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Dexamethasone reduces death by up to 1/3rd in COVID-19 patients with severe respiratory complications

M3 India Newsdesk Jun 22, 2020

Chief Investigators of the RECOVERY Trial have declared that the latest study showed that one death would be prevented by low cost dexamethasone treatment of around 8 ventilated patients or around 25 patients requiring oxygen alone.


For our comprehensive coverage and latest updates on COVID-19 click here.


Finally, a modest, but decisive victory against COVID-19, a common enemy ruthlessly marching forward causing irreparably adverse impacts including death and destruction to many thousands of people worldwide. On June 16, 2020 Professor Peter Horby and Professor Martin Landray, the Chief Investigators of the RECOVERY (Randomised Evaluation of COVid-19 thERapY) Trial declared that the latest study showed that one death would be prevented by low cost dexamethasone treatment of around 8 ventilated patients or around 25 patients requiring oxygen alone. This means that the repurposed drug reduces deaths by up to one third in hospitalized patients with severe respiratory complications of COVID-19.

The unique nature of the trial was that it was a randomised control trial, the gold standard in such epidemiological studies. This is indeed a breakthrough.

The RECOVERY (Randomised Evaluation of COVid-19 thERapY) trial was established In March 2020, as a randomised clinical trial to test six potential treatments for COVID-19. This was a follow up of the advice from the UK New and Emerging Respiratory Virus Threats Advisory Group (NERVTAG) that several possible treatments should be evaluated, including Lopinavir-Ritonavir, low-dose corticosteroids, and Hydroxychloroquine. This group also advised that other treatments will soon emerge that require evaluation. A World Health Organization (WHO) expert group issued broadly similar advice. The team enrolled over 11,500 patients from over 175 NHS hospitals in the UK.


The Study

Low-dose Dexamethasone (a type of steroid, which is used in a range of conditions typically to reduce inflammation) was one of the six drugs/procedure under trial. The team halted recruitment to the dexamethasone arm on June 8, 2020 since in the view of the trial Steering Committee, the trial has already enrolled sufficient number of patients to establish whether or not the drug had a meaningful benefit.

The researchers randomised a total of 2104 patients 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.


Results

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 and by one fifth in other patients receiving oxygen only. There was no benefit among those patients who did not require respiratory support.

Overall dexamethasone reduced the 28-day mortality rate by 17% with a highly significant trend showing greatest benefit among those patients requiring ventilation. However, they found no evidence of benefit for patients who did not require oxygen and they did not study patients outside the hospital setting. Follow-up is complete for over 94% of participants.


Expert remarks

According to Horby Professor of Emerging Infectious Diseases in the Nuffield Department of Medicine, University of Oxford, and one of the Chief Investigators for the trial, "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."

A statement from the RECOVERY trial group quoted Martin Landray, Professor of Medicine and Epidemiology at the Nuffield Department of Population Health, University of Oxford, one of the Chief Investigators, "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."


Science Media Centre published comments on this breakthrough discovery from many experts.

Dr. Penny Ward, visiting Professor in Pharmaceutical Medicine at King’s College London and Chair of the Education and Standards Committee of the Faculty of Pharmaceutical Medicine, stated that at last some good news for COVID-19 patients with respiratory failure requiring ventilator support in ICU, the group in whom antiviral therapy with remdesivir was less successful and in whom fatality rate is highest.

“Clinicians will need to see the detailed results of the trial, particularly those in patients not requiring oxygen therapy/ventilator support, as the breakdown of outcomes by disease stage suggests that the timing for start of steroid use may be relevant to use the treatment most efficiently. That said, for patients going onto a ventilator, good news today. Congratulations to the RECOVERY team, great news for patients most severely affected, looking forward to seeing the publication.”

Dr. Ayfer Ali, Assistant Professor in the Strategy and International Group specialising in drug repurposing, Warwick Business School said, “The results seem to be extremely encouraging and this will be now one of the most important tools against COVID-19 in seriously ill patients. Dexamethasone is cheap and easily available in tablet form. As such it can be much more easily deployed than the anti-malarial drug remdesivir, which needs to be administered in hospital as an infusion. This would also be the first drug that actually shows reduction in death rates, rather than just lowering duration of disease.”

While accepting that this shows the potential of drug repurposing, Dr. Ali added that now we have to wait for the full results to be peer-reviewed and remember that it is not a cure for all, just one more tool. “The important thing is to determine which patients should get this drug, as presumably not all would need it, and what would be the most appropriate time to start treatment in COVID-19 positive patients as clearly this drug should not be taken as a preventative measure,” he cautioned.

Prof. Simon Maxwell, Professor of Clinical Pharmacology and Prescribing, University of Edinburgh, termed this is the first major breakthrough in the therapeutics of COVID-19 infection. “It demonstrates the efficacy of a simple, cheap, familiar and widely successful treatment in those who are most severely affected. Although many units have already been using corticosteroid therapy, these results provide confidence that this treatment delivers a better outcome for many patients. Today’s results also emphasise the importance of conducting carefully controlled randomised clinical trials as the only means of providing reliable information to guide healthcare providers and patients facing this unprecedented challenge," he clarified.

Prof. Robin Ferner, Honorary Professor of Clinical Pharmacology, University of Birmingham and Honorary Consultant Physician, City Hospital Birmingham said, “The Oxford Group’s important results, based on a scientific trial in over 6000 NHS patients, show that dexamethasone – a common, widely used, inexpensive medicine – can save lives in seriously ill patients with COVID-19. It is not a treatment for mild disease. We hope the data on which these results are based will be published as soon as possible so that doctors can confidently put the treatment into practice.”

Dr. Stephen Griffin, Associate Professor in the School of Medicine, University of Leeds stated that Profs Horby, Landray and the clinical team involved all deserve immense credit. “This outcome for patients suffering from severe COVID-19 in need of respiratory assistance is of tremendous importance. It highlights the enormous power of the RECOVERY trial to confidently assign benefit, or lack thereof, to the numerous therapies postulated to help treat SARS-CoV2 infected patients, he clarified.

“The fact that dexamethasone helps patients in severe respiratory distress highlights the probable contribution of immune-mediated pathology in COVID-19. It will be of great interest to determine the precise mechanisms by which lung tissue damage has presumably been reduced. The low cost and broad availability of this drug means that there is potential for considerable clinical impact by including it as part of standard treatment. Nevertheless, it will be important to assess how this important success might be further-improved in order to increase patient survival, perhaps through the combination of low dose dexamethasone with other inflammatory mediators, or with virus-targeted therapies, such as Remdesivir,” he suggested more research.


Acknowledging that this is a major breakthrough, Dr. Nick Cammack, COVID-19 Therapeutics Accelerator Lead, Wellcome Trust, noted that dexamethasone is the first and only drug that has made a significant difference to patient mortality for COVID-19.

“Potentially preventing 1 death in every 8 ventilated patients would be remarkable. Finding effective treatments like this will transform the impact of the COVID-19 pandemic on lives and economies across the world. While this study suggests dexamethasone only benefits severe cases, countless lives will be saved globally,” he asserted.

“Dexamethasone must now be rolled out and accessed by thousands of critically ill patients around the world. It is highly affordable, easy to make, can be scaled up quickly and only needs a small dosage. Any and every successful treatment against COVID-19 must be made available to everyone who needs it globally, regardless of their ability to pay,” he hoped.


“The first drug proven to cut deaths from COVID-19 is not some new, expensive medicine but an old, cheap-as-chips steroid. That is something to celebrate because it means patients across the world could benefit immediately,” Fergus Walsh, Health Correspondent BBC said.

Walsh noted Dexamethasone has been used since the early 1960s to treat a wide range of conditions, such as rheumatoid arthritis and asthma. “Unlike dexamethasone, remdesivir is a new drug with limited supplies and a price has yet to be announced,” he clarified.

Michelle Roberts, Health editor, BBC News online gave some cost estimates quoting Prof. Martin Landray one of the Chief Investigators of the RECOVERY trial- “The treatment is up to 10 days of dexamethasone and it costs about £5 (₹478) per patient. So essentially it costs £35 (₹3345) to save a life. This is a drug that is globally available."


On June 16, 2020 John Lauerman and Jason Gale in bloombergquint.com quoted Andrew Hill, a senior research fellow at the University of Liverpool as saying that a 10 day course of the medication bought in India to treat COVID-19 would cost about 20 pence (25 cents). They noted that Hill studied the cost of drugs on the WHO list of “essential” medicines in 2018.

“This is a treatment which should be affordable for anyone in need, in any country,” Hill said in an email to Lauerman and Gale.


While applauding the modest victory in treating severely affected COVID-19 patients, we have to patiently wait for the arrival of an effective vaccine which seems to be more time consuming.

 

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

Dr K S Parthasarathy is a freelance science journalist and a former Secretary of the Atomic Energy Regulatory Board. He is available at ksparth@yahoo.co.uk

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