In a recent study published on the medRxiv * prepress server, researchers evaluated the impact of modern causal inference methods on estimating the effect of corticosteroids on coronavirus-related mortality 2019 (COVID-19).
Study: Corticosteroids in COVID-19: Optimizing Observational Research through Target Trial Emulations. Image credit: luchschenF / Shutterstock
Observational research has provided great opportunities to understand causal effects in the absence of randomized trials. However, the accuracy of observational research depends on a variety of analytical and design options.
About the study
In the present study, the researchers described the advantages of using modern causal inference methods compared to standard research approaches in estimating the effect of corticosteroids on mortality rates caused by coronavirus 2 infections (SARS- CoV-2) of severe acute respiratory syndrome.
The approach proposed by the team that used modern causal inference was a question-first approach. This method used an objective test framework and a roadmap outlining causal inference. The roadmap used helped design a free time-alignment study and similar design biases and mitigated the erroneous specification bias of the model with optimal machine learning estimators. The team also described a randomized trial that could hypothetically analyze the impact of corticosteroids in patients with severe COVID-19.
The hypothetical trial population included adults admitted for COVID-19 to New York Presbyterian Hospital (NYPH) / Weill Cornell, Lower Manhattan Hospital, or NYPH Queens. Infections were confirmed by reverse polymerase-transcriptase chain reaction (RT-PCR) assays in nasopharyngeal swabs collected from patients. The team randomized patients on the first day of hospital admission to receive standard care with corticosteroid administration or standard care without any corticosteroid treatment.
The dose of corticosteroid administered was 0.5 mg per kg body weight of methylprednisolone corticosteroid, which was equivalent for 24-hour periods for six days. The corticosteroids included in the study were hydrocortisone, prednisolone, prednisone, methylprednisolone, and dexamethasone. The team defined criteria for severe hypoxia such as the onset of high-flow ventilation mask, nasal cannula, invasive or non-invasive mechanical ventilation, or a level of oxygen saturation below 93%.
The primary outcome of the study included reported mortality within 28 days of randomization. The estimate of interest was the 28-day variation in mortality rates between the two randomized groups.
The emulation of the target trial used data from patients who met the criteria for inclusion in the study between March 3 and May 15, 2020. The team obtained information related to demographics, intubation, comorbidity, death and hospital discharge from electronic health records. Participants were monitored for 28 days after hospitalization until they were discharged or transferred to another hospital. The team evaluated the impact of a hypothetical dynamic treatment program in which each patient was treated for six days with corticosteroids if and when the patient presented with severe hypoxia.
Results
The study cohort consisted of a total of 3298 patients with a mean age of 65 years with almost 60% men and an average body mass index (BMI) of 27. Approximately 31% of patients had diabetes mellitus. , 14% had coronary artery disease, 54% had hypertension and 4.8% had kidney disease. A total of 1,690 patients met the randomization criteria for severe hypoxia, while 423 patients reported a history of corticosteroid reception during the follow-up period. In addition, 699 patients died within 28 days of randomization.
The team also noted that 20% of patients who completed the duration of the study received no corticosteroid treatment, while 30% of patients died after corticosteroid treatment. The estimated mortality rate was 32% among individuals who did not receive corticosteroids, while 23% of patients who received corticosteroids for six days showed severe hypoxia. This indicated a 9.6% reduction in mortality rates between corticosteroid treatment and hypothetical non-corticosteroid treatment groups.
In the emulation trial of the target trial, among the 1,690 patients who met the hypoxia criteria, 72 patients were treated with corticosteroids within one day after the diagnosis of hypoxia, while 191 hypoxic patients received corticosteroids. in five days. Among these, 18 and 451 patients succumbed to one and five days of hypoxia without any corticosteroid treatment, respectively.
Conclusion
Overall, the results of the study showed that the current standard used for clinical research could not sufficiently recover a proper treatment approach instead of a modern causal inference method. Researchers believe that the present study showed the importance of incorporating these innovative methods into future research designs.
* Important news
medRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, guided by clinical practice or health-related behavior, or treated as established information.