Interleukin-6 receptor antagonists in critically ill patients with covid-19
Publication date
2021-04-22
Authors
Gordon, Anthony C.
Mouncey, Paul R.
Al-Beidh, Farah
Rowan, Kathryn M.
Nichol, Alistair D.
Arabi, Yaseen M.
Annane, Djillali
Beane, Abi
van Bentum-Puijk, Wilma
Berry, Lindsay R.
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Supervisors
Document Type
Article
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taverne
Abstract
BACKGROUND: The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support-free days, on an ordinal scale combining in-hospital death (assigned a value of −1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support-free days, or both. RESULTS Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support-free days was 10 (interquartile range, −1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, −1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists. CONCLUSIONS In critically ill patients with Covid-19 receiving organ support in ICUs, treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival.
Keywords
Adult, Aged, Antibodies, Monoclonal, Humanized/adverse effects, COVID-19/complications, Critical Illness, Female, Hospital Mortality, Humans, Intensive Care Units, Male, Middle Aged, Odds Ratio, Receptors, Interleukin-6/antagonists & inhibitors, Respiration, Artificial, Taverne, General Medicine, Research Support, Non-U.S. Gov't, Randomized Controlled Trial, Multicenter Study, Journal Article
Citation
Gordon, A C, Mouncey, P R, Al-Beidh, F, Rowan, K M, Nichol, A D, Arabi, Y M, Annane, D, Beane, A, van Bentum-Puijk, W, Berry, L R, Bhimani, Z, Bonten, M J M, Bradbury, C A, Brunkhorst, F M, Buzgau, A, Cheng, A C, Detry, M A, Duffy, E J, Estcourt, L J, Fitzgerald, M, Goossens, H, Haniffa, R, Higgins, A M, Hills, T E, Horvat, C M, Lamontagne, F, Lawler, P R, Leavis, H L, Linstrum, K M, Litton, E, Lorenzi, E, Marshall, J C, Mayr, F B, McAuley, D F, McGlothlin, A, McGuinness, S P, McVerry, B J, Montgomery, S K, Morpeth, S C, Murthy, S, Orr, K, Parke, R L, Parker, J C, Patanwala, A E, Pettilä, V, Rademaker, E, Santos, M S, Saunders, C T, Seymour, C W, Derde, L P G, REMAP-CAP Investigators & Cremer, O 2021, 'Interleukin-6 receptor antagonists in critically ill patients with covid-19', The New England journal of medicine, vol. 384, no. 16, pp. 1491-1502. https://doi.org/10.1056/NEJMoa2100433