Higher-dose dexamethasone for patients with COVID-19 and hypoxaemia?

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 colleagues⁴ and Granholm and colleagues⁵ 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 Group⁷ 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

© 2023 Issarawat Tattong/Getty Images

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.