High mortality in COVID-19 patients on oxygen therapy with higher dose corticosteroids

Key takeaways:

• Higher dose vs. low dose corticosteroids raises the risk for mortality by 60% in this patient population.
• Those on higher dose corticosteroids also had more cases of pneumonia and high blood sugar.

Higher dose corticosteroids heightened the risk for mortality in patients hospitalized with COVID-19 who need oxygen therapy compared with usual care/low dose corticosteroids, according to study results published in The Lancet.

These results were also presented at this year’s European Congress of Clinical Microbiology and Infectious Diseases.

“Among hospitalized patients with COVID-19 who require oxygen or ventilatory support, low-dose corticosteroids reduce the risk of death,” the RECOVERY Collaborative Group wrote. “However, among patients requiring simple oxygen only, higher doses of corticosteroids increase the risk of death compared with low-dose corticosteroids. It remains unclear whether using a higher dose of corticosteroids is beneficial among patients requiring non-invasive or invasive ventilation — the RECOVERY trial continues to study this.”

In a randomized, controlled and open-label platform trial, the RECOVERY Collaborative Group analyzed 1,272 adults (60% men; 19% with diabetes) hospitalized with COVID-19 between May 25, 2021, and May 13, 2022, with hypoxia on simple or no oxygen to determine the effects of a higher dose of corticosteroids on 28-day mortality.

Notably, recruitment of these specific patients was ended on May 13, 2022, because of safety concerns reported by the data monitoring committee, according to researchers.

As Healio previously reported, early results from the RECOVERY trial showed that low-dose dexamethasone reduced the risk for death by one-third in ventilated patients with COVID-19. When the final paper was published in July, there were no major changes in this data.

Most patients in this study received simple oxygen only (n = 1,264), leaving only eight patients from the cohort who did not receive any oxygen.

Of the total cohort, 659 adults (65% aged younger than 70 years) were treated with usual care and higher dose corticosteroids (20 mg dexamethasone per day for 5 days than 10 mg per day for 5 days or until discharge), whereas 613 adults (64% aged younger than 70 years) were treated with only usual care, with 530 patients (87%) receiving low-dose corticosteroids (6 mg dexamethasone per day for 10 days or until discharge).

In terms of 28-day mortality, researchers found that more patients on higher dose corticosteroids died than patients receiving usual care (123 patients [19%] vs. 75 patients [12%]). This signals that those treated with an increased dose of corticosteroids had a 60% (rate ratio, 1.59; 95% CI, 1.2-2.1) higher risk for death, according to a press release from the European Society of Clinical Microbiology and Infectious Diseases.

Further, subgroup analysis that individually looked at age (< 70 years vs. 70-79 years vs. 80 years), sex, ethnicity (white vs. Black, Asian or minority ethnic), country (U.K. vs. other countries) and days since symptom onset ( 7 days vs. > 7 days) also demonstrated increased mortality in those receiving higher dose steroids.

Following these findings, researchers conducted a systemic review and meta-analysis of seven trials (n = 1,193) plus their trial that all evaluated high and low doses of corticosteroids in patients mainly on simple or no oxygen, and they found a mortality rate ratio of 1.35 (95% CI, 1.07-1.7).

Back in their main analysis, researchers noted a comparable rate between the treatment groups when evaluating discharge within 28 days, but the risk for future invasive mechanical ventilation or death was elevated in those receiving higher dose corticosteroids vs. usual care (131 patients vs. 80 patients; RR = 1.52; 95% CI, 1.18-1.97).

Additionally, the higher dose corticosteroids group had 64 cases of pneumonia unrelated to their COVID infection vs. 37 cases in the usual care group. Of the higher dose cohort, 142 had hyperglycemia and therefore needed a higher insulin dose compared with 87 patients in the usual care cohort. Four out of five serious adverse events experienced in those on higher dose corticosteroids were linked to hyperglycemia, whereas the remaining one was associated with gastrointestinal bleeding, according to researchers. Importantly, every event was resolved.

“It remains an open question whether increasing the dose of corticosteroids above 6 mg dexamethasone per day is helpful for patients with COVID-19 requiring noninvasive or invasive mechanical ventilation — the RECOVERY trial continues to seek an answer for that question,” the RECOVERY Collaborative Group wrote.

This study by the RECOVERY team adds to growing literature about corticosteroid treatment for patients with COVID-19 but contradicts results from the COVID STEROID 2 trial, which found that in a cohort of 1,000 patients on various types of oxygen, those on higher dose corticosteroids had lower mortality than those on standard-dose corticosteroids, according to an accompanying editorial by Anders Perner, MD, PhD, professor in intensive care at Rigshospitalet, University of Copenhagen, and an honorary professor of the The George Institute for Global Health in Sydney, and Balasubramanian Venkatesh, MD, director of intensive care at The Wesley Hospital in Brisbane, Australia.

“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 vs. a standard dose of dexamethasone,” Perner and Venkatesh wrote. “The oxygen flow rates associated with harm and benefit cannot be defined precisely at present, but are probably greater than 10 L per minute, 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 vs. standard-dose dexamethasone in patients with COVID-19 and hypoxemia have undergone meta-analysis.”

References:

• Higher dose corticosteroids associated with a 60% increased risk of death in hypoxic COVID-19 patients requiring only non-invasive oxygen therapy (The Lancet/RECOVERY trial). https://www.eurekalert.org/news-releases/985722. Published April 12, 2023. Accessed April 18, 2023.
• Perner A, et al. The Lancet. 2023;doi:10.1016/S0140-6736(23)00587-1.
• Peto L, et al. Higher dose corticosteroids in hospitalized COVID-19 patients with hypoxia but not requiring ventilatory support (RECOVERY): A randomized, controlled, open-label, platform trial. Presented at: European Congress of Clinical Microbiology and Infectious Diseases; April 15-18, 2023; Copenhagen, Denmark.