105 IL-6 inhibitors in hospitalised COVID-19 patients 5 remained when the analysis was restricted to patients who survived (Supplementary Table 6) or those with a complete hospital LOS (supplementary methods and Supplementary Table 7). As a post-hoc analysis, we plotted the median hospital LOS and the number of admissions over time (Supplementary Figure 4). A total of 90 patients had two separate COVID-19 related hospital admissions, with less than 90 days between the two admissions. For the main analysis, the period in between hospitalization was included in the hospital LOS, assuming they were transferred to another hospital. Given that this might not be the case for everyone, we randomly sampled 25%, 50% and 75% of these 90 patients and only used the duration of their first hospital admission as the LOS. The results were similar, with a shorter hospital admission for patients receiving low dose tocilizumab and sarilumab compared with the 8 mg/kg group (Supplementary Tables 8, 9 and 10). After correction for confounding, ICU LOS was shorter for the low dose tocilizumab group compared with the 8 mg/kg group (Supplementary Table 11). When restricting to patients who survived (Supplementary Table 12) or those with complete LOS data (Supplementary Table 13), no differences were found. Discussion We found that in hospitalized patients with COVID-19, those treated with tocilizumab with an 8 mg/kg dosing regimen had a survival benefit if compared to fixed dose tocilizumab and sarilumab. While there is no significant difference between 8 mg/kg and low dose tocilizumab, the hazard rate estimate was similar to the hazard rate estimate for fixed dose and sarilumab. In a subset of ICU admitted patients, the 8 mg/kg group also had an improved survival at 60 days compared with the sarilumab group, but not to the other tocilizumab dosing groups. Those receiving 8 mg/ kg tocilizumab had a lower risk of progressing to the combined outcome of ICU admission or death than the other three treatment groups. ICU LOS was shorter for low dose tocilizumab than for the 8 mg/kg group. Hospital LOS was longest in the 8 mg/kg and fixed dose groups. At present, comparisons between the different doses of tocilizumab and/ or sarilumab in COVID-19 patients have mostly been made between separate studies. A 2021 meta-analysis, including over 3000 patients and 6500 controls from 33 different trials compared different doses of tocilizumab between studies. This study found a lower mortality in the 8 mg/kg tocilizumab group compared with controls, but not in the 400 mg, 400-800 mg or <400 mg tocilizumab groups or sarilumab17. In addition, a phaseII RCT comparing 4 mg/kg and 8 mg/kg tocilizumab found a trend towards higher mortality at day 28 in the 4 mg/kg group, although no formal analysis was performed given the small sample size18. Several studies have focused on ICU admitted patients. The REMAP-CAP trial compared 8 mg/kg tocilizumab with 400 mg sarilumab and standard of care, and both IL-6 inhibitors were found to improve survival compared with standard of care2. No direct comparison of sarilumab and tocilizumab was performed.
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