99 IL-6 inhibitors in hospitalised COVID-19 patients 5 regimen, low dose tocilizumab consisted of a 400mg fixed dose of tocilizumab, and starting November 2021 (group called “Low dose tocilizumab”). After three weeks, due to persisting shortages, sarilumab 400mg was advised, and formed the final group in our analysis (group called “Sarilumab 400 mg”), see Figure 1. To account for variation, a 100mg range was used for all fixed doses. Patients who received a dose that did not fit one of these groups were excluded from the analysis. Bodyweight was not available for any of the patients in our database. Only the first dose of IL-6 inhibitors was studied. Statistical analyses Medians and interquartile ranges (IQR) were used to describe continuous variables. Categorical variables were summarized as frequency and percentage. 95% confidence intervals were calculated. We corrected for relevant differences in baseline characteristics15. First, to compare survival, several analyses were performed. A Kaplan-Meier survival analysis was done to compare the unadjusted survival between the treatment groups using a log-rank test. Next, a multivariable Cox proportional hazards analysis was performed, determining the difference in survival between the different treatment groups when correcting for age, sex, immunocompromised status and CCI. A sensitivity analysis including only ICU admitted patients was performed. Second, a Cox proportional hazard analysis was performed to determine the effect of the allocation to different treatment groups on the combined outcome of mortality or ICU admission. Events were counted from at least 24 hours after the IL-6 inhibitor was administered and the hazard ratio was corrected for age, sex, immunocompromised status and CCI. Finally, a linear regression analysis was done to analyze the effect of different treatment groups on the ICU- and hospital length of stay 8 mg/kg tocilizumab Fixed dose tocilizumab Low dose tocilizumab Sarilumab 400mg 0.00 0.25 0.50 0.75 1.00 Mar−2021 Apr−2021 May−2021 Jun−2021 Jul−2021 Aug−2021 Sep−2021 Oct−2021 Nov−2021 Dec−2021 Jan−2022 Proportion of circulating virus variants in population Variant Alpha Beta Delta Gamma Omicron Figure 1: Proportion of different SARS-CoV-2 variants and the recommended IL-6 inhibitor during the study period in the Netherlands, using publicly available data from the National Institute for Public Health and the Environment14. The different IL-6 inhibitor treatment periods were added to this information.
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