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Dexamethasone's benefits for COVID-19 critical illness were replicated in a Brazilian randomized trial, while a World Health Organization-sponsored patient-level meta-analysis of ongoing randomized trials concluded that it's a class effect across corticosteroids.

Both sets of data, along with two other multicenter randomized controlled trials of corticosteroids in critically-ill patients with COVID-19, appeared simultaneously in JAMA on Wednesday.

All three trials halted enrollment in June 2020 after the U.K.-based RECOVERY trial announced in a press release that dexamethasone cut mortality, with published results showing 36% reduction in mechanically-ventilated patients and 18% in patients on supplemental oxygen.

New Dexamethasone Results

The randomized 299 patients in Brazil with COVID-19 and moderate to severe acute respiratory distress syndrome (ARDS) by the Berlin definition to 20-mg IV dexamethasone daily for 5 days, then 10 mg daily for 5 days or until ICU discharge atop standard care or to standard care alone.

For the primary outcome, dexamethasone increased days alive and days free from mechanical ventilation during the first 28 days to a mean 6.6 versus 4.0 among controls (P=0.04), reported Luciano Azevedo, MD, PhD, of Hospital Sirio-Libanes in São Paulo, and colleagues.

"This reduction is relevant in the context of a pandemic, in which an inexpensive, safe, and widely available intervention like dexamethasone increases even modestly the number of ventilator-free days and may reduce the risk of ventilatory complications, ICU length of stay, and burden to the health care system," the group concluded.

Dexamethasone also reduced the acute morbidity of the disease, with lower mean Sequential Organ Failure Assessment (SOFA) scores at day 7 than with usual care (6.1 vs 7.5, P=0.004).

However, unlike in the RECOVERY trial, CoDEX showed no impact on all-cause mortality at 28 days (56.3% vs 61.5% with standard care alone, HR 0.97, 95% CI 0.72-1.31).

In an accompanying editorial, Hallie Prescott, MD, of the University of Michigan in Ann Arbor, and Todd Rice, MD, of Vanderbilt University in Nashville, Tennessee, argued that this difference could be explained by the early halt to the trial leaving it "underpowered to adequately evaluate the effect of corticosteroids on mortality."

Dexamethasone yielded no increase in secondary infections (21.9% vs 29.1% with standard care), and -- albeit with a little more need for insulin for glucose control (31.1% vs 28.3%) -- fewer cases of other serious adverse events (3.3% vs 6.1%).

Hydrocortisone Results

Two other underpowered studies released alongside CoDEX were and .

REMAP-CAP in the ICU for respiratory or cardiovascular organ support to a fixed 7-day course of IV hydrocortisone (50 mg every 6 hours), a shock-dependent course (50 mg every 6 hours when shock was clinically evident), or no hydrocortisone.

Both the fixed-dose and shock-dependent hydrocortisone regimens were likely better than none for the primary endpoint of organ support-free days, with 93% and 80% probability in Bayesian models, but neither met prespecified criteria for statistical superiority, "precluding definitive conclusions," according to the researchers.

CAPE COVID was the only double-blind study, to continuous IV infusion of hydrocortisone 200 mg/d or a saline placebo. For the primary endpoint of death or persistent dependence on mechanical ventilation or high-flow oxygen therapy at day 21, hydrocortisone came out similar to placebo (42.1% vs 50.7%, P=0.29).

Cross-Corticosteroid Meta-Analysis

All three studies, along with invasive mechanically-ventilated patients from RECOVERY and an additional three randomized trials (DEXA-COVID 19, CAPE STEROID, and Steroids-SARI), were aggregated prospectively by the WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) working group.

"The clinical trial groups agreed to share data, even prior to acceptance of their individual trial data for primary publication," Prescott and Rice noted.

The meta-analysis included a total of 1,703 critically ill patients with COVID-19 who were recruited through June 9, 2020 (selected to limit influence by the RECOVERY results). They were randomized to systemic dexamethasone, hydrocortisone, or methylprednisolone or to receive usual care or placebo.

Overall, these drugs reduced 28-day mortality by a relative 34% compared with controls (fixed-effects OR 0.66, 95% CI 0.53-0.82) with little inconsistency between the trial results, reported Jonathan Sterne, PhD, of the University of Bristol in England, and colleagues.

Mortality effect size appeared similar between drugs, with odds ratios of 0.64 for dexamethasone, 0.69 for hydrocortisone, and 0.91 for methylprednisolone (based on a single trial with 47 patients and 26 deaths).

These findings suggested "the benefit is a general class effect of glucocorticoids and not specific to any particular corticosteroid," the editorialists noted.

The meta-analysis also suggested similar effects of lower- versus higher-dose corticosteroid regimens, "although these estimates were imprecise, leaving the question of dose less definitively answered," the editorialists noted.

"Although the meta-analysis suggests corticosteroids might not be associated with improved mortality in critically ill patients with COVID-19 and shock, this result is prone to bias by both off-protocol corticosteroid use in the usual care group as well as exclusion of patients already receiving corticosteroids at screening," they added.

While the editorialists cautioned that "the exact threshold at which an individual patient should be prescribed corticosteroids remains unclear," Sterne's group concluded "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."

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