JAMA today published the results of three randomized controlled trials spanning 12 countries, a prospective meta-analysis, and a commentary, all but one—which had inconclusive results—supporting the use of systemic corticosteroids in critically ill COVID-19 patients, regardless of age, sex, duration of symptoms before treatment, or the need for mechanical ventilation.
Safe, inexpensive, and widely available, corticosteroids like dexamethasone, hydrocortisone, and methylprednisolone are believed to treat COVID-19 by reducing lung inflammation in patients who require supplemental oxygen.
Lower 28-day death rates
The meta-analysis of the three corticosteroid trials published today, plus four other such trials, showed that 28-day rates of death from any cause were lower in COVID-19 patients given corticosteroids than in those given usual care or a placebo. The study, conducted by the World Health Organization (WHO) Rapid Evidence Appraisal for COVID-19 Therapies (REACT) investigators, analyzed data from 1,703 patients enrolled in the trials.
Three trials each in the meta-analysis involved hydrocortisone and dexamethasone, and one focused on methylprednisolone.
Of 678 total patients randomly assigned to receive corticosteroids, 222 died (33%), compared with 425 of 1,025 patients (41%) who received usual care or placebo. The summary odds ratio (OR) for death was 0.64 (95% confidence interval [CI], 0.50 to 0.82; P < .001) among patients receiving dexamethasone versus standard care or placebo. The OR for hydrocortisone was 0.69 (95% CI, 0.43 to 1.12; P = .13), while it was 0.91 (95% CI, 0.29 to 2.87; P = .87) for methylprednisolone.
Of the six studies that reported serious adverse events, 64 occurred among 354 patients (18%) given corticosteroids, while 80 occurred among 342 patients (23%) receiving standard care or placebo.
"These trial results from diverse clinical and geographic settings suggest that in the absence of compelling contraindications, a corticosteroid regimen should be a component of standard care for critically ill patients with COVID-19," the authors wrote. "The optimal dose and duration of treatment could not be assessed in this analysis, but there was no evidence suggesting that a higher dose of corticosteroids was associated with greater benefit than a lower dose of corticosteroids."
Updated corticosteroid guidance
As a result of these studies, today the WHO updated its guidance for healthcare professionals and decision-makers on the use of corticosteroids in COVID-19 patients, according to a WHO press release. The organization recommends the use of systemic corticosteroids for treating patients who have severe or critical coronavirus illness but not for those with non-serious disease.
In collaboration with the nonprofit agency Magic Evidence Ecosystem Foundation, the WHO said it began creating the guidelines after preliminary RECOVERY trial results on the beneficial effects of dexamethasone were published on Jun 22. Final results of the UK trial, also encouraging, were published on Jul 17. Most corticosteroid trials in seriously ill COVID-19 patients were stopped after the RECOVERY trial because the evidence it generated was sufficiently strong to warrant offering the drugs.
Survival, need for assisted breathing
One of the three trials published in JAMA today, the Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) study, led by researchers in London, found that treating 137 coronavirus patients in the intensive care unit (ICU) with 50 or 100 milligrams of hydrocortisone four times a day for 7 days led to a 93% chance of survival and less need for extra oxygen than in 101 patients receiving no hydrocortisone.
In comparison, the 146 patients given hydrocortisone only when they went into shock had an 80% chance of a good outcome.
Study coauthor Anthony Gordon, MD, of the Imperial College Healthcare NHS Trust, said that the corticosteroid trials give doctors more than one choice of therapy for critically ill COVID-19 patients. "Steroids are not a cure, but they help improve outcomes," he said in an Imperial College London press release. "Having a choice of different types of steroids, all of which seem to improve patient recovery, is great as it helps ease the problem of drug supply issues."
A second hydrocortisone study, this one by researchers in France as part of the ongoing Community-Acquired Pneumonia: Evaluation of Corticosteroids (CAPE COD) trial, showed that low-dose hydrocortisone didn't significantly reduce death or continued need for mechanical ventilation of high-flow oxygen support after 21 days compared with placebo. Among the 76 patients in the hydrocortisone group, 32 (42.1%) died, versus 37 of 73 (50.7%) in the placebo group. No serious adverse events were reported.
However, the authors said that, like other corticosteroid COVID-19 trials, the study was stopped early because of slow enrollment after the first wave of the epidemic in France and anticipation of the publication of preliminary results of the RECOVERY trial "and likely was underpowered to find a statistically and clinically important difference in the primary outcome."
The researchers noted that hydrocortisone treatment was not tied to an increase in the rate of secondary infections, a known risk of corticosteroid treatment—particularly in patients with pneumonia receiving mechanical ventilation.
The third study published today, the Brazilian COVID-19 Dexamethasone (CoDEX) trial, found that patients given dexamethasone didn't require mechanical ventilation for, on average, 6.6 of their first 28 days in the ICU (95% CI, 5.0 to 8.2), versus only 4.0 days (95% CI, 2.9 to 5.4) in the group receiving standard care (difference, 2.6 days; 95% CI, 0.2 to 4.38; P = .04).
Of the dexamethasone group, 33 patients (21.9%) developed secondary infections, compared with 43 (29.1%) in the usual care group. Forty-seven dexamethasone patients (31.1%) required insulin for glucose control, versus 42 (28.3%) of the standard care group. And 5 patients in the dexamethasone group (3.3%) had other serious adverse events, versus 9 (6.1%) in the usual care group.
Evidence and hope
In a commentary in the same journal, Hallie Prescott, MD, MSc, of the University of Michigan at Ann Arbor, and Todd Rice, MD, MSci, of Vanderbilt University, said that these clinical trials and meta-analysis will give providers more confidence in prescribing corticosteroids and have shifted standard treatment of severe COVID-19 to include these drugs.
They also lauded the research networks' ability and willingness to collaborate, coordinate, and share data to rapidly complete studies in a time of unprecedented clinical burden from COVID-19.
"With these efforts and with rigorous evidence comes hope," Prescott and Rice wrote. "Despite the widespread morbidity and mortality, and societal disruption caused by this pandemic, the work and collaboration of these networks provide hope for advancing science and humanity through this pandemic and beyond."