february 2021 • NEJM

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

The REMAP-CAP Investigators

DOI: 10.1056/NEJMoa2100433

Content curated by:David Rodrigues

Key message

Os inibidores da Il-6 tocilizumab e sailumab demonstraram, num ensaio clinico aleatorizado, eficácia para tratamento de doentes com covid-19 severa admitidos em unidades de cuidados intensivos.

Analysis

Population

Doentes com COVID-19 severa

Method

Ensaio clinico aleatorizado que envolveu adultos com Covid-19. Nas 24 horas após o início do suporte de órgãos na unidade de cuidados intensivos (UCI) foram aleatoriamente designados para receber tocilizumab (8 mg/kg de peso corporal), sarilumab (400 mg) ou tratamento padrão (controlo). O outcome primário foi definido como dias livres de suporte de órgãos respiratórios e cardiovasculares.

Results

353 pacientes foram atribuidos a tocilizumab, 48 para sarilumab e 402 para controlo. o número médio de dias sem suporte de órgão foi de 10 (intervalo interquartil, -1 a 16) no grupo tocilizumab, 11 (intervalo interquartil, 0 a 16) no grupo sarilumab e 0 (intervalo interquartil, -1 a 15) no grupo de controle. Os odds ratios cumulativos medianos ajustados foram 1,64 (intervalo de credibilidade de 95%, 1,25 a 2,14) para tocilizumab e 1,76 (intervalo de credibilidade de 95%, 1,17 a 2,91) para sarilumab em comparação com o controlo.

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. (REMAP-CAP ClinicalTrials.gov number,