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Dexamethasone Cuts Death Rate in COVID-19
Group on Respiratory Support
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Mark Mascolini
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COVID-19 patients requiring mechanical ventilation or oxygen without ventilation had significantly lower 28-day all-cause mortality when randomized to dexamethasone rather than to standard care in the multicenter RECOVERY trial [1]. But mortality did not differ between the dexamethasone group and the usual-care group in people who did not need respiratory support for COVID-19.
RECOVERY investigators noted that inflammatory organ injury may affect people with advanced COVID-19. Yet the role of glucocorticoids in quelling this inflammation remains controversial. They mounted this randomized open-label trial to assess the value of the glucocorticoid dexamethasone in people admitted to the hospital with COVID-19.
Trial participants received care at 1 of 176 National Health Service organizations in the United Kingdom. Participants had to have clinically suspected or lab-confirmed SARS-CoV-2 infection. An initial requirement that patients had to be at least 18 years old was removed on May 9, 2020. The investigators randomized participants in a 2-to-1 ratio to receive standard care alone or standard care plus oral or intravenous dexamethasone at a dose of 6 mg once daily for up to 10 days or until hospital discharge, whichever came first. The primary endpoint was all-cause mortality within 28 days of randomization.
The analysis involved 2104 people randomized to dexamethasone and 4321 randomized to standard care. Age averaged 66.9 years in the dexamethasone group and 65.8 years in the control group. Two thirds of both groups (64%) were men, and in both groups a median of 2 days had passed since hospital admission. Similar proportions in the dexamethasone and control groups did not receive oxygen support (24% and 24%), received oxygen only (61% and 60%), and received invasive mechanical ventilation (15% and 16%). The same proportion in each group (56%) had any previous coexisting disease.
Twenty-eight days after randomization, people receiving dexamethasone had significantly lower 28-day all-cause mortality than the standard-care group (22.9% versus 25.7%, age-adjusted rate ratio [RR] 0.83, 95% confidence interval [CI] 0.75 to 0.93, P < 0.001).
Among participants requiring invasive mechanical ventilation, all-cause mortality was one third lower in the dexamethasone group (29.3% versus 41.4%, age-adjusted RR 0.64, 95% CI 0.51 to 0.81). Among people who needed oxygen support without ventilation, mortality was about 20% lower in those receiving dexamethasone (23.3% versus 26.2%, age-adjusted RR 0.82, 95% CI 0.72 to 0.94). Age-adjusted absolute drops in 28-day all-cause mortality with dexamethasone were 12.3 percentage points (95% CI 6.3 to 17.6) in people needing mechanical ventilation and 4.2 percentage points (95% CI 1.4 to 6.7) in people needing oxygen but not ventilation.
Dexamethasone had no mortality advantage among people who did not need oxygen or mechanical ventilation (17.8% versus 14.0%, age-adjusted RR 1.19, 95% CI 0.91 to 1.55). Results proved similar when researchers limited the analysis to 5698 people (89%) PCR-positive for SARS-CoV-2.
Compared with the control group, participants randomized to dexamethasone spent less time in the hospital (median 12 versus 13 days) and had a 10% higher chance of discharge within 28 days (RR 1.10, 95% CI 1.03 to 1.17). The researchers saw a trend toward lower progression to a prespecified composite outcome of invasive mechanical ventilation or death in the dexamethasone group (RR 0.92, 95% CI 0.84 to 1.01). Risk of progression to mechanical ventilation alone was almost 25% lower in people randomized to dexamethasone (RR 0.77, 95% CI 0.62 to 0.95).
The RECOVERY team observed that their findings confirm results of a previous multicenter Spanish trial in 277 people with acute respiratory distress syndrome requiring mechanical ventilation, which found 15% lower mortality at 60 days with dexamethasone versus usual care [2]. The investigators also noted that RECOVERY enrolled about 15% of all in-hospital COVID-19 patients in the United Kingdom, and mortality in their standard-care group reflected overall mortality in hospitalized COVID-19 patients across the country.
The authors cautioned that high dexamethasone doses may do more harm than good, as may dexamethasone therapy given when controlling SARS-CoV-2 replication is more important and inflammation is minimal. Finally, they noted that recently updated UK and US National Institutes of Health guidelines recommend glucocorticoids in hospitalized COVID-19 patients.
References
1. The RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19-preliminary report. N Engl J Med. July 17, 2020. https://doi.org/10.1056/NEJMoa2021436
2. Villar J, Ferrando C, MartÃnez D, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020;8:267-276.
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