Critical Care Alert: Interleukin-6 Antagonists in Critically Ill Patients with COVID-19

ARTICLE
The REMAP-CAP Investigators. Interleukin-6 receptor antagonists in critically ill patients with COVID-19. N Engl J Med. Feb. 25, 2021; ahead of print. doi:10.1056/nejmoa2100433

OBJECTIVE
To evaluate the efficacy of interleukin-6 antagonists - tocilizumab and sarilumab on survival and organ support in critically ill patients with coronavirus disease 2019 (COVID-19).

BACKGROUND
While much is still left to be known about COVID-19, research has supported the theory that an excessive host inflammatory response is responsible for much of the morbidity and mortality caused by the disease. The RECOVERY trial provided evidence that targeting the immune cascade, specifically with the use of glucocorticoids, improved patient outcomes for patients with severe COVID infection.¹ Interleukin-6 (IL-6), a cytokine released as part of the acute-phase response to infection, has also been investigated as a possible target for therapeutic treatment. Interestingly enough, a genomic analysis of critically ill patients with COVID-19 showed that genetic variants in the IL-6 inflammatory pathway are associated with life-threatening disease.²

Tocilizumab and sarilumab are monoclonal antibodies that inhibit membrane-bound and soluble IL-6 receptors, both are currently used to treat inflammatory conditions such as rheumatoid arthritis. Based on early data, there was no consensus on the clinical benefit of these two immunomodulating drugs for the treatment of COVID-19. However, this study, as part of the REMAP-CAP trial, investigated the effectiveness of tocilizumab and sarilumab on survival and organ support for COVID patients in the ICU.

The Randomized, Embedded, Multifactorial Adaptive Platform trial for Community-Acquired Pneumonia (REMAP-CAP) consists of various interventional domains and was designed to determine effective treatment options for patients with severe pneumonia in both pandemic and non-pandemic settings. The first patient was randomized into the Immune Modulation Therapy domain on April 19 as tocilizumab became available and June 20 for sarilumab.

DESIGN
International, multi-center, open-label, adaptive platform trial using the drugs tocilizumab and sarilumab

POPULATION
Inclusion Criteria

• Critically ill patients ages 18 or older
• Clinically suspected or microbiologically confirmed COVID-19 infection
• Severe disease state and receiving respiratory or cardiovascular organ support
  • Respiratory support: defined as invasive or noninvasive mechanical ventilation, including through high-flow nasal cannulae if flow rate was >30 L/min and the fraction of inspired oxygen was more than 0.4.
  • Cardiovascular support: defined as the intravenous infusion of any vasopressor or inotrope
• Patients had to be enrolled within 24 hours after starting organ support in the ICU

Exclusion Criteria

• Death was deemed imminent and inevitable during the next 24 hours AND one or more of the patient, substitute decision-maker, or attending physician is not committed to full active treatment
• Previous participation in REMAP-CAP within 90 days
• Known condition or treatment resulting in ongoing immune suppression including neutropenia prior to this admission

INTERVENTION
Eligible patients participating in REMAP-CAP were randomized into the COVID-19 Immune Modulation Therapy domain, which included five interventions - this study focuses on individuals who were administered one of two interleukin-6 receptor antagonists - tocilizumab or sarilumab.

Tocilizumab was administered as an intravenous infusion over a period of 1 hour, at a dose of 8 mg per kg (up to a maximum of 800 mg). If clinical improvement was deemed insufficient by the provider, the dose could be repeated 12 to 24 hours later. Sarilumab was administered as a one-time 400 mg dose via intravenous infusion.

CONTROL
No immune modulation

Of note, other aspects of standard patient care were provided to individuals which was site-dependent. As of June 17, 2020, randomization to the corticosteroid domain for COVID-19 closed therefore, glucocorticoids were permitted according to the recommended standard of care.

OUTCOMES
Primary Outcome

• The number of respiratory and cardiovascular organ support-free days up to day 21

Secondary Outcomes

• Hospital survival and mortality
• 90-day survival (time to event)
• Respiratory and cardiac support-free days
• Time to ICU and hospital discharge
• World Health Organization (WHO) ordinal scale (range: 0-8, where 0 = no illness, 1-7 = increasing level of care, and 8 = death)
• Progression to invasive mechanical ventilation, extracorporeal membrane oxygenation (ECMO), or death among those not ventilated at baseline

KEY RESULTS
Of the 895 patients that underwent randomization into the Immune Modulation Therapy domain, 306 were assigned to tocilizumab, 48 to sarilumab, and 412 to control. The vast majority of patients were enrolled after the dexamethasone result from the RECOVERY trial and of these, 93% (610 of 654) were treated with glucocorticoids at enrollment or within the following 48 hours.

Primary Outcomes
Median number of organ support free days:

• Tocilizumab group: 10 (interquartile range: -1 to 16); median adjusted odds ratios were 1.64 (95% credible interval, 1.25 - 2.14)
• Sarilumab group: 11 (interquartile range: 0 to 16); median adjusted odds ratios were 1.76 (95% credible interval, 1.17 - 2.91)
• Control group: 0 (interquartile range: -1 to 15)
• Probability of superiority to control for tocilizumab and sarilumab is >99.9% and 99.5% respectively

In-hospital mortality

• Pooled interleukin-6 receptor antagonist group: 27% (108 of 395 patients); median odds ratio were 1.64 (95% credible interval, 1.14 - 2.35) and 2.01 (95% credible interval, 1.18 - 4.71) for tocilizumab and sarilumab respectively
• Control group: 36% (142 of 397 patients)
• Probability of superiority of tocilizumab and sarilumab are 99.6% and 99.5% respectively when compared to control

Of note, the treatment effect in patients who received a combination therapy of either tocilizumab or sarilumab and glucocorticoids were greater than any intervention on its own showing a possible synergistic effect.

Secondary Outcomes
The interleukin-6 antagonists - tocilizumab and sarilumab were effective vs. control for all secondary outcomes, including 90-day survival, time to ICU and hospital discharge, and improvement in the WHO ordinal scale at day 14.

There were no serious adverse events reported in the sarilumab group but 9 serious adverse events in the tocilizumab group, including five bleeding events, two cardiac events, one deterioration in vision, and one secondary bacterial infection. In the control group, there were 11 serious adverse groups reported, including seven thromboses and four bleeding events.

STRENGTHS

• The international and robust experimental design of the REMAP-CAP allows the results to be applicable to the wider critically ill patient population with COVID-19.
• Roche Products and Sanofi provided the IL-6 antagonists used in the study but played no role in the trial design, data analysis, and manuscript production.
• Compared to previously reported trials, this study includes patients already receiving respiratory support.
• This study incorporates patients treated with glucocorticoids as a standard part of care.

LIMITATIONS

• The trial uses an open-label design
• This is a preliminary report, and some data points remain missing, including eleven outcomes.
• The trial uses a Bayesian design, this complex statistical method for analysis may be difficult for many clinicians.

EM TAKE-AWAYS
Several studies have shown that IL-6 is highly associated with COVID-19 disease severity and mortality. These findings support the concept that IL-6 antagonism as a therapeutic strategy could result in improved patient outcomes and the results of this study reinforces it. This trial showed that the use of tocilizumab and sarilumab improved morbidity and mortality in patients with severe COVID-19 compared to the usual standard of care alone. There was also an additive effect when combined with glucocorticoids.

The design of this study is important for the field of emergency medicine because all patients were started on the therapy within 24 hours of requiring organ support. The identification of a critically ill-patient often begins in the ED therefore, this offers us an opportunity to begin IL-6 therapy while organ dysfunction is still reversible.

There are some with reservations about starting immunomodulating drugs for critically ill individuals; however, this study shows no increase in adverse events compared to control.

Based on this early data, the use of interleukin-6 antagonists for severe COVID-19 appears very promising when started early in a critical patients’ course.  However, it is important to remember data from earlier trials, including that of the COVACTA³ trial, which did not show a reduction in mortality (there were many differences between these trials, and it should be reviewed separately).

REFERENCES

1. RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with COVID-19—preliminary report. N Engl J Med. 2021; 384:693-704.
2. Pairo-Castineira E, Clohisey S, Klaric L, et al. Genetic mechanisms of critical illness in COVID-19. Nature. 2021;591(7848):92-8.
3. Rosas IO, Bräu N, Waters M, et al. Tocilizumab in hospitalized patients with severe COVID-19 pneumonia. N Engl J Med. 2021 Feb 25.