97 IL-6 inhibitors in hospitalised COVID-19 patients 5 Introduction The efficacy of dexamethasone in COVID-19 patients who need supplemental oxygen, supports the notion that in severely ill patients pulmonary damage is caused by an uncontrolled systemic inflammatory response1,2. Subsequently, interleukin-6 (IL6) - a proinflammatory cytokine- was found to be associated with worse outcomes in hospitalized patients2–4. Shortly thereafter, several large randomized controlled trials (RCTs) showed that addition of an IL-6 inhibitor reduced in-hospital mortality as well as the need for invasive mechanical ventilation (IMV) in severely ill patients2,3,5. From the beginning of 2021 onwards, Dutch national guidelines recommended that hospitalized COVID-19 patients are to be treated with 8 mg/kg tocilizumab if they need ≥6 liters/minute of supplemental oxygen and have a serum C-reactive protein (CRP) value of ≥75 mg/L (7.5 mg/dL)6. Prior to global implementation of IL-6 inhibition as additional medical treatment for severe COVID-19, no dose-finding studies were performed. Due to the increased use caused by the ongoing pandemic, many countries had to deal with shortages of IL-6 inhibitors4,7. Due to these shortages the recommended treatment in the Netherlands was altered several times. These adaptations involved the switch from an 8 mg/kg-based to a weight-based or fixed dose recommendation, then to tocilizumab 400 mg and finally to sarilumab 400 mg (see Figure 1)5,8–11. A comparison of survival between patients treated with the different IL-6 inhibitor regimens has not yet been performed. Natural experiments (sometimes called quasi-randomized trials) are an efficient way to study real-world data and can provide information on causal relationships, with effect sizes similar to those found in RCTs12. In natural experiments, the treatment is not allocated by the researcher and ideally unrelated to confounding factors, under the assumption of the absence of secular trends in patients or pathogen characteristics12. Concealment of treatment allocation, preventing physicians’ preferences when deciding on treatments, is one of the purposes of randomization. Since treatment with either 8 mg/kg doses tocilizumab, fixed dose tocilizumab, low dose tocilizumab or sarilumab was determined only by the moment of hospitalization, this approximates randomization of the different treatment groups. Using real world data, we aimed to compare outcomes between hospitalized COVID-19 patients who were treated with different IL-6 inhibitors and different dosing regimens driven by drug shortages in the Netherlands. Methods Study population Patients aged ≥ 18 years, who were hospitalized for COVID-19 and received i.v. treatment with tocilizumab or sarilumab between March 15, 2021 up to and including December 31, 2021 were eligible for inclusion. Patients who received treatment with an IL-6 inhibitor for a disease other than COVID-19 were excluded from the analyses.
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