Dexamethasone in Patients Hospitalized for COVID-19

In participants who were not on invasive mechanical ventilation but required supplemental oxygen at the time of enrollment, dexamethasone reduced the risk of death, from 26.2% in the usual care group to 23.3% in the dexamethasone group. In these participants, dexamethasone also reduced the need for mechanical ventilation, from 10.2% in the usual care group to 7.3% in the dexamethasone group. Version 1.0


Summary Background
In some people, infection with SARS-CoV-2, the virus causing COVID-19, triggers an overreaction of the immune system that can result in severe injury to a number of organs including the lungs, heart and kidneys.
The drug dexamethasone is a corticosteroid that decreases the immune response. Therefore, it could be beneficial in people with COVID-19, but could also be harmful as it may prevent the immune system's ability to contain the viral infection.
Recently, the results of the large RECOVERY trial became available, which compared dexamethasone in addition to usual care with usual care alone.

Questions
Does dexamethasone reduce the risk of death in adults hospitalized for COVID-19? Does dexamethasone reduce the need for mechanical ventilation?

Findings
The RECOVERY trial was a randomized controlled trial in 6,425 adults hospitalized for COVID-19: 2,104 were randomized to receive dexamethasone (6mg daily for up to 10 days), and 4,321 were randomized to receive usual care.
The effect of dexamethasone depended on the level of respiratory support that participants received at the time of enrollment into the study.
In participants who received mechanical ventilation at the time of enrollment, dexamethasone reduced the risk of death, from 41.4% in the usual care group to 29.3% in the dexamethasone group.
In participants who were not on invasive mechanical ventilation but required supplemental oxygen at the time of enrollment, dexamethasone reduced the risk of death, from 26.2% in the usual care group to 23.3% in the dexamethasone group. In these participants, dexamethasone also reduced the need for mechanical ventilation, from 10.2% in the usual care group to 7.3% in the dexamethasone group.   Table. This is an open access document distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided that the original work is properly cited.

Dexamethasone in Patients Hospitalized for COVID-19
In participants who did not require supplemental oxygen or mechanical ventilation at the time of enrollment, dexamethasone tended to increase the risk of death at 28 days, from 14.0% in the usual care group to 17.8% in the dexamethasone group.

Interpretation
The RECOVERY trial provides conclusive evidence for the use of dexamethasone (6mg daily for up to 10 days) to reduce the risk of death in hospitalized patients with COVID-19 who require supplemental oxygen and/or mechanical ventilation.
Dexamethasone also reduces the need for future mechanical ventilation in hospitalized patients with COVID-19 who require supplemental oxygen.
In patients with COVID-19 who do not require supplemental oxygen or mechanical ventilation, dexamethasone is not effective and could even be harmful.

Background
In some people, infection with SARS-CoV-2, the virus causing COVID-19, triggers an overreaction of the immune system that can result in severe injury to a number of organs including the lungs, heart and kidneys.
Dexamethasone, a corticosteroid, decreases the immune response. This could be beneficial because it prevents an overwhelming response from the immune system but could also be harmful as it may prevent the immune system's ability to contain the viral infection.
Studies of prior outbreaks of respiratory infections have suggested potential harm of corticosteroids. For instance, in a prospective cohort study of 309 severely ill adults infected with the virus causing Middle East Respiratory Syndrome (MERS), people who received corticosteroids were less likely to clear the virus than people who did not (adjusted hazard ratio 0.35, 95% confidence interval 0.17 to 0.72), and there was no difference in the number of deaths. 1 In a meta-analysis of observational studies of people with influenza, those who received corticosteroids were more likely to die than those who did not (hazard ratio 1.75, 95% confidence interval 1.30-2.36). 2 Conversely, in a randomized controlled trial of 277 patients with acute respiratory distress syndrome (ARDS) of different causes who received invasive mechanical ventilation at the time of randomization, the number of deaths at 60 days was reduced from 36.2% in the usual care group to 20.9% in the dexamethasone group (difference 15.3%, 95% confidence interval 4.9% to 25.9%). 3 The trial was performed before the COVID-19 pandemic and therefore did not include patients with COVID-19.
On July 17, 2020, the RECOVERY trial was published. 4 To date, this is the largest randomized trial on the effect of dexamethasone in hospitalized patients with COVID-19.

Questions
Does dexamethasone reduce the risk of death within 28 days after randomization in adults hospitalized for COVID-19? Does dexamethasone reduce the need for invasive mechanical ventilation in adults hospitalized for COVID-19 who do not receive invasive mechanical ventilation?

Findings
The RECOVERY trial is a large randomized controlled trial conducted in the United Kingdom comparing a range of possible treatments. A total of 6,425 adults hospitalized for COVID-19 were enrolled: 2,104 participants were randomized in a 1:2 ratio to receive dexamethasone (6mg daily for up to 10 days) in addition to usual care, and 4,321 participants were randomized to receive usual care alone.
The effect of dexamethasone depended on the level of respiratory support that participants received at the time of randomization (p-value for trend <0.001).
In 1,007 participants who received invasive mechanical ventilation at the time of randomization, the risk of death at 28 days after randomization was reduced from 41.4% in the usual care group to 29.3% in the dexamethasone group (rate ratio 0.64, 95% confidence interval 0.51 to 0.81). The number-needed-to-treat to prevent 1 death was 9.
In participants who were not on invasive mechanical ventilation but required supplemental oxygen at the time of randomization, the risk of death at 28 days was reduced from 26.2% in the usual care group to 23.3% in the dexamethasone group (rate ratio 0.82, 95% confidence interval 0.72 to 0.94). The number-needed-to-treat to prevent 1 death was 35. In these participants, dexamethasone also reduced the need for mechanical ventilation, from 10.2% in the usual care group to 7.3% in the dexamethasone group (rate ratio 0.74, 95% confidence interval 0.59 to 0.92; Horby P, personal communication). The number-needed-to-treat to prevent 1 participant from receiving invasive mechanical ventilation was 35.
In 1,535 participants who did not receive supplemental oxygen at the time of randomization, dexamethasone tended to increase the risk of death at 28 days, from 14.0% in the usual care group to 17.8% in the dexamethasone group (rate ratio 1.19, 95% confidence interval 0.91 to 1.55).
Assuming that dexamethasone would be given to hospitalized patients with COVID-19 who require supplemental oxygen, but not to patients who do not require supplemental oxygen, and that the characteristics of patients with COVID-19 in hospitals in Ontario are similar to the characteristics of patients included in RECOVERY, we estimate that the appropriate implementation of dexamethasone into routine care of hospitalized patients with COVID-19 would reduce deaths in hospitalized patients in Ontario by 15% (95% confidence interval 4% to 24%) and the need for invasive mechanical ventilation by 24% (95% confidence interval 6% to 39%).

Interpretation
The large, well-performed RECOVERY trial provides strong, conclusive evidence that dexamethasone (6mg daily for up to 10 days) reduces the risk of death in hospitalized patients with COVID-19 who require supplemental oxygen and/or invasive mechanical ventilation.
Dexamethasone also reduces the need for future invasive mechanical ventilation in hospitalized patients with COVID-19 who are not on invasive mechanical ventilation but require supplemental oxygen.
In patients with COVID-19 who do not require supplemental oxygen or mechanical ventilation, dexamethasone is not effective and could even be harmful.
Although the RECOVERY trial was open to a pediatric population, the overwhelming majority of patients included in the trial were adults and results have yet to be reported for the subgroup of children. Decisions on the use of dexamethasone in children would therefore need to be made on a case-by-case basis, taking into account illness severity and using pediatric equivalent doses.
Residents of long-term care homes with COVID-19 who were not hospitalized were not included in RECOVERY. Decisions on the use of dexamethasone in residents of long-term care homes who require supplemental oxygen would therefore need to be made on a case-by-case basis with attention to the potential for side effect, including increase in serum glucose levels (especially in patients with diabetes), fluid retention and neuropsychiatric adverse effects.
The results of RECOVERY should not be extrapolated to doses higher than 6mg of dexamethasone daily, to other corticosteroids, or to the treatment of patients without COVID-19.
Dexamethasone is widely available, inexpensive and straightforward to implement into routine care of patients with COVID-19 who require supplemental oxygen or mechanical ventilation in all hospitals in Ontario.