Inexpensive steroids can reduce death risk among severely ill Covid-19 patients by 20%, study reveals
Inexpensive and readily available steroids improve survival in seriously ill coronavirus patients, reveals an analysis of data pooled by scientists and clinicians from trials conducted in 12 countries. These drugs reduce the risk of death among very ill Covid-19 patients by 20%, according to the meta-analysis of seven clinical trials that evaluated the efficacy of corticosteroids or steroids in 1,703 critically ill coronavirus patients. Corticosteroids are a class of drugs that lowers inflammation and modulates immune system activity, and evidence now strongly suggests that they reduce the lung inflammation in patients with Covid-19 who are seriously ill and require oxygen support for their breathing difficulties.
The study by an international team of scientists, which was coordinated by the World Health Organisation (WHO) with analyses led by the National Institute for Health Research (NIHR) researchers at the University of Bristol, looked at mortality over a 28-day period after the start of treatment. They found that treatment with one of the three corticosteroids -- dexamethasone, hydrocortisone, or methylprednisolone -- led to an estimated 20% reduction in the risk of death. This is equivalent to around 68% of patients surviving after treatment with corticosteroids, compared to around 60% surviving in the absence of corticosteroids. The dexamethasone finding is mainly based on results from the RECOVERY (Randomised Evaluation of Covid-19 therapy) trial, which were included in the analysis.
The seven randomized control trials -- which is the best type of study to examine the effect of medical intervention, according to experts -- recruited 1,703 critically ill patients, spanning five continents and including some of the countries hardest hit by Covid-19. The authors explain that the mortality results were consistent across the seven trials with two types of corticosteroid, dexamethasone, and hydrocortisone, giving similar effects. Too few patients were included in trials of methylprednisolone to allow its effect to be estimated with precision. Of 678 severely ill patients who received steroids, 32.7% died, compared with 41.45% of patients receiving usual care or placebo. “The 28-day mortality was lower in patients randomized to corticosteroids: 222 deaths among 678 patients randomized to corticosteroids compared with 425 deaths among 1,025 patients randomized to usual care or placebo,” the findings state.
There was evidence of benefit from steroids regardless of whether patients were receiving invasive mechanical ventilation at the time they started treatment. The effect of corticosteroids appeared similar regardless of age, sex, or how long patients had been ill. The team behind the review includes the lead researchers for all of the seven trials and scientists from the US, Brazil, Canada, China, France, Spain, and the UK. The work is part of the WHO Rapid Evidence Appraisal for Covid-19 Therapies (REACT) initiative.
“Our review is good news in the effort to treat Covid-19 and provides important new information that builds on the findings of the RECOVERY trial. 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,” writes Jonathan Sterne, professor of medical statistics and epidemiology, University of Bristol and deputy director of the NIHR Bristol Biomedical Research Centre. The findings have been published in JAMA.
Improved outcomes
In the hydrocortisone study, for example, 403 patients with suspected or confirmed Covid-19 who required respiratory or cardiovascular organ support (such as mechanical ventilation or drugs to support their blood pressure) were enrolled between March and June 2020. The cohort included patients of mixed ethnicities in the US, the UK, Ireland, Australia, the Netherlands, New Zealand, Canada, and France, and they were randomly assigned to different treatment regimes. One group was treated with a fixed dose of 50mg hydrocortisone four times a day for seven days, another group was treated with hydrocortisone only if their blood pressure dropped, and a third group received no hydrocortisone.
The data from 121 hospitals in eight countries show that using the fixed-dose of hydrocortisone led to a 93% chance of a better outcome -- that is, 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%. “We now have more than one choice of steroid 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,” explains senior author Dr Anthony Gordon, professor of anesthesia and critical care at Imperial College London and an NIHR research professor.
The findings were made through the “Randomized Embedded Multifactorial Adaptive Platform-Community Acquired Pneumonia (REMAP-CAP) trial,” one of seven randomized control trials to test steroids. The analysis combining all the trial data reinforces the June results of the RECOVERY trial, which found the steroid dexamethasone reduced deaths by 29% in ventilated coronavirus patients, concludes the team.
“It is relatively rare in medicine that you find drugs where the evidence of their effectiveness in saving lives is so consistent. This is, in many respects, the single clearest answer we've had so far on how to manage terribly ill Covid-19 patients. People on ventilators or oxygen and under intensive care should definitely be given corticosteroids,” writes lead author Dr Derek Angus, professor and chair of the Department of Critical Care Medicine at the University of Pittsburgh and chief health care innovation officer at University of Pittsburgh Medical Center (UPMC).
REMAP-CAP and the other corticosteroid trials did not test the drugs in patients with less severe Covid-19. Steroids are not currently recommended for these patients because they can dampen the immune system and have serious side effects. It was also mostly conducted in resource-rich countries, so the findings may not translate to low- and middle-income countries, caution experts.
“The publication of our results, those of the other trials as well as the prospective meta-analysis, all within seven weeks of the RECOVERY publication, is a great example of what we can accomplish with global collaboration. And the joint effort of so many people across the globe to deliver this trial has been especially inspiring,” says co-author Dr Lennie Derde from the University Medical Center in Utrecht, the Netherlands.
WHO issues guidance on steroids
Based on the newly-published evidence, the World Health Organization (WHO) has issued new treatment guidelines, strongly recommending steroids to treat severely and critically ill patients, but not to those with mild disease. Such patients should receive 7-10 days of treatment, according to a WHO panel.
“The panel made two recommendations: a strong recommendation for systemic (that is, intravenous or oral) corticosteroid therapy (such as 6 mg of dexamethasone orally or intravenously daily or 50 mg of hydrocortisone intravenously every 8 hours) for 7 to 10 days in patients with severe and critical Covid-19, and a conditional recommendation not to use corticosteroid therapy in patients with nonsevere Covid-19,” suggests WHO. It adds, “Given the moderate certainty evidence of an important reduction in the risk of death, the panel concluded that all or almost all fully informed patients with severe or critical Covid-19 would choose treatment with systemic corticosteroids. Moreover, the panel believed that other perspectives (that is, costs, equity, the feasibility of implementation), and patient values and preferences would not alter decisions.”
The WHO, however, warned against the use of the steroids in patients with non-severe illness, stating that “indiscriminate use of any therapy for Covid-19 would potentially rapidly deplete global resources and deprive patients who may benefit from it most as potentially life-saving therapy.”