Effect of 12 mg vs 6 mg of Dexamethasone on the Number of Days Alive Without Life Support in Adults With COVID-19 and Severe Hypoxemia: The COVID STEROID 2 Randomized Trial

Abstract

Importance: A daily dose with 6 mg of dexamethasone is recommended for up to 10 days in patients with severe and critical COVID-19, but a higher dose may benefit those with more severe disease.

Objective: To assess the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia.

Design, setting, and participants: A multicenter, randomized clinical trial was conducted between August 2020 and May 2021 at 26 hospitals in Europe and India and included 1000 adults with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation. End of 90-day follow-up was on August 19, 2021.

Interventions: Patients were randomized 1:1 to 12 mg/d of intravenous dexamethasone (n = 503) or 6 mg/d of intravenous dexamethasone (n = 497) for up to 10 days.

Main outcomes and measures: The primary outcome was the number of days alive without life support (invasive mechanical ventilation, circulatory support, or kidney replacement therapy) at 28 days and was adjusted for stratification variables. Of the 8 prespecified secondary outcomes, 5 are included in this analysis (the number of days alive without life support at 90 days, the number of days alive out of the hospital at 90 days, mortality at 28 days and at 90 days, and ≥1 serious adverse reactions at 28 days).

Results: Of the 1000 randomized patients, 982 were included (median age, 65 [IQR, 55-73] years; 305 [31%] women) and primary outcome data were available for 971 (491 in the 12 mg of dexamethasone group and 480 in the 6 mg of dexamethasone group). The median number of days alive without life support was 22.0 days (IQR, 6.0-28.0 days) in the 12 mg of dexamethasone group and 20.5 days (IQR, 4.0-28.0 days) in the 6 mg of dexamethasone group (adjusted mean difference, 1.3 days [95% CI, 0-2.6 days]; P = .07). Mortality at 28 days was 27.1% in the 12 mg of dexamethasone group vs 32.3% in the 6 mg of dexamethasone group (adjusted relative risk, 0.86 [99% CI, 0.68-1.08]). Mortality at 90 days was 32.0% in the 12 mg of dexamethasone group vs 37.7% in the 6 mg of dexamethasone group (adjusted relative risk, 0.87 [99% CI, 0.70-1.07]). Serious adverse reactions, including septic shock and invasive fungal infections, occurred in 11.3% in the 12 mg of dexamethasone group vs 13.4% in the 6 mg of dexamethasone group (adjusted relative risk, 0.83 [99% CI, 0.54-1.29]).

Conclusions and relevance: 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. However, the trial may have been underpowered to identify a significant difference.

Trial registration: ClinicalTrials.gov Identifier: NCT04509973 and ctri.nic.in Identifier: CTRI/2020/10/028731.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Munch reported receiving grants from the Novo Nordisk Foundation, Pfizer, Fresenius Kabi, and Sygeforsikringen “danmark.” Dr Benfield reported receiving grants from the Novo Nordisk Foundation, the Simonsen Foundation, the Erik and Susanna Olesen Charitable Fund, the Lundbeck Foundation, and the Kai Hansen Foundation; receiving grants and personal fees from GlaxoSmithKline, Pfizer, and Gilead; and receiving personal fees from Boehringer Ingelheim, Merck Sharp and Dohme, and Pentabase ApS. Dr Cioccari reported receiving grants from Edwards Lifesciences, Phagenesis Ltd, and Nestle. Dr Divatia reported receiving personal fees from Edwards Lifesciences. Dr Helleberg reported receiving personal fees for serving on advisory boards from GlaxoSmithKline, AstraZeneca, Sobi, Merck Sharp and Dohme; receiving personal fees for speaking from GlaxoSmithKline and Merck Sharp and Dohme; and receiving travel reimbursement from Gilead and GlaxoSmithKline. Dr Shukla reported receiving grants from the George Institute of Global Health. Dr Ulrik reported receiving personal fees from GlaxoSmithKline, AstraZeneca, Teva, Boehringer Ingelheim, Sanofi, Chiesi, and Orion Pharma. Dr Granholm reported receiving grants from the Novo Nordisk Foundation, Pfizer, Fresenius Kabi, and Sygeforsikringen “danmark.” Mrs Kjær reported receiving grants from the Novo Nordisk Foundation, Pfizer, and Fresenius Kabi. Dr Meyhoff reported receiving grants from the Novo Nordisk Foundation, Pfizer, and Fresenius Kabi. Ms Vesterlund reported receiving grants from the Novo Nordisk Foundation and the Rigshospitalet. Dr Hammond reported receiving grants from the National Health and Medical Research Council and Baxter Healthcare. Ms Micallef reported receiving personal fees from Righospitalet and the George Institute for Global Health. Mr Leistner reported receiving grants from the Novo Nordisk Foundation. Mrs Kristensen reported receiving grants from the Novo Nordisk Foundation, Pfizer, and Fresenius Kabi. Dr T. Jensen reported receiving grants from the Novo Nordisk Foundation and receiving nonfinancial support from the Research Council at Rigshospitalet. Mr Gleipner-Andersen reported receiving grants from the Novo Nordisk Foundation, Pfizer, and Fresenius Kabi. Dr V. Jha reported receiving grants from GlaxoSmithKline, Baxter International, and NephroPlus and receiving personal fees from Baxter International and AstraZeneca. Dr Venkatesh reported receiving grants from the Medical Research Future Fund Practitioner Fellowship and receiving personal fees from Baxter International. Dr Perner reported receiving grants from the Novo Nordisk Foundation, Pfizer, Fresenius Kabi, and Sygeforsikringen “danmark.” No other disclosures were reported.

Figures

Figure 1.. Screening, Randomization, and Follow-up of Patients in the COVID STEROID 2 Trial

aThere were 33 patients who met more than 1 criterion. bProvided data at baseline and for the analysis of serious adverse reactions. cRequired exclusion by the Swiss ethics committee.

Figure 2.. Distributions of the Primary Outcome and Time to Death Curves to Day 90

A, Life support was defined as invasive mechanical ventilation, circulatory support, or kidney replacement therapy. There were missing data in 11 patients for the primary outcome. Red represents the worse outcomes and blue represents better outcomes. B, There were 14 patients who were not followed up for the full 90 days (7 patients in each intervention group) and who were included until the last day they were known to be alive. The median follow-up time was 90 days (IQR, 24-90 days) in the 12 mg of dexamethasone group and 90 days (IQR, 20-90 days) in the 6 mg of dexamethasone group. The time to death was compared post hoc using unadjusted Cox regression.

Figure 3.. Median Days Alive Without Life Support and the Adjusted Mean Differences in the 7 Predefined Subgroups

aAdjusted for the stratification variables of site, age younger than 70 years, and use of invasive mechanical ventilation unless otherwise indicated. The median differences for the outcomes of days alive without life support and days out of the hospital and the analyses of the single components of the composite outcomes appear in eTable 8 in Supplement 2. bDefined as life support or cardiopulmonary resuscitation at randomization.