Log in to MyACC
Interleukin-6 Receptor Antagonists in Critically Ill Patients With COVID-19
Quick Takes
- Tocilizumab is a monoclonal antibody against interleukin-6 (IL-6), a cytokine thought to be central to the hyperinflammatory phase of COVID-19. Sarilumab is a monoclonal antibody to the IL-6 receptor.
- Tocilizumab and sarilumab were highly effective in improving outcomes including survival in critically ill patients with COVID-19.
- Findings of this trial dramatically contrast that of other clinical trials of tocilizumab performed in less ill patients. Timing of treatment and patient selection are crucial in defining effectiveness of anti-inflammatory therapies.
Study Questions:
Are interleukin-6 (IL-6) antagonists (tocilizumab and sarilumab) effective in improving outcomes of critically ill patients with coronavirus disease (COVID-19)?
Methods:
The REMAP-CAP (Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia) is an international adaptive platform trial funded by industry and designed to determine effective treatment strategies for patients with severe pneumonia in both pandemic and nonpandemic settings. REMAP-CAP includes 113 sites across six countries. The authors leveraged REMAP-CAP to randomize critically ill adult patients with COVID-19 within 24 hours of admission to the intensive care unit (ICU) and receiving respiratory (invasive and noninvasive) or cardiovascular organ support (inotrope or vasopressor support), to tocilizumab (8 mg/kg up to two doses), sarilumab (400 mg, one dose) or control (no immune modulation). The primary outcome was the number of respiratory and cardiovascular organ support–free days up to day 21. Deaths within the hospital are assigned the worst outcome (–1). A higher number represents faster recovery.
Results:
A total of 353 patients were assigned to tocilizumab, 48 to sarilumab, and 402 to control. Participants were mostly men (73%), White (72%), with a mean age of 61 years. Corticosteroids were administered to the majority of patients (>80%). Both tocilizumab and sarilumab were efficacious with regard to the primary outcome: the median number of organ support–free days was 10 (interquartile range [IQR], −1 to 16) in the tocilizumab group, 11 (IQR, 0 to 16) in the sarilumab group, and 0 (interquartile range, −1 to 15) in the control group. The in-hospital mortality in the pooled IL-6 receptor antagonist groups was 27%, as compared with 36% in the control group. The median adjusted odds ratios for in-hospital survival were 1.64 (95% confidence interval, 1.14-2.35). Tocilizumab and sarilumab were effective across all secondary outcomes, including 90-day survival, time to ICU and hospital discharge, and improvement in the World Health Organization ordinal scale at day 14.
Conclusions:
In critically ill patients with COVID-19 receiving organ support in ICUs, treatment with the IL-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival.
Perspective:
IL-6 is a pleiotropic inflammatory cytokine thought to play an important role in the pathophysiology of severe COVID-19, with multiple observational studies showing a strong correlation with outcomes and a recent genomic analysis suggesting variants in IL-6 are linked to severe disease. These findings have formed a solid rationale for targeting IL-6 using tocilizumab (monoclonal antibody to IL-6) and sarilumab (monoclonal antibody to the IL-6 receptor) as a strategy to treat patients with severe COVID-19. Results of most randomized trials using tocilizumab had disappointing results. These trials enrolled patients with varying disease severity, including larger proportions of patients that were not critically ill; and less likely to be in the hyperinflammatory phase of the disease. Findings from REMAP-CAP are encouraging and consistent with reports of the large observational study in critically ill patients, STOP-COVID, which provided initial evidence supporting the benefit of tocilizumab in this patient population. Clearly, timing of treatment and patient selection are crucial in defining effectiveness of anti-inflammatory therapies.
Clinical Topics: COVID-19 Hub, Prevention, Novel Agents
Keywords: Adrenal Cortex Hormones, Antibodies, Monoclonal, Anti-Inflammatory Agents, Coronavirus, COVID-19, Critical Illness, Cytokines, Hospital Mortality, Intensive Care Units, Interleukin-6, Patient Discharge, Primary Prevention, Receptors, Interleukin-6
< Back to Listings
