Objectives: To compare the clinical characteristics and outcomes of critically ill coronavirus disease (COVID-19) patients requiring mechanical ventilation (MV), receiving interleukin 6 receptor (IL6R) antagonists, steroids, or a combination of both.
Design: An international, multicenter, observational study derived from the COVID-2019 Viral Infection and Respiratory Illness University Study (VIRUS) registry and conducted through the Discovery Network, the Society of Critical Care Medicine. Marginal structural modeling was used to adjust for time-dependent confounders, and observations were weighted using the inverse probability of treatment weight. Sensitivity analysis was conducted to emulate a target trial design.
Setting: 168 hospitals in 16 countries.
Patients: adult ICU patients ( > 18 years) requiring MV for COVID-19 between March 01, 2020, and January 10, 2021.
Intervention: None.
Measurements and Main Results: A total of 860 patients met eligibility criteria: 589 received steroids, 170 IL-6R antagonists, and 101 combination therapy, and the groups were balanced after adjustment. The median daily steroid dose was 7.5 mg dexamethasone or equivalent (IQR: 6 to 14 mg); 80.8% received low-dose and 19.2% high-dose steroids (> 15 mg/day of dexamethasone or equivalent). The median C-reactive protein level was > 75 mg/L in majority of our cohort. The use of IL6R antagonists alone or in combination was not associated with a significant difference in ventilator free days (VFD) compared to steroids alone (adjusted incidence rate ratio [95% CI]): IL6R antagonists (1.12 [0.88,1.4]), combination (0.83 [0.6,1.14]). Patients treated with low or high-dose steroids had non-significant differences in VFD compared to IL6R antagonists (beta= 0.62, 95% CI -1.54, 2.78 for low-dose steroid; beta= -1.19, 95% CI -3.85, 1.47 for high-dose steroid). The use of IL6R antagonists alone or in combination was not associated with a significant difference in 28 day mortality compared to steroids alone (adjusted odds ratio [95% CI]): IL6R antagonists alone (0.68 [0.44,1.07]), combination (1.07 [0.67,1.7]). There was no difference in hospital mortality compared to steroids alone (aOR 0.68, 95% CI 0.43,1.09 for IL6R antagonist, aOR 1.23, 95 % CI 0.72,2.11 for combination). The findings of sensitivity analysis were consistent with the primary analysis. The rate of liver dysfunction was higher in the IL6R antagonist (p=0.038), while the rate of bacteremia did not differ among the three groups.
Conclusions: We observed no difference in outcomes between mechanically ventilated adult ICU patients who received IL6R antagonists, steroids, or combination therapy and those who received IL6R antagonists or low or high dose steroids. Further trials are needed to evaluate high-dose steroids as substitutes for IL6R antagonists in resource-limited settings.