The cheap steroid hydrocortisone can cut Covid-19 deaths by almost a third in the sickest patients, research has found.
An analysis co-ordinated by the World Health Organisation (WHO) of seven different studies found three steroids – hydrocortisone, methylprednisolone and dexamethasone – reduce the risk of death in critically ill coronavirus patients by 20 per cent.
It bumped up to 31 per cent for hydrocortisone, a drug widely used to treat allergic disorders, skin conditions, ulcerative colitis, arthritis, lupus, multiple sclerosis, or lung problems.
The study, from the University of Bristol, is one of three published today in the Journal of the American Medical Association (JAMA), that suggests steroids improve survival of the most seriously ill Covid-19 patients.
Another found hydrocortisone can improve outcomes by up to 93 per cent in critically ill patients – measured by either a greater chance or survival or a reduced need for organ support in intensive care.
The results come from the REMAP-CAP trial, which involves more than 50 research teams around the world in around 13 countries, including 88 patients treated at Imperial College Healthcare NHS Trust Hospitals.
Today’s announcement makes hydrocortisone the second widely-used steroid to become a breakthrough treatment for Covid-19.
Dexamethasone has already been approved by NHS officials for use on critically ill patients after results showed it cut their risk of death.
Oxford University scientists claimed dexamethasone may save up to 35 per cent of patients relying on ventilators — the most dangerously ill — and reduce the odds of death by a fifth for all patients needing oxygen at any point.
NHS chief executive Sir Simon Stevens said today: ‘Just as we did with dexamethasone, the NHS will now take immediate action to ensure that patients who could benefit from treatment with hydrocortisone do so, adding a further weapon in the armoury in the worldwide fight against Covid-19.’
The World Health Organization issued the same guidelines and said it recommended the use of the drug.
Critically ill patients who received hydrocortisone (pictured) intravenously for seven days had a 93 per cent better recovery odds – measured by either a greater chance or survival or less need for organ support
NHS chief executive Sir Simon Stevens said today: ‘The NHS will now take immediate action to ensure that patients who could benefit from treatment with hydrocortisone do so’
The journal edition today, publishing three clinical trials and a meta-analysis, concluded that a range of steroids – all safe, cheap and readily available – can improve the outcomes of patients receiving intensive care.
Steroids are anti-inflammatory drugs, and evidence strongly suggests that they reduce the lung inflammation in seriously ill patients with Covid-19.
WHAT IS HYDROCORTISONE AND HOW DOES IT HELP COVID-19 PATIENTS?
Hydrocortisone is a common steroid which is used to control the body’s immune system and to reduce swelling, itching and pain.
It is used for a huge range of conditions and can come in the form of creams, pills, or injections.
People who might have had hydrocortisone in the past include those who have had skin problems like eczema or dermatitis, people with arthritis, asthmatics, or those with haemorrhoids, painful joints, persistent mouth ulcers, or colitis.
The steroid is an anti-inflammatory drug and evidence strongly suggests that they can reduce lung inflammation (swelling) in patients with Covid-19 who are seriously ill and require oxygen support for their breathing difficulties.
Greg Kyle, a professor of pharmacy (Head of Discipline) at the Queensland University of Technology, said: ‘These drugs dampen down the immune system response to Covid.
‘In some people with Covid-19, the immune system generates a hyper-response, for reasons that are not clearly understood.
‘This severe reaction results in the body attacking itself and generating severe symptoms and death. The steroids calm this reaction down – just like pruning a hedge. We don’t want to kill the hedge (that is, completely stop the immune system), we want to trim it back so it is not running rampant, but rather is controlled and still able to function.’
Martin Landray, professor of medicine and epidemiology at the University of Oxford, who leads on the RECOVERY trial, said data showed hydrocortisone was not effective in patients with milder cases of disease.
He said: ‘This is not a treatment for prevention, this is not a treatment for early out patients, general practice type cases, this is a treatment for people who are sick.
‘This is a treatment for people who are in hospital who need oxygen, who’ve got complications from Covid.’
Steroids are immunosuppressants – that is, they suppress the immune system. They are useful for conditions like lupus, which causes inflammation to the joints, skin and other organs.
Professor Kyle said: ‘They are useful when the immune system is running rampant, but using them in an otherwise healthy person will suppress their immune system and might leave them more vulnerable to an infection – including Covid-19 or any other pathogen, for example influenza.’
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The review co-ordinated by the World Health Organisation (WHO) and analysed by the National Institute for Health Research (NIHR) at the University of Bristol, involved an international team of researchers who analysed seven trials spanning 12 countries.
They involved three different types of anti-inflammatory corticosteroids.
It looked at patient mortality over a 28-day period after treatment with one of three types of corticosteroids – dexamethasone, hydrocortisone and methylprednisolone.
The seven control trials recruited 1,703 critically ill coronavirus patients from 12 countries from February to June. The study included patients who were taking part in the Oxford University-based RECOVERY trial.
Patients were randomised to either receive one of the three drugs or a placebo.
The study found that the steroids benefited patients regardless of whether they were on a ventilator.
But researchers said it appeared to have a greater effect on those who did not require medication to support their blood pressure.
There were 222 deaths among the 678 patients randomized to corticosteroids (32 per cent) and 425 deaths among the 1,025 patients randomized to usual care or placebo (41 per cent).
The researchers said overall the steroids reduced the risk of death in critically ill coronavirus patients by 20 per cent, but to different degrees.
Researchers said the mortality results were consistent across the seven trials, with dexamethasone and hydrocortisone giving ‘similar effects’.
Dexamethasone reduced deaths by 36 per cent and hydrocortisone by 31 per cent.
But there were too few patients involved in tests of methylprednisolone to enable researchers to estimate its impact with precision.
Only one trial, which enrolled 47 patients of whom 26 died, evaluated methylprednisolone. It suggested the drug reduced deaths by nine per cent.
Although the findings are promising, it is important to note researchers only followed up whether patients had died 28 days later.
Stephen Evans, a professor of pharmacoepidemiology, London School of Hygiene and Tropical Medicine, said: ‘The findings are generally consistent and show that mortality is notably reduced, to about 30-32 per cent. It is important to acknowledge that, though this is a notable benefit, nearly a third of these critically ill patients were still dying.’
He said the analysis reported in the paper was a ‘tour-de-force’.
‘The methods are of the very highest standard for combining results from several trials answering the same question,’ he said.
Lead researcher Jonathan Sterne, professor of medical statistics and epidemiology at the University of Bristol, said: ‘Steroids are a cheap and readily available medication, and our analysis has confirmed that they are effective in reducing deaths amongst the people most severely affected by Covid-19.
‘The results were consistent across the trials and show benefit regardless of age or sex.’
He explained that the findings pointed to ‘eight fewer deaths for every a hundred critically ill patients assigned to corticosteroids’.
Commenting today, Dr Gaetan Burgio, Department of Immunology and Infectious Disease at the Australian National University, who was not involved in the research, said: ‘I would anticipate recommendations from the WHO to widely implement the use of systemic corticosteroids for critically ill COVID-19 patients requiring oxygen as a standard of care.’
But the study leaves a major question unanswered, said Dr Elena Schneider-Futschik, a researcher in cystic fibrosis and other respiratory diseases at the Department of Pharmacology and Therapeutics, University of Melbourne.
‘What is the optimal dose?,’ she said, noting that all seven trials had looked at varying levels.
‘Low-dose corticosteroids have been shown to be beneficial. But using high-dose corticosteroids for Covid-19 has been associated with the risk of secondary infections, long-term complications and prolonged virus shedding.
‘Corticosteroid treatment is a double-edged sword but the evidence shows that severely ill patients benefit from corticosteroid treatment.’
One of the three randomised trials published today was the REMAP-CAP trial, led in the UK by Professor Anthony Gordon from Imperial College London with collaborators from the Intensive Care National Audit and Research Centre.
Professor Gordon, Chair in Anaesthesia and Critical Care at Imperial and a Consultant in Intensive Care Medicine at Imperial College Healthcare NHS Trust, said: ‘At the beginning of the year at times it felt almost hopeless, knowing that we had no specific treatments. It was a very worrying time.
Dexamethasone has already been approved by NHS officials for use on critically ill patients after results of the world’s biggest Covid-19 drug trial found it could cut their risk of death
WHAT IS DEXAMETHASONE?
Dexamethasone is a type of corticosteroid medication which is used as an anti-inflammatory to treat a wide-rang of conditions.
It was first made in 1957 by US physician Philip Showalter Hench and was approved for medical use in 1961.
The drug, which is sold under the brand names Ozurdez and Baycadron, is on the World Health Organization’s List of Essential Medicines.
It is given via an injection or a once-a-day tablet and is used to treat a variety of afflictions.
It is even used to help reduce the side effects of chemotherapy in cancer patients.
The steroid is also used to treat conditions that cause inflammation, conditions related to immune system activity, and hormone deficiency.
These include:
allergic reactionsrheumatoid arthritis psoriasis lupuseczema flare-ups of intestinal disease, such as ulcerative colitis multiple sclerosispre-treatment for chemotherapy to reduce inflammation and side effects from cancer medicationsadrenal insufficiency (a condition where the adrenal glands don’t produce enough hormones)
Dexamethasone is known to cause a number of mild to moderate side effects, including vomiting, heartburn, anxiety, high blood pressure, muscle weakness and insomnia.
What did the RECOVERY trial show?
On June 16, 2020, a trial to test possible treatments for coronavirus patients was started by the Nuffield Departments of Public Health and of Medicine at the University of Oxford.
While the trial is expected to continue until June 2021, a preliminary report on its findings was published on July 18.
Some 11,800 Covid-19 patients had enrolled in the trial as of June.
The trial, Randomised Evaluation of Covid-19 therapy (RECOVERY) trial, found dexamethasone improves survival rates of hospitalised patients with Covid-19 receiving oxygen or on a ventilator.
However, this was only the case in patients who were struggling to breathe and needed respiratory support.
People who didn’t require breathing support saw a worse survival rate if they were treated with the drug, although this may have been coincidence.
The World Health Organisation (WHO) states that dexamethasone should be reserved for seriously ill and critical patients receiving Covid-19 treatment in a hospital setting.
The WHO Director-General said: ‘WHO emphasizes that dexamethasone should only be used for patients with severe or critical disease, under close clinical supervision. There is no evidence this drug works for patients with mild disease or as a preventative measure, and it could cause harm.’
Based on those preliminary results, dexamethasone treatment has been recommended by the National Institutes of Health in the US, and by the NHS in the UK.
It’s only for patients with Covid-19 who are mechanically ventilated or who require supplemental oxygen but are not mechanically ventilated.
Dexamethasone has not been recommended in patients with COVID-19 who do not require supplemental oxygen or hospitalisation.
How does it help Covid-19 patients?
In coronavirus patients, the steroid reduces inflammation in the lungs triggered by an overreaction by the immune system.
One in 10 symptomatic Covid-19 patients are thought to suffer from the nasty symptom, known as acute respiratory distress syndrome (ARDS).
ARDS causes the immune system to become overactive and attack healthy cells in the lungs.
This makes breathing difficult and the body eventually struggles to get enough oxygen to vital organs.
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‘Yet less than six months later, we’ve found clear, reliable evidence in high quality clinical trials of how we can tackle this devastating disease.’
Professor Gordon added: ‘The studies published today show that we now have more than one choice of treatment for those who need it most.
‘Steroids are not a cure, but they help improve outcomes. Having a choice of different types of steroids, all of which seem to improve patient recovery, is great as it helps ease the problem of drug supply issues.’
In the REMAP-CAP study, funded by the National Institute for Health Research and supported by the NIHR Imperial Biomedical Research Centre, 403 patients with suspected or confirmed Covid-19 were enrolled between March and June 2020.
They each required respiratory or cardiovascular organ support, such as mechanical ventilation or drugs to support their blood pressure.
The cohort included patients of mixed ethnicities in the UK, Ireland, Australia, the US, the Netherlands, New Zealand, Canada and France.
Patients were randomly assigned to different treatment regimes. One group were treated with a fixed dose of 50mg hydrocortisone four times a day for seven days, while another group were treated with hydrocortisone only if their blood pressure dropped, known as the ‘shock-dependant group’.
A third group received no hydrocortisone known as the ‘control group’.
The trial showed that using the fixed dose of hydrocortisone led to a 93 per cent chance of a better outcome, measured by a greater chance of survival and less need for organ support, than not using hydrocortisone.
If the hydrocortisone was given only when the blood pressure was low, the chance of a better outcome was 80 per cent.
Confirming the NHS would fast track hydrocortisone into hospitals, Sir Stevens said: ‘One of the distinctive benefits of having our NHS is that we’ve been able to mobilise quickly and at scale to help researchers test and develop proven coronavirus treatments.’
Professor Jonathan Van-Tam, deputy chief medical officer, hailed the work of UK researchers and trial participants.
He said: ‘It is impressive to see so many UK participants willing to take part in studies, and able to volunteer due to the rapid recruitment response of the NIHR’s Clinical Research Network.
‘Research such as this will make the difference in controlling this virus.
‘These findings offer further evidence that corticosteroids can be an important part of COVID-19 treatment for severe patients.’
The findings follow the groundbreaking results of the RECOVERY trial in June, which revealed that another steroid, called dexamethasone, helped improve recovery of patients with Covid-19.
Dexamethasone reduced deaths by up to a third among patients on ventilators, and by a fifth for those on oxygen, leading to its use in the NHS ever since.
Scientists from Brazil, Canada, China, France, Spain, the UK and the USA were involved in the study.
Martin Landray, professor of medicine and epidemiology at the University of Oxford, who leads on the RECOVERY trial, said: ‘These drugs have been around for decades, they are the sort of drugs that every medical student learns almost as soon as they open a clinical pharmacology text book.’
He said dexamethasone and hydrocortisone, which can be taken orally or intravenously, were ‘widely available, cheap, well understood drugs’.
As an example, he said treating 12 people with dexamethasone costs around £60.
But he warned that the ‘impressive’ results ‘are not sufficient to lead to a complete resumption … of life as we knew it’.
He said that social distancing and wearing face masks ‘remain as important as ever’.
Professor Gordon, an intensive care consultant, said hydrocortisone could be used ‘straight away’, with it being available in intensive care units in the UK.
But Professor Landray said data showed hydrocortisone was not effective in patients with milder cases of disease.
He said: ‘This is not a treatment for prevention, this is not a treatment for early out patients, general practice type cases, this is a treatment for people who are sick.
‘This is a treatment for people who are in hospital who need oxygen, who’ve got complications from Covid.’
The second randomised trial published today in JAMA was conducted on France, led by Dr Pierre-François Dequin, Chru Hôpitaux De Tours.
But unlike its comparative studies, it did not any benefit of hydrocortisone for reducing death or dependence on mechanical ventilation after 21 days.
Hydrocortisone was given to 76 Covid-19 patients who were compared to 73 given a placebo. Some 42.1 per cent and 50.7 per cent of patients died in each group, respectively.
But the researchers believe there was not enough enrolled in the study to sufficiently assess if hydrocortisone was useful for Covid-19 patients.
The trial was terminated prematurely after the positive findings of the dexamethasone trial. The same happened in the REMAP-CAP trial.
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