King's College London and a NIHR Clinician Scientist, said: "COVID-19 is a serious illness. Our research shows that interleukin-6 antagonists reduce deaths from COVID-19, i.e. save lives, and prevent progression to severe illness necessitating breathing support with a ventilator. Further, interleukin-6 antagonists appear even more effective when used alongside corticosteroids. Our research findings reflect the incredible research effort from scientists worldwide since the start of the pandemic. On a personal note, I am grateful to the patients and their families for their willingness to participate in research during these challenging times."
Jonathan Sterne, Professor of Medical Statistics and Epidemiology, University of Bristol, Deputy Director of the National Institute for Health Research Bristol Biomedical Research Centre (NIHR Bristol BRC) and Director of Health Data Research UK South West, said: "Clinical trials assessing the efficacy of monoclonal antibodies that block interleukin-6 in hospitalised patients with COVID-19 have variously reported benefit, no effect and harm. By rapidly combining 95 per cent of the worldwide data from these trials, we have shown that these drugs work consistently in reducing death and severe COVID-19 disease across countries and health care settings, and that they work better among patients who are also receiving corticosteroids."
Claire Vale, Principal Research Fellow at the MRC Clinical Trials Unit at UCL (University College London), said: "These results, which will lead to better outcomes for patients hospitalized with COVID-19, reflect a huge global effort. Bringing together this information in such a short space of time has only been possible thanks to the overwhelming commitment of all the doctors and teams who ran the trials, and of course, the patients who took part in them."
'Association between administration of interleukin-6 antagonists and mortality among hospitalized patients with COVID-19: a meta-analysis' by Shankar-Hari M, Vale C, J Sterne et al in JAMA.
Notes to editors:
Link to WHO guidance (new guidance will be available at 20 H CEST on 6 July 2021): https://apps.who.int/iris/bitstream/handle/10665/342368/WHO-2019-nCoV-therapeutics-2021.2-eng.pdf)
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