Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19

Anthony C Gordon, Paul R Mouncey, Farah Al-Beidh, Kathryn M Rowan, Alistair D Nichol, Yaseen M Arabi, Djillali Annane, Abi Beane, Wilma van Bentum-Puijk, Lindsay R Berry, Zahra Bhimani, Marc J M Bonten, Charlotte A Bradbury, Frank M Brunkhorst, Adrian Buzgau, Allen C Cheng, Michelle A Detry, Eamon J Duffy, Lise J Estcourt, Mark Fitzgerald, Herman Goossens, Rashan Haniffa, Alisa M Higgins, Thomas E Hills, Christopher M Horvat, Francois Lamontagne, Patrick R Lawler, Helen L Leavis, Kelsey M Linstrum, Edward Litton, Elizabeth Lorenzi, John C Marshall, Florian B Mayr, Daniel F McAuley, Anna McGlothlin, Shay P McGuinness, Bryan J McVerry, Stephanie K Montgomery, Susan C Morpeth, Srinivas Murthy, Katrina Orr, Rachael L Parke, Jane C Parker, Asad E Patanwala, Ville Pettilä, Emma Rademaker, Marlene S Santos, Christina T Saunders, Christopher W Seymour, Manu Shankar-Hari, Wendy I Sligl, Alexis F Turgeon, Anne M Turner, Frank L van de Veerdonk, Ryan Zarychanski, Cameron Green, Roger J Lewis, Derek C Angus, Colin J McArthur, Scott Berry, Steve A Webb, Lennie P G Derde
New England Journal of Medicine 2021 February 25

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. (REMAP-CAP number, NCT02735707.).

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