Jury Still Out on Value of Higher Dose of Dexamethasone for Severe COVID-19

NEW YORK (Reuters Health) – A higher dose of dexamethasone may not help severely ill COVID-19 patients survive longer without life support, according to a new clinical trial, but larger studies are needed.

“Among patients with COVID-19 and severe hypoxemia, 12 mg/d of dexamethasone compared with 6 mg/d of dexamethasone did not result in statistically significantly more days alive without life support at 28 days,” the COVID STEROID 2 Trial Group writes in JAMA. “However, the trial may have been underpowered to identify a significant difference.”

Dr. Anders Perner of Rigshospitalet in Copenhagen, Denmark, and his colleagues note that a daily dose of 6 mg of dexamethasone is recommended for up to 10 days in patients with severe and critical COVID-19.

To test if a higher dose worked better, the team randomly assigned 1,000 patients at 26 hospitals in Europe and India to receive either 6 mg or 12 mg of intravenous dexamethasone for up to 10 days. The patients (mean age, 65; 31% women) all had COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation.

Median survival time without life support in both groups was similar: 22.0 days in the 12 mg group and 20.5 days in the 6 mg group (adjusted mean difference, 1.3 days; P=0.07).

Mortality at 28 days was 27.1% in the 12 mg group and 32.3% in the 6 mg group (adjusted relative risk, 0.86; 99% confidence interval, 0.68 to 1.08). At the end of the 90-day follow-up, mortality was 32.0% in the 12 mg group and 37.7% in the 6 mg group (aRR, 0.87; 99% CI, 0.70 to 1.07).

Serious adverse reactions, including invasive fungal infections and septic shock, were reported in 11.3% of patients in the 12 mg group and in 13.4% in the 6 mg group (aRR, 0.83; 99% CI, 0.54 to 1.29).

“These findings suggest the possibility that higher doses of dexamethasone than the recommended dose of 6 mg/d may benefit patients with COVID-19 who have more severe disease,” the authors write. “However, there are concerns about adverse reactions with the use of higher doses of glucocorticoids, particularly reports of severe fungal infections, such as mucormycosis, in patients with COVID-19 treated with glucocorticoids.”

In a linked editorial, Dr. Steven A. Webb of Monash University in Melbourne, Australia, and colleagues write, “This mortality difference, if real, would be of substantial clinical importance, but there is a possibility that the difference may have arisen due to chance.”

“Importantly,” they add, “the occurrence of serious adverse events was not different between the 2 doses.”

“Many critically ill patients with COVID-19 are still needing life support and are dying,” Dr. Perner told Reuters Health by email. “To improve treatment as fast as possible, it is important to test simple, readily available interventions.”

“More trials are needed to test the optimal duration of steroid treatment in the sickest patients. Comparative trials on higher-dose dexamethasone vs. other anti-inflammatory agents are also needed,” he said.

The research team continues to follow patients for longer durations and is pooling data from four trials to compare standard- vs. higher-dose dexamethasone in patients with critical COVID-19.

The Novo Nordisk Foundation funded the study.

SOURCES: https://bit.ly/3k06gYq and https://bit.ly/3pZU7qn JAMA, online October 21, 2021.

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