Early in the COVID-19 pandemic, the RECOVERY trial showed that anti-inflammatory therapy
with 6 mg daily dexamethasone improved survival in patients requiring oxygen supplementation.
1
Additional anti-inflammatory therapy with either interleukin-6 (IL-6) inhibitors or
the Janus kinase inhibitor baricitinib was later shown to provide further benefit
to such patients.2, 3 However, because IL-6 inhibitors and Janus kinase inhibitors
might be less appropriate for some patients (eg, those who are pregnant or who have
liver or kidney impairment) and are likely to be unavailable in some health-care systems
because of high cost, finding alternatives to these drugs is important. A simple alternative
would be to increase the dose of dexamethasone. In the international, blinded COVID
STEROID 2 trial, which evaluated 12 mg versus 6 mg doses of dexamethasone in patients
with COVID-19 and severe hypoxaemia, Munch and colleagues
4
and Granholm and colleagues
5
found that mortality at 28, 90, and 180 days was five percentage points lower in patients
assigned to 12 mg dexamethasone than in those assigned to 6 mg dexamethasone.4, 5
Although these results were not significant, a preplanned Bayesian analysis indicated
a 95% probability of benefit on mortality with the higher dose.
6
In this issue of The Lancet, the RECOVERY Collaborative Group
7
reports the results of a multicentre, multicountry, randomised, open-label platform
trial evaluating a higher dose of dexamethasone (20 mg once daily for 5 days followed
by 10 mg once daily for 5 days) compared with usual care (6 mg dexamethasone once
daily for 10 days) in 1272 patients with COVID-19 receiving no oxygen (n=8) or simple
oxygen supplementation (n=1264). 769 (60%) participants were male and 503 (40%) were
female, with a mean age of 61·1 (SD 17·5) years; 688 (54%) were Asian, 454 (36%) were
White, 14 (1%) were Black, and 116 (9%) were of other or unknown ethnicity. These
patients were a subgroup of the RECOVERY trial population, which also included patients
who were ventilated and on extracorporeal membrane oxygenation (ECMO). Enrolment into
this subgroup was closed early following one of the repeated interim analyses and
consequent recommendation from the data monitoring committee. The enrolment of the
subgroup of patients who are ventilated or on ECMO continues. Death at 28 days (the
primary outcome) occurred in 123 (19%) of 659 participants allocated to higher-dose
dexamethasone and in 75 (12%) of 613 patients allocated to usual care (rate ratio
1·59, 95% CI 1·20–2·10). The occurrence of non-COVID-19 pneumonia and hyperglycaemia
was also higher in the higher-dose group.
7
Strengths of this study include the pragmatic design; the use of mortality as the
primary outcome; and the enrolment of patients in different health-care systems (including
those of the UK, Nepal, Indonesia, Viet Nam, South Africa, and Ghana), which affords
generalisability. Because adaptive stopping of recruitment into intervention groups
and subgroups continues to be used in the RECOVERY trial, the repeated interim analyses
are an important asset. The decision to stop recruitment was made by the data monitoring
committee; however, the criteria for such a decision are not clear. This lack of transparency
is a limitation and somewhat reduces the confidence in the observed effect size, although
not in its direction. The scarcity of data regarding the flow rate of oxygen is also
challenging. Almost all patients were recorded as receiving simple oxygen at enrolment;
however, in the absence of further details, such flow rates can range from 1 L/min
to 20 L/min. Of the patients who died by day 28, more than three-quarters of those
in both groups seem to have died without receiving invasive mechanical ventilation.
The use or not of mechanical ventilation was a post-randomisation intervention and
was possibly influenced by treatment limitations for patients with multiple comorbidities,
resource constraints, and clinician decisions. The effect of this intervention on
the final distribution of mortality between the two groups remains unclear, particularly
in an unblinded trial. 28-day mortality in the group that received standard-dose dexamethasone
was 12%, which seems to be high for a cohort of patients who were not critically ill,
of whom more than half were vaccinated, and—based on the period of enrolment—many
of whom were probably infected with the omicron (B.1.1.529) rather than the delta
(B.1.617.2) variant. Other recent trials of interventions reported lower mortality
in hospitalised, non-critically ill patients with COVID-19 from similar geographical
settings.8, 9
How do we reconcile the subgroup results of the RECOVERY trial with the results of
other trials of corticosteroids in the treatment of COVID-19? The COVID STEROID 2
trial enrolled 1000 patients with COVID-19 receiving at least 10 L/min of oxygen (54%
of patients), continuous positive airway pressure or non-invasive ventilation (25%
of patients), or invasive ventilation (21% of patients). The 28-day mortality in the
higher-dose group was 27·1% compared with 32·6% in the standard-dose group (adjusted
risk ratio 0·86, 99% CI 0·68–1·08); the CIs of the mortality estimates therefore do
not overlap between the two trials. Like RECOVERY, the COVID STEROID 2 trial also
enrolled many patients in Asia (38% in India), but patients allocated to the higher
dose received less dexamethasone (12 mg daily for up to 10 days) than those in the
higher-dose group in the RECOVERY trial. Overall, the patients enrolled in the COVID
STEROID 2 trial seemed to be more critically ill, but the two trial populations did
appear to overlap in severity (eg, 25% of the population in the COVID STEROID 2 trial
would probably have been eligible for the RECOVERY trial subgroup on the basis of
oxygen flow rates at baseline [<20 L/min], but there were no data on flow rates at
baseline in the RECOVERY subgroup). Other trials have found benefit from higher doses
of dexamethasone versus placebo in mechanically ventilated patients with COVID-19,
and dexamethasone versus standard care in mechanically ventilated patients with non-COVID-19
acute respiratory distress syndrome.10, 11
With changing SARS-CoV-2 strains and increased use of vaccination, and therefore potentially
fewer patients becoming critically ill from COVID-19, predicting the future use of
anti-inflammatory strategies in these patients is difficult. Patients with COVID-19
receiving low-flow oxygen are likely to be harmed by high doses of dexamethasone,
whereas those receiving higher-flow oxygen or mechanical ventilation could benefit
from a high dose versus a standard dose of dexamethasone. The oxygen flow rates associated
with harm and benefit cannot be defined precisely at present, but are probably greater
than 10 L/min, which was the inclusion criterion in the COVID STEROID 2 trial. We
will be better informed when the results of the subgroup of patients on ventilation
or ECMO in the RECOVERY trial become available and when all trials of higher-dose
versus standard-dose dexamethasone in patients with COVID-19 and hypoxaemia have undergone
meta-analysis.
12
Nurse checking with fingertip pulse oximeter oxygen saturation meter SPO2 PR blood
monitor finger to middle aged adult patient man,Home care nurse service
© 2023 Issarawat Tattong/Getty Images
2023
AP and BV were investigators on the COVID STEROID 2 trial, which was funded by the
Novo Nordisk Foundation. AP receives research funding from the Novo Nordisk Foundation
and Sygeforsikringen danmark, and has received honorarium from Novartis for participating
on an advisory board. The Department of Intensive Care, Rigshospitalet has received
funding for research from Pfizer within the past 3 years and has done contract research
for AM-Pharma. BV is supported by a National Health and Medical Research Council Investigator
Research Fellowship and has received institutional research support from Baxter.