Dexamethasone
Joey Sweeney, PharmD, BCPS
We know that dexamethasone reduces morbidity and mortality associated with COVID-19 infections. Does a higher daily intake of dexamethasone reduce morbidity and mortality further? Munch and colleagues answered this question in the COVID STEROID 2 Trial Group paper recently published in JAMA. While outcomes in patients were improved, the results were not statistically significant.
Earlier studies have found dexamethasone to be beneficial for COVID-19 patients at daily doses of 6 mg to 16 mg. One of the larger investigations, the Randomized Evaluation of COVID-19 Therapy (RECOVERY) study, showed that 6 mg/day of dexamethasone, when used for up to 10 days, reduced mortality in patients.
But other studies have hinted that a higher dose may provide additional benefits for patients with severe COVID-19 disease, although the risk of acute fungal infections may outweigh any advantages.
High-dose investigated
This COVID STEROID 2 trial aimed to study both the efficacy and safety profiles of a higher 12 mg daily dose of dexamethasone in hospitalized adult patients with COVID-19 and corresponding severe hypoxemia using the primary endpoint of increased days alive without life support at 28 days.
The investigator-initiated, inter-national, parallel group, stratified, blinded, randomized clinical trial evaluated data from 982 patients who completed the study at the 90-day mark.
Twenty-six hospitals across Den-mark, India, Sweden, and Switzerland enrolled patients 18 years or older with confirmed SARS-CoV-2 infection requiring an oxygen flow rate of 10 L/min or greater, and/or use of mechanical ventilation (noninvasive or invasive).
Patients were excluded if they were already on systemic glucocorticoids at a higher dose than 6 mg dexamethasone or equivalent, had invasive fungal infection, active tuberculosis, known hypersensitivity to dexamethasone, and/or were pregnant.
Tocilizumab was appropriately used partway through this trial after a previous study, the REMAP-CAP trial, showed benefits in patient outcomes, including survival.
The researchers of the COVID STEROID 2 trial appropriately estimated that a sample size of 1,000 patients would be needed to ensure an 85% power in order to detect a 15% reduction in 28-day mortality.
The statistical foresight and inclusion of this power calculator illustrates the high-quality of this study. The primary limitation of the research appears to be its sample size, however. With a principal endpoint difference of about 4% between the 2 groups, a larger sample size is needed to detect the statistical significance of this variance.
Statistical insignificance
The baseline characteristics of the treatment groups differed only with diabetes status. Researchers found a significantly larger number of people with diabetes were in the 6 mg group.
“Slight baseline imbalance is not uncommon in randomized trials [due] to random error,” said Anders Perner, MD, PhD, chief physician and professor at Rigshospitalet, the largest hospital in Denmark and one of the sites of the COVID STEROID 2 trial. “We did analyze the effect of this in an adjusted analysis.” More information about this analysis was noted in the paper.
Primary endpoint results showed that the higher dose group had more days alive without life support than the lower dose group. However, the difference was small (1.3 days) and not statistically significant.
Secondary endpoints were also favorable for the higher dose group (4.4 more days survival at 90 days without life support), although this was not statistically significant either.
At 28 and 90 days without life support, survival was higher in the 12 mg group, although this was also statistically insignificant.
The lower-dose group had more serious adverse events, which illustrates that there does not appear to be increased risk of serious adverse events if a larger dose was prescribed.
While the results of this study do not dictate clinicians move toward giving patients a 12-mg dexamethasone dose, it does show that the risks of moving to a higher dose are unlikely to result in added serious adverse events. Clinicians can use this knowledge when considering initiating or changing the dose of dexamethasone in seriously ill COVID-19 patients. ■