Interleukin-6 receptor antagonist treatment improves outcomes in patients with COVID-19 infection [Classics Series]

This study summary is an excerpt from the book 2 Minute Medicine’s The Classics in Medicine: Summaries of the Landmark Trials

1. Treatment with tocilizumab and sarilumab increased the number of days without respiratory or cardiovascular organ support in patients with COVID-19 infection.

2. Interleukin-6 receptor antagonists improved in-hospital survival for patients diagnosed with COVID-19 and receiving organ support in the intensive care unit (ICU).

Original Date of Publication: April 2021

Study Rundown: Thus far, only glucocorticoids had been shown to improve survival in critically ill patients with coronavirus disease 2019 (COVID-19). Tocilizumab and sarilumab are monoclonal antibodies against receptors of interleukin-6 (IL-6), a key molecule in the acute-phase inflammatory response. This trial investigated the effectiveness of tocilizumab and sarilumab on organ support and survival in critically ill patients with COVID-19. Treatment with tocilizumab and sarilumab was found to improve the number of days critically ill patients in the ICU went without organ support. Furthermore, IL-6 receptor antagonist treatment improved 90-day survival in the same patient group compared to the control group. The study was not without limitations, such as the lack of reporting on long-term outcomes and small sample size in the sarilumab group. This study’s results are significant, and its pragmatic, international design suggests results from this study may be generalized to use IL-6 receptor antagonist treatment in critically ill COVID-19 patients; however, caution must be taken as the standard of care may differ in other ICUs.

Click to read the study in NEJM

In-Depth [randomized control trial]: This randomized control trial randomized 895 patients at 113 sites across six countries. Critically ill patients admitted to the ICU on organ support and ≥18 years of age were included. Patients previously participated in another study within 90 days or a presumption of imminent death were excluded from the study. The patients were randomized to one of five interventions – tocilizumab, sarilumab, anakinra (IL-1 receptor antagonist), interferon beta-1a, and control. The primary outcome was number of respiratory and cardiovascular organ support-free days up to day 21. The median number of organ support-free days for treatment modalities were 10 days with tocilizumab treatment (interquartile range, -1 to 16); 11 days with sarilumab treatment (interquartile range, 0 to 16); and 0 days in the control group 0 (interquartile range, -1 to 15). The median adjusted odds ratios for organ support-free days were 1.64 for tocilizumab treatment (95%CI 1.25-2.14) and 1.76 for sarilumab treatment (95%CI 1.17-2.91). The in-hospital mortality for IL-6 receptor antagonist groups was 27% (108 of 395 patients) compared to 36% (142 of 397) patients in the control group. The median adjusted odds ratios for in-hospital survival were 1.64 in the tocilizumab treatment (95%CI 1.14-2.35) and 2.01 in the sarilumab treatment (95%CI 1.18-4.71). Therefore, IL-6 receptor antagonist therapy in critically ill ICU patients with COVID-19 was shown to improve outcomes, including survival.

The REMAP-CAP Investigators. Interleukin-6 Receptor Antagonists in Critically Ill Patients with COVID-19. N Engl J Med. 2021 Apr 22;384(16):1491–502.

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