LONDON – New evidence from seven randomized controlled trials and a simultaneously conducted meta-analysis has again demonstrated that corticosteroids show significant benefit in patients who are critically ill with COVID-19, reducing length of hospital stay and cutting 28-day mortality.

That confirms the finding of the U.K. Recovery trial, which reported on June 16 that dexamethasone has a statistically significant impact on mortality in the most severely affected patients.

That led to an immediate change in standard of care. As one example, prescriptions for dexamethasone rose from 7% to 8% of patients at the end of May to more than 55% by the end of June, in one U.S. hospital system.

The Recovery results led to randomized trials at centers worldwide, evaluating the efficacy of three corticosteroids – dexamethasone, hydrocortisone and prednisolone – to be stopped early, so that all patients could be treated. At the same time there was agreement that the meta-analysis be conducted.

“This is really very unusual in science… the decision was taken to combine results in a prospective manner,” said Jonathan Sterne, professor in the department of population health science at Bristol University Medical School, who is lead author of the meta-analysis, published on Sept. 2 in the Journal of the American Medical Association, alongside studies on which it is based.

“What we found reinforces the result of the Recovery trial,” Sterne said. “The overall results support the Recovery trial finding that corticosteroids reduce mortality in the sickest patients with COVID.”

With a “p” value of 0.0001, the data are definitive, said Sterne. “These were critically ill patients: 32% died vs. 40% on standard of care. That’s a 20% relative reduction, or eight fewer deaths for every 100 patients.”

Martin Landray, professor of medicine and epidemiology at Oxford University and chief investigator of the Recovery trial, said the findings of the meta-analysis double the amount of evidence that corticosteroids reduce the risk of death. The result from Recovery was compelling in its own right, but there are always questions about reproducibility in different settings.

“The answer from the meta-analysis of seven randomized trials is consistent,” Landray said. “It’s good to have confirmation.”

The data also confirm the benefit is not confined to people on mechanical ventilation, but applies to all patients requiring oxygen therapy. “[Patients] should probably be prescribed [corticosteroids] when they need oxygen,” Landray said.

While there is less evidence for the benefits of prednisolone than of dexamethasone and hydrocortisone, the totality of the data indicates corticosteroids should routinely be used to treat COVID-19 patients in intensive care.

“We understand now it is a class effect – there is more than one choice, which means there should be better world supply,” said Anthony Gordon, critical care consultant at Imperial College London, who led one of the individual trials included in the meta-analysis.

Immediate action

In total, the meta-analysis, which was coordinated by the World Health Organization (WHO), includes 1,703 patients in five continents and in some of the countries that have been hardest hit by the pandemic.

Sterne said the results were shown in advance of publication to WHO, which will be updating its care guidelines at the same time as the papers are published in JAMA. In the U.K., the chief medical officer sent a letter to all doctors, to update care guidelines. “Research findings are getting put into immediate action – it’s incredible,” Sterne said.

In the trials, corticosteroids were administered at low doses, either orally or intravenously. There were no safety issues. “There is absolutely no sign that administering corticosteroids increased serious side effects, and side effects were generally lower to patients assigned to corticosteroids,” said Sterne.

The improvement was seen regardless of which of the many manifestations of COVID-19 pathology, from lung disease to cardiovascular complications or kidney disease, were to the fore.

“These are people at very high risk, for whom there are no other treatments, and the drugs cost next to nothing,” said Landray. A typical course of treatment with corticosteroids is £60 (US$80). “There aren’t many things you can do in intensive care units that cost less than £60,” Landray said.

For Landray, the combined data and subsequent swift move to action is a potent demonstration of the power of randomized trials. “The meta-analysis extends the evidence of the Recovery trial and provides reproducibility, and you can shift almost immediately in putting it into practice,” he said.

That compares to controversies over the use of hydroxychloroquine and convalescent plasma, where there is scientific rationale, but limited objective evidence, Landray said. “Randomized trials give you the answer, and you can put it into practice without debate and prevarication.”

The U.K.-wide Recovery trial is ongoing, with randomization to one of these arms: usual care; usual care plus low-dose dexamethasone (which is now only recruiting children); usual care plus the antibiotic azithromycin; usual care plus convalescent plasma collected from donors who have recovered from COVID-19 and containing antibodies against the SARS-CoV-2 virus.

There is a second randomization for participants who deteriorate following initial treatment, in which they are assigned to either the IL-6 inhibitor Actemra (tocilizumab) or control.

To date, the Recovery trial has recruited 12,301 patients at 176 sites. The readout of the remaining arms rests on the state of the pandemic and recruitment is low at present, with community transmission on the rise in the U.K., but no parallel increase in the number of patients requiring hospital care.

As someone who has treated many seriously affected patients, Gordon put the demonstration of the benefits of corticosteroids into context, noting one-third of seriously ill patients are still dying. “As important as these results are, it’s not a cure. It’s a huge step forward: working in the ICU in March, we didn’t know how to treat [COVID-19]. Now having clear evidence there is something that will help is a huge bonus,” Gordon said.