In critically ill patients with coronavirus disease 2019 (COVID-19) receiving organ support in intensive care units (ICUs), treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival, according to a study published in The New England Journal of Medicine.
The findings came from an ongoing international, adaptive platform trial known as Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP). Adult patients with COVID-19 were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight – up to a maximum of 800 mg), sarilumab (400 mg), or standard care (control) within 24 hours after starting organ support in the ICU. At the time of analysis, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to standard care. Baseline characteristics were balanced across intervention groups and typical of a critically ill population with COVID-19.
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.
Researchers reported that 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. Meanwhile, 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 compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively.
On the other hand, in-hospital mortality in the pooled interleukin-6 receptor antagonist groups was 27% (108 of 395 patients), compared with 36% (142 of 397 patients) in the control group. The median adjusted odds ratios for in-hospital survival were 1.64 (95% credible interval, 1.14 to 2.35) for tocilizumab and 2.01 (95% credible interval, 1.18 to 4.71) for sarilumab compared with control, yielding posterior probabilities of superiority of 99.6% and 99.5%, respectively.
Further, 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%.
“We found that in critically ill patients with COVID-19, the interleukin-6 receptor antagonists tocilizumab and sarilumab were both effective as compared with the current standard of care, which included glucocorticoids in the majority of patients (>80%),” wrote Anthony C. Gordon, Imperial College London, London, United Kingdom, and colleagues. “The benefit was consistent across primary and secondary outcomes and across subgroups and secondary analyses.”
“We saw both a shorter time to clinical improvement and lower mortality with tocilizumab and with sarilumab than with control. It is therefore possible that the maximum clinical benefit from interleukin-6 inhibition (ie, improved survival) is seen in the most severely ill patients with COVID-19, who are at the highest risk for death,” the authors added.
“However, it is important to note that in our trial, patients had to be enrolled within 24 hours after starting organ support in the ICU. This may be an important factor to maximise effectiveness: treating critically ill patients early, while any developing organ dysfunction may be more reversible,” the authors highlighted.
“The pragmatic, international design of REMAP-CAP means that our results are probably generalisable to the wider critically ill patient population with COVID-19, although the standard of care may vary in other ICUs and over time, and other populations may include different high-risk patients,” the authors added.