September 02, 2020
Administering steroids to people critically ill with COVID-19 appears beneficial and could be lifesaving for some, a new meta-analysis and multiple related studies suggest.
Critically ill patients who received systemic corticosteroids were 34% less likely to die over 28 days, for example, compared with others who received usual care or placebo in a prospective meta-analysis of seven randomized controlled trials.
The meta-analysis was published online in JAMA September 2, 2020.
Based on the findings of the meta-analysis, which the World Health Organization (WHO) sponsored, the organization issued Living Guidance on corticosteroids for COVID-19 the same day.
"We recommend systemic corticosteroids for the treatment of patients with severe and critical COVID-19," WHO stated in an email to journalists. "We suggest not to use corticosteroids in the treatment of patients with non-severe COVID-19 as the treatment."
The studies included in the meta-analysis assessed corticosteroid efficacy among 1703 critically ill patients with confirmed or suspected COVID-19. Median age was 60 years and 29% of participants were women.
There were 222 deaths among 678 patients randomly assigned to corticosteroids and 425 deaths among 1025 patients randomly assigned to usual care or placebo, for a summary odds ratio of 0.66 (95% confidence interval, 0.53 - 0.82; P?<?.001) favoring steroid treatment.
A Strong Enough Signal to Stop Other Studies
While the studies were under way, results of the UK-based Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial were announced on June 16. RECOVERY showed a strong benefit for dexamethasone over placebo in this randomized trial with 6425 patients.
"The signal seen in this trial led most ongoing trials of corticosteroids to suspend recruitment," meta-analysis lead author Jonathan A. C. Sterne, MA, MSc, from the University of Bristol in the United Kingdom, notes.
Three additional reports, published simultaneously in JAMA along with the meta-analysis, were among the studies halted early. These trials examined specific agents in patients with severe COVID-19.
In the COVID-19 Dexamethasone (CoDEX) randomized clinical trial, investigators found that addition of dexamethasone to usual care versus usual care alone significantly improved the number of days alive and days patients were free of mechanical ventilation over 28 days. This study of 299 patients from 41 intensive care units in Brazil evaluated people with COVID-19 and moderate-to-severe acute respiratory distress syndrome (ARDS).
Another research team evaluated hydrocortisone for improving organ support and mortality among 403 people with severe COVID-19 over 21 days. The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial compared a 7-day, fixed-dose course of hydrocortisone and dosing, based on the appearance of shock, with no hydrocortisone therapy.
The investigators reported a 93% likelihood that the fixed-dose strategy was superior to no hydrocortisone for improving organ support–free days within 21 days. In addition, they found an 80% likelihood that the shock-dependent dosing was superior to no such therapy regarding the same outcome.
Although their findings suggest benefit, the REMAP-CAP researchers cautioned about drawing definitive conclusions because the trial was stopped early and did not meet any statistically significant prespecified endpoints.
In another randomized clinical trial of hydrocortisone, investigators assessed people with acute respiratory failure and found that hydrocortisone was not associated with a notable reduction in treatment failure rates. Although this rate was lower at 42% versus 51% in the placebo group, the difference was not statistically significant.
Practice Changing Results?
"At the onset of the coronavirus disease 2019 (COVID-19) pandemic, guidance regarding corticosteroids was mixed," Hallie C. Prescott, MD, at the University of Michigan, Ann Arbor, and Todd W. Rice, MD, from Vanderbilt University in Nashville, Tennessee, write in an editorial accompanying the meta-analysis and related studies.
"Overall, the meta-analysis indicates that administration of steroids is clearly associated with benefit among critically ill patients with COVID-19, although the exact threshold at which an individual patient should be prescribed corticosteroids remains unclear," they write.
They also point out that these agents are inexpensive and readily available.
The meta-analysis and three related studies represent "an important step forward in the treatment of patients with COVID-19. While the RECOVERY results were embraced because they provided hope in the treatment of this catastrophic disease, numerous study limitations prevented complete confidence in using corticosteroids in hospitalized patients with COVID-19."
"These trials and the meta-analysis have strengthened confidence, further defined the benefit, and shifted usual care of COVID-19–related ARDS to include corticosteroids," they added.
Sterne reported receiving grants from the UK National Institute for Health Research (NIHR). Prescott reported that she serves on the Surviving Sepsis Campaign Guidelines Panel. Rice reported personal fees from Cumberland Pharmaceuticals and personal fees from Avisa Pharma outside the submitted work.