IL-6 antagonists reduce risk of death in hospitalised COVID-19 patients, finds analysis

Based on new study data, the World Health Organization (WHO) is recommending the use of interleukin-6 (IL-6) antagonists alongside corticosteroids for the treatment of patients with severe or critical COVID-19.

The analysis published in the Journal of the American Medical Association (JAMA) showed that hospitalised COVID-19 patients treated with drugs to inhibit the effects of IL-6 – namely the antibodies tocilizumab and sarilumab – reduced risk of death and the need for mechanical ventilation. The analysis took data from 27 randomised trials involving 10,930 patients, 6,449 of which received IL-6 antagonists and 4,481 usual care or placebo.

The study, co-ordinated by WHO in partnership with King’s College London, University of Bristol, University College London and Guy’s and St Thomas’ NHS Foundation Trust, all UK, found that when IL-6 antagonists were administered with corticosteroids, the risk of death was reduced by 17 percent, compared to the use of corticosteroids alone. In patients not on mechanical ventilation, the risk of mechanical ventilation or death was reduced by 21 percent, compared to corticosteroids alone.

Researchers at the WHO’s Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group were prompted to co-ordinate the study after trials of IL-6 antagonists reported inconsistent results, ranging from benefit to no effect or harm.  

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.

Results of the pooled analysis suggest the risk of dying within 28 days is lower in patients receiving interleukin-6 antagonists – 22 percent versus an assumed risk of 25 percent 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 percent.

The study also looked at the effect of these drugs on whether patients progressed to mechanical ventilation or death. Among patients treated with both corticosteroids and IL-6 antagonists, the risk was found to be 26 percent, compared with an assumed 33 percent in those receiving usual care.

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, commented: “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 percent 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.”

Dr Janet Diaz, Lead for Clinical management, WHO Health Emergencies, added: “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.”