COVID-19 treatment combinations and associations with mortality in a large multi-site healthcare system

Introduction During the early months of the COVID-19 pandemic, mortality associated with the disease declined in the United States. The standard of care for pharmacological interventions evolved during this period as new and repurposed treatments were used alone and in combination. Though these medications have been studied individually, data are limited regarding the relative impact of different medication combinations. The objectives of this study were to evaluate the association of COVID-19-related mortality and observed medication combinations and to determine whether changes in medication-related practice patterns and measured patient characteristics, alone, explain the decline in mortality seen early in the COVID-19 pandemic. Methods A retrospective cohort study was conducted at a multi-hospital healthcare system exploring the association of mortality and combinations of remdesivir, corticosteroids, anticoagulants, tocilizumab, and hydroxychloroquine. Multivariable logistic regression was used to identify predictors of mortality for both the overall population and the population stratified by intensive care and non-intensive care unit admissions. A separate model was created to control for the change in unmeasured variables over time. Results For all patients, four treatment combinations were associated with lower mortality: Anticoagulation Only (OR 0.24, p < 0.0001), Anticoagulation and Remdesivir (OR 0.25, p = 0.0031), Anticoagulation and Corticosteroids (OR 0.53, p = 0.0263), and Anticoagulation, Corticosteroids and Remdesivir (OR 0.42, p = 0.026). For non-intensive care unit patients, the same combinations were significantly associated with lower mortality. For patients admitted to the intensive care unit, Anticoagulation Only was the sole treatment category associated with decreased mortality. When adjusted for demographics, clinical characteristics, and all treatment combinations there was an absolute decrease in the mortality rate by 2.5% between early and late periods of the study. However, when including an additional control for changes in unmeasured variables overtime, the absolute mortality rate decreased by 5.4%. Conclusions This study found that anticoagulation was the most significant treatment for the reduction of COVID-related mortality. Anticoagulation Only was the sole treatment category associated with a significant decrease in mortality for both intensive care and non-intensive care patients. Treatment combinations that additionally included corticosteroids and/or remdesivir were also associated with decreased mortality, though only in the non-intensive care stratum. Further, we found that factors other than measured changes in demographics, clinical characteristics or pharmacological interventions accounted for an additional decrease in the COVID-19-related mortality rate over time.