106 Chapter 5 Study strengths and limitations The study has several strengths. First, real world data based on health insurance claims reflect the heterogeneity of patients and make our findings generalizable. Second, the large number of patients in our study meant that all treatment groups had a sufficient number of patients to make meaningful comparisons with other groups and perform sensitivity analyses. Even though the change in recommended dosing was driven by drug shortages, there are no known cases where patients did not receive any treatment with IL-6 inhibitors because of these shortages. Finally, while important, setting up an RCT to compare these different treatments would be expensive and time consuming, and a natural experiment is an efficient way to determine the effect of different treatments and doses of IL-6 inhibitors in COVID-19 patients. Our study has several weaknesses, mostly related to the use of real-world data. Even though the point in time of COVID-19 infection is mostly random, there are several factors that might have an influence, like sex, age and social economic status. While we were able to correct some of them, we did not have data on all potential confounders that could have influenced the timing of SARS-CoV-2 infection. Second, it was not possible to differentiate between weight based dosing and 600 mg fixed dose tocilizumab in our data, hence we combined those two groups, even though ideally we would combine 8 mg/kg and weight based dosing (which are almost identical) and compare with 600mg fixed dose tocilizumab. For patients who weigh 75 kg or more, a fixed dose of 600 mg tocilizumab would lead to <8 mg/kg, which could explain the differences between the 8 mg/kg and fixed dose groups. We found no evidence for a dose-response relationship, as the hazard rates for mortality did not increase with decreasing doses. This may have been influenced by other factors that influence our outcome measures and changed during the course of our study, like the case-mix, the vaccination coverage and the dominant strain. While the case-mix may have changed during the pandemic, we were able to adjust for some potential differences. No data on vaccination status was available, and this could lead to an underestimation of our results, as the increased vaccination coverage during the course of 2021 will have protected against mortality. Patients were not systematically tested for specific virus strains, but the alpha strain is thought to lead to increased ICU admission and in-hospital mortality compared to the delta strain, both in vaccinated and unvaccinated patients19. Similar to the increased vaccination coverage, the decreased mortality of the Delta variant compared to Alpha could lead to underestimation of our results. Number needed to treat considerations Since from our data we cannot estimate a NNT comparing 8 mg/kg tocilizumab to placebo, we use data from the RECOVERY trial5, with a NNT of 25. This means that if 1000 patients are treated with tocilizumab 8 mg/kg instead of placebo, approximately 40 additional lives would be saved. In times of drug shortages, there are different options. If 500 treatments are available for a population of 1000 people, and 500 of them are given the 8 mg/kg dose, an additional 20 lives would be saved. Between
RkJQdWJsaXNoZXIy MTk4NDMw