Dexamethasone reduces death by one third in patients with severe COVID

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Dexamethasone reduced deaths by one-third in ventilated patients (rate ratio 0.65 [95% confidence interval 0.48 to 0.88]; p=0.0003) and by one fifth in other patients receiving oxygen only (0.80 [0.67 to 0.96]; p=0.0021). There was no benefit among those patients who did not require respiratory support (1.22 [0.86 to 1.75]; p=0.14).

https://www.recoverytrial.net/files/recovery_dexamethasone_statement_160620_v2final.pdf

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Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of COVID-19 In March 2020, the RECOVERY (Randomised Evaluation of COVid-19 thERapY) trial was established as a randomised clinical trial to test a range of potential treatments for COVID-19, including low-dose dexamethasone (a steroid treatment).

Over 11,500 patients have been enrolled from over 175 NHS hospitals in the UK. On 8 June, recruitment to the dexamethasone arm was halted since, in the view of the trial Steering Committee, sufficient patients had been enrolled to establish whether or not the drug had a meaningful benefit. A total of 2104 patients were randomised to receive dexamethasone 6 mg once per day (either by mouth or by intravenous injection) for ten days and were compared with 4321 patients randomised to usual care alone.

Among the patients who received usual care alone, 28-day mortality was highest in those who required ventilation (41%), intermediate in those patients who required oxygen only (25%), and lowest among those who did not require any respiratory intervention (13%). Dexamethasone reduced deaths by one-third in ventilated patients (rate ratio 0.65 [95% confidence interval 0.48 to 0.88]; p=0.0003) and by one fifth in other patients receiving oxygen only (0.80 [0.67 to 0.96]; p=0.0021). There was no benefit among those patients who did not require respiratory support (1.22 [0.86 to 1.75]; p=0.14).

Based on these results, 1 death would be prevented by treatment of around 8 ventilated patients or around 25 patients requiring oxygen alone. Given the public health importance of these results, we are now working to publish the full details as soon as possible.

Peter Horby, Professor of Emerging Infectious Diseases in the Nuffield Department of Medicine, University of Oxford, and one of the Chief Investigators for the trial, said: ‘Dexamethasone is the first drug to be shown to improve survival in COVID-19. This is an extremely welcome result. The survival benefit is clear and large in those patients who are sick enough to require oxygen treatment, so dexamethasone should now become standard of care in these patients. Dexamethasone is inexpensive, on the shelf, and can be used immediately to save lives worldwide.’

Martin Landray, Professor of Medicine and Epidemiology at the Nuffield Department of Population Health, University of Oxford, one of the Chief Investigators, said: ‘Since the appearance of COVID-19 six months ago, the search has been on for treatments that can improve survival, particularly in the sickest patients. These preliminary results from the RECOVERY trial are very clear – dexamethasone reduces the risk of death among patients with severe respiratory complications. COVID-19 is a global disease – it is fantastic that the first treatment demonstrated to reduce mortality is one that is instantly available and affordable worldwide.’ The UK Government’s Chief Scientific Adviser,

Sir Patrick Vallance, said: ‘This is tremendous news today from the Recovery trial showing that dexamethasone is the first drug to reduce mortality from COVID-19. It is particularly exciting as this is an inexpensive widely available medicine. ‘This is a ground-breaking development in our fight against the disease, and the speed at which researchers have progressed finding an effective treatment is truly remarkable. It shows the importance of doing high quality clinical trials and basing decisions on the results of those trials.’

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Coronavirus breakthrough: dexamethasone is first drug shown to save lives

In a large trial, a cheap and widely available steroid cut deaths by one-third among patients critically ill with COVID-19.

 

Heidi Ledford

 

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The steroid dexamethasone was given to thousands of people critically ill with coronavirus in a randomized, controlled trial.Credit: Dr P. Marazzi/Science Photo Library

An inexpensive and commonly used steroid can save the lives of people seriously ill with COVID-19, a randomized, controlled clinical trial in the United Kingdom has found. The drug, called dexamethasone, is the first shown to reduce deaths from the coronavirus that has killed more than 430,000 people globally. In the trial, it cut deaths by about one-third in patients who were on ventilators because of coronavirus infection.

“It’s a startling result,” says Kenneth Baillie, an intensive-care physician at the University of Edinburgh, UK, who serves on the steering committee of the trial, called RECOVERY. “It will clearly have a massive global impact.”

 

The RECOVERY trial, launched in March, is one of the world’s biggest randomized, controlled trials for coronavirus treatments; it is testing a range of potential therapies. The study enrolled 2,100 participants who received dexamethasone at a low or moderate dose of six milligrams per day for ten days, and compared how they fared against about 4,300 people who received standard care for coronavirus infection.

The effect of dexamethasone was most striking among critically ill patients on ventilators. Those who were receiving oxygen therapy but were not on ventilators also saw improvement: their risk of dying was reduced by 20%. The steroid had no effect on people with mild cases of COVID-19 — those not receiving oxygen or ventilation.

The RECOVERY study announced the findings in a press release on 16 June, but its researchers say that they are aiming to publish their results quickly and that they are sharing their findings with regulators in the United Kingdom and internationally.

Rigorous study

“It is a major breakthrough,” says Peter Horby, an infectious-disease specialist at the University of Oxford, UK, and a chief investigator on the trial. Use of steroids to treat viral respiratory infections such as COVID-19 has been controversial, Horby notes. Data from steroid trials during outbreaks of SARS (severe acute respiratory syndrome) and Middle East respiratory syndrome caused by related coronaviruses were inconclusive, he says. Nevertheless, given dexamethasone’s widespread availability, and some promising results from steroid studies in previous outbreaks, Horby says RECOVERY investigators felt it important to test the treatment in a rigorous clinical trial.

Treatment guidelines from the World Health Organization and many countries have cautioned against treating people with coronavirus with steroids, and some investigators were concerned about anecdotal reports of widespread steroid treatment. The drugs suppress the immune system, which could provide some relief from patients whose lungs are ravaged by an over-active immune response that sometimes manifests in severe cases of COVID-19. But such patients may still need a fully functioning immune system to fend off the virus itself.

 

Dozens of coronavirus drugs are in development — what happens next?

The RECOVERY trial suggests that at the doses tested, the benefits of steroid treatment may outweigh the potential harm. The study found no outstanding adverse events from the treatment, investigators said. “This treatment can be given to pretty much anyone,” says Horby.

And the pattern of response — with a greater impact on severe COVID-19 and no effect on mild infections — matches the notion that a hyperactive immune response is more likely to be harmful in long-term, serious infections, says Anthony Fauci, head of the US National Institute of Allergy and Infectious Disease. “When you’re so far advanced that you’re on a ventilator, it’s usually that you have an aberrant or hyperactive inflammatory response that contributes as much to the morbidity and mortality as any direct viral effect.”

“Finding effective treatments like this will transform the impact of the COVID-19 pandemic on lives and economies across the world,” said Nick Cammack, head of the COVID-19 Therapeutics Accelerator at Wellcome, a UK biomedical research charity in London, in a statement. “While this study suggests dexamethasone only benefits severe cases, countless lives will be saved globally.”

Easy to administer

So far, the only drug shown to benefit COVID-19 patients in a large, randomized, controlled clinical trial is the antiviral drug remdesivir. Although remdesivir¹ was shown to shorten the amount of time that patients may need to spend in the hospital, it did not have a statistically significant effect on deaths.

Remdesivir is also in short supply. Although the drug’s maker — Gilead Sciences of Foster City, California — has taken steps to ramp up production of remdesivir, it is currently available only to a limited number of hospitals around the world. And remdesivir is complex to administer: it must be given by injection over the course of several days.

Dexamethasone, by contrast, is a medical staple found on pharmaceutical shelves worldwide and is available as a pill — a particular benefit as coronavirus infections continue to rise in countries with limited access to healthcare. “For less than £50, you can treat 8 patients and save one life,” said Martin Landray, an epidemiologist at the University of Oxford, and another chief investigator on the RECOVERY trial.

The findings could also have implications for other severe respiratory illnesses, Baillie adds. For example, steroid treatments for a condition called acute respiratory distress syndrome are also controversial. “This really gives us a very good reason to look closely at that, because the mortality benefit is so extraordinarily large,” Baillie says. “I think this will affect patients well beyond COVID-19.”

doi: 10.1038/d41586-020-01824-5

https://www.nature.com/articles/d41586-020-01824-5?utm_source=Nature+Briefing&utm_campaign=7fb7c54efa-briefing-dy-20200616&utm_medium=email&utm_term=0_c9dfd39373-7fb7c54efa-44664341

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Major study finds common steroid reduces deaths among patients with severe Covid-19

By MATTHEW HERPER @matthewherper

JUNE 16, 2020

Reprints

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APSTOCK

Acheap, readily available steroid drug reduced deaths by a third in patients hospitalized with Covid-19 in a large study, the first time a therapy has been shown to possibly improve the odds of survival with the condition in the sickest patients.

Full data from the study have not been published or subjected to scientific scrutiny. But outside experts on Tuesday immediately embraced the top-line results. The drug, dexamethasone, is widely available and is used to treat conditions including rheumatoid arthritis, asthma, and some cancers.

In a statement, Patrick Vallance, the U.K. government’s chief scientific adviser, called the result “tremendous news” and “a ground-breaking development in our fight against the disease.” Scott Gottlieb, a former commissioner of the U.S. Food and Drug Administration, called it “a very positive finding” in an interview on CNBC. “I think it needs to be validated, but it certainly suggests that this could be beneficial in this setting.”

 

Atul Gawande, the surgeon, writer and public health researcher, urged caution, tweeting, “after all the retractions and walk backs, it is unacceptable to tout study results by press release without releasing the paper.”

The study randomly assigned 2,104 patients to receive six milligrams of dexamethasone once a day, by mouth or intravenous injection. These were compared to 4,321 patients assigned to receive usual care alone. 

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In patients who needed to be on a ventilator, dexamethasone reduced the death rate by 35%, meaning that doctors would prevent one death by treating eight ventilated patients. In those who needed oxygen but were not ventilated, the death rate was reduced 20%, meaning doctors would need to treat 25 patients to save one life. Both results were statistically significant.

There was no benefit in patients who didn’t require any oxygen. The researchers running the study, called RECOVERY, decided to stop enrolling patients on dexamethasone on June 8 because they believed they had enough data to get a clear result.

“Dexamethasone is the first drug to be shown to improve survival in COVID-19,” Peter Horby, one of the lead investigators of the study and a professor in the Nuffield Department of Medicine at the University of Oxford, said in a statement. He added that the drug should now become the standard treatment for patients with Covid-19 who need oxygen. “Dexamethasone is inexpensive, on the shelf, and can be used immediately to save lives worldwide.’”

A different arm of the same study showed on June 5 that hydroxychloroquine, widely touted as a potential Covid treatment, had no benefit in hospitalized patients. Yesterday, based in part on those results, the Food and Drug Administration revoked an Emergency Use Authorization for using hydroxychloroquine in those patients.

 

From the start of the pandemic in March, researchers have focused on two different stages of Covid-19, which will likely require very different interventions. Some drugs are designed to directly combat the novel coronavirus, SARS-CoV-2, that causes the disease. The first medicine shown to have a benefit, remdesivir from the biotech firm Gilead Sciences, falls into this category, even though, because it must be given intravenously, it has been tested in hospitalized patients. Remdesivir shortens the course of infection, but has not been shown to save lives.

After patients have become profoundly sick, the problem starts to become not only the virus but their own immune system, which attacks the lungs, a condition called acute respiratory distress syndrome, or ARDS. For these patients, doctors have believed, they would need to dampen patients’ immune response even as they fought the virus.

Initially, excitement in this area fell on new and expensive drugs, such as Actemra, a rheumatoid arthritis drug from Roche that is used to treat a similar condition caused by some cancer immunotherapies. But a study in patients who needed oxygen showed no benefit from a similar drug, although another arm in sicker patients is continuing. The National Institutes of Health is conducting a study of an Eli Lilly pill targeting rheumatoid arthritis, an extension of the study that showed remdesivir has a benefit.

Dexamethasone, which reached the market 59 years ago, seemed an unlikely candidate to help these patients; it was seen as too crude a way of tamping down the immune system. In guidelines for physicians treating the disease, the NIH doesn’t even mention the therapy.

Studies that are testing other medicines may now need to incorporate the use of the drug, which could complicate analyzing the results. A spokesperson for Regeneron, which is testing Covid-19 drugs focused on both attacking the virus and dampening the immune system, said the company’s studies are written so that when a new medicine becomes the standard of care, it becomes available to patients in the trial.

Some studies have shown a benefit for using dexamethasone in acute respiratory distress syndrome not related to Covid-19, although the benefit was smaller than in RECOVERY. 

The result, should it hold up to further scrutiny, shows the benefit of the strategy of Horby and Martin Landray, the Oxford researchers who designed the study, leveraging the U.K. health system to start a study of multiple inexpensive potential Covid-19 therapies — including hydroxychloroquine, dexamethasone, and also some older HIV medicines. Several months into the Covid-19 pandemic, two of the most important results come from this single study.

Neither of those results, however, have been scrutinized or published.

 

About the AuthorReprints

Matthew Herper

Senior Writer, Medicine

Matthew covers medical innovation — both its promise and its perils.

 

 [email protected]

 

 @matthewherper

https://www.statnews.com/2020/06/16/major-study-finds-common-steroid-reduces-deaths-among-patients-with-severe-covid-19/