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Review 2: "Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 – Preliminary report"

IL-6 receptor inhibitor therapy likely reduces morbidity and mortality in a select group of patients if used within 24 hours of worsening clinical status. Both reviewers considered the multi-center, placebo-controlled randomized control trial results to be strong.

Published onMar 01, 2021
Review 2: "Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 – Preliminary report"
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key-enterThis Pub is a Review of
Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 – Preliminary report
Description

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 of commencing organ support in an intensive care unit, were randomized to receive either tocilizumab (8mg/kg) or sarilumab (400mg) or standard care (control). The primary outcome was an ordinal scale combining in-hospital mortality (assigned −1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with pre-defined triggers to declare superiority, efficacy, equivalence or futility.Results Tocilizumab and sarilumab both met the pre-defined triggers for efficacy. At the time of full analysis 353 patients had been assigned to tocilizumab, 48 to sarilumab and 402 to control. Median organ support-free days were 10 (interquartile range [IQR] −1, 16), 11 (IQR 0, 16) and 0 (IQR −1, 15) for tocilizumab, sarilumab and control, respectively. Relative to control, median adjusted odds ratios were 1.64 (95% credible intervals [CrI] 1.25, 2.14) for tocilizumab and 1.76 (95%CrI 1.17, 2.91) for sarilumab, yielding >99.9% and 99.5% posterior probabilities of superiority compared with control. Hospital mortality was 28.0% (98/350) for tocilizumab, 22.2% (10/45) for sarilumab and 35.8% (142/397) for control. All secondary outcomes and analyses supported efficacy of these IL-6 receptor antagonists.Conclusions In critically ill patients with Covid-19 receiving organ support in intensive care, treatment with the IL-6 receptor antagonists, tocilizumab and sarilumab, improved outcome, including survival. (ClinicalTrials.gov number: NCT02735707)

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

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Review:

A very interesting part of the global evaluation of different treatment cohorts supporting the role of IL6 inhibitors in the reduction of mortality in ICU and duration of hospitalization.

Based on treatment arm allocation, the sarilumab cohort is relatively small (48 pts) compared to tocilizumab and the control, which may lead to a misbalance and some wrong assumptions regarding sarilumab.

However, there is a need to provide more details and information, such as:

1. A list of the standard of treatment medicines in all research cohorts. It’s not clear that all groups were equally balanced especially for remdesivir.

2. Dexamethasone dosage and duration of treatment in each cohort is not clear and may have an impact on the outcome.

  1. The disease duration and clinical symptoms like high temperature (>38C) may be important to compare between groups.

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