Since the start of the COVID-19 pandemic, effective treatments have been urgently needed. Many large studies into the same therapies have taken place at once. Combining evidence across trials is the best way to be more certain of a treatment’s effects.
Work like this usually takes many months or even years, but the pandemic has meant scientists have had to radically change their approach to get the best evidence out as quickly as possible.
Co-ordinated by the World Health Organisation (WHO), researchers from institutions across the world, including NIHR ARC West, have worked together to combine emerging findings from studies into COVID-19 treatments.
With the international research group, we looked at results from studies of two treatment approaches for people who are very ill with COVID-19:
Combining the often unpublished findings from randomised control trials – the best test of a medicine – ARC West researchers analysed the data from these trials.
Trials, including the RECOVERY trial, had demonstrated that corticosteroids were an effective treatment for very ill COVID-19 patients. They reduced the risk of death among hospitalised patients who had been put on a mechanical ventilator to help with their breathing.
The analysis across seven randomised control trials looked at mortality over a 28-day period after the start of treatment.
The scientists found that treatment with one of the three corticosteroids (dexamethasone, hydrocortisone or methylprednisolone) led to an estimated 20 per cent reduction in the risk of death. This is equivalent to around 68 per cent of patients surviving after treatment with corticosteroids, compared to around 60 per cent surviving without them. The dexamethasone finding is mainly based on results from the RECOVERY trial, which were included in the analysis.
The seven trials recruited 1,703 critically ill patients in total, spanning five continents and including some of the countries hardest hit by COVID-19. The analysis included critically ill patients from the RECOVERY trial, which reported its findings in June 2020.
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.
There was evidence of benefit from corticosteroids regardless of whether patients were receiving invasive mechanical ventilation at the time they started treatment. The benefit appeared greater among patients who were not so sick that they needed medicine to support their blood pressure, although the results were not definitive in this regard. The effect of corticosteroids appeared similar regardless of age, sex or how long patients had been ill.
In severely ill COVID-19 patients, the immune system overreacts, generating cytokines such as interleukin-6. Clinical trials have been testing whether interleukin-6 antagonists – drugs that inhibit the effects of interleukin-6, such as tocilizumab and sarilumab – benefit hospitalised patients with COVID-19. These trials have variously reported benefit, no effect and harm.
This analysis of 27 randomised trials involving nearly 11,000 patients in 28 countries, found that treating hospitalised COVID-19 patients with interleukin-6 antagonists reduces the risk of death and the need for mechanical ventilation.
The researchers found that interleukin-6 antagonists were most effective when administered with corticosteroids. In hospitalised patients, administering one of these drugs in addition to corticosteroids reduces the risk of death by 16 per cent, compared with corticosteroids alone. In patients not on mechanical ventilation, the risk of mechanical ventilation or death was reduced by 21 per cent, compared to corticosteroids alone.
Results showed that the risk of dying within 28 days is lower in patients receiving interleukin-6 antagonists. Across all treated patients, the risk of death is 22 per cent compared with an assumed risk of 25 per cent in those receiving only usual care.
Importantly, improvements in outcomes were greater in patients who also received corticosteroids. In these patients, the risk of dying within 28 days is 21 per cent in patients receiving interleukin-6 antagonists compared with an assumed 25 per cent in patients receiving usual care. This means that for every 100 such patients, four more will survive.
The study also looked at the effect of these drugs on whether patients progressed to mechanical ventilation or death. Among patients also treated with corticosteroids, the risk was found to be 26 per cent for those receiving interleukin-6 antagonists compared with an assumed 33 per cent in those receiving usual care. This means that for every 100 of these patients, seven more will survive and avoid mechanical ventilation.
Corticosteroids combined with interleukin-6 antagonists are now part of the standard care for patients with severe COVID-19. According to NHS figures, by March 2021 the use of dexamethasone had already saved more than 1 million lives worldwide and 22,000 lives in the UK.
The corticosteroid analysis, which was the first to publish, was the result of unprecedented co-operation between study teams, guideline developers and journals in response to the global pandemic. This ground-breaking collaboration saw results shared between research teams and with guideline developers before they were published, and papers reporting individual trials, the meta-analysis and international treatment guidelines published simultaneously on 2 September 2020. We hope that learning from this ground-breaking approach will help us respond to future health emergencies.
The University of Bristol is internationally renowned and one of the very best in the UK, due to its outstanding teaching and research, its superb facilities and highly talented students and staff. Its students thrive in a rich academic environment which is informed by world-leading research. It hosts the Elizabeth Blackwell Institute for Health Research.