Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death.
In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the preliminary results of this comparison.
A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.91 to 1.55).
In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others
Our preliminary results show that among hospitalized patients with Covid-19, the use of dexamethasone for up to 10 days resulted in lower 28-day mortality than usual care in patients who were receiving invasive mechanical ventilation at randomization (by 12.3 age-adjusted percentage points, a proportional reduction of approximately one third) and those who were receiving oxygen without invasive mechanical ventilation (by 4.1 age-adjusted percentage points, a proportional reduction of approximately one fifth). However, there was no evidence that dexamethasone provided any benefit among patients who were not receiving respiratory support at randomization, and the results were consistent with possible harm in this subgroup. The benefit was also clear in patients who were being treated more than 7 days after symptom onset, when inflammatory lung damage is likely to have been more common. In a recent trial involving patients with acute respiratory distress syndrome who were undergoing mechanical ventilation, mortality at 60 days was 15 percentage points lower among those receiving dexamethasone than among those receiving usual care, a finding that was consistent with our results.
The RECOVERY trial was designed to provide a rapid and robust assessment of the effect of readily available potential treatments for Covid-19 on 28-day mortality. Approximately 15% of all hospitalized patients with Covid-19 in the United Kingdom were enrolled in the trial, and mortality in the usual care group was consistent with the overall case fatality rate for hospitalized patients with Covid-19 in the United Kingdom.7 Only essential data were collected at hospital sites, with additional information (including longer-term mortality) ascertained through linkage with routine data sources. We did not collect information on physiologic, laboratory, or virologic measures. The protocol combines the methods that were used in large, simple trials of treatments for acute myocardial infarction in the 1980s with the opportunities provided by digital health care in the 2020s. The trial has progressed rapidly, as is essential for studies during epidemics.These preliminary results for dexamethasone were announced on June 16, 2020, nearly 100 days after the protocol was first drafted, and were adopted into U.K. practice later the same day.
Glucocorticoids have been widely used in syndromes closely related to Covid-19, including SARS, Middle East respiratory syndrome (MERS), severe influenza, and community-acquired pneumonia. However, the evidence to support or discourage the use of glucocorticoids under these conditions has been weak owing to the lack of data from sufficiently powered randomized, controlled trials. In addition, the evidence base has suffered from heterogeneity in glucocorticoid doses, medical conditions, and disease severity. It is likely that the beneficial effect of glucocorticoids in severe viral respiratory infections is dependent on a selection of the right dose, at the right time, in the right patient. High doses may be more harmful than helpful, as may such treatment given at a time when control of viral replication is paramount and inflammation is minimal. Slower clearance of viral RNA has been observed in patients with SARS, MERS, and influenza who were treated with systemic glucocorticoids, but the clinical significance of these findings is unknown.Unlike with SARS, in which viral replication peaks in the second week of illness,viral shedding in SARS-CoV-2 appears to be higher early in the illness and declines thereafter.The greater mortality benefit of dexamethasone in patients with Covid-19 who are receiving respiratory support and among those recruited after the first week of their illness suggests that at that stage the disease may be dominated by immunopathological elements, with active viral replication playing a secondary role. This hypothesis would caution against extrapolation of the effect of dexamethasone in patients with Covid-19 to patients with other viral respiratory diseases with a different natural history.
The RECOVERY trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with Covid-19 who are receiving respiratory support. We found no benefit (and the possibility of harm) among patients who did not require oxygen. Before the completion of the trial, many Covid-19 treatment guidelines stated that the use of glucocorticoids was either contraindicated or not recommended.Dexamethasone is on the list of essential medicines of the World Health Organization and is readily available worldwide at low cost. Guidelines issued by the U.K. chief medical officers and by the National Institutes of Health in the United States have already been updated to recommend the use of glucocorticoids in patients hospitalized with Covid-19
Reference & Source information: https://www.nejm.org/
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