Dexamethasone: A Potential Gamechanger in the Fight Against COVID-19?

At around the 6-month mark of the COVID-19 pandemic, research efforts have revealed a potential weapon to add to the treatment arsenal against the virus, a drug that has historically played a crucial role in oncology treatment: the inexpensive, and widely accessible, corticosteroid dexamethasone.

The agent has been in circulation since the 1960s, and utilized in the medical community to decrease inflammation in several different conditions, including inflammatory disorders and cancers, according to the World Health Organization (WHO).¹ Since 1977, dexamethasone has been listed on the WHO Model List of Essential Medicines in multiple formulations. The agent is now off patent and available in most countries at an affordable cost.

Now, preliminary results from the RECOVERY trial conducted in the United Kingdom are showing that the agent reduced mortality by approximately one-third in patients with COVID-19 who were on ventilators (rate ratio [RR] 0.65; 95% CI, 0.48-0.88; P = .0003).² Moreover, for other patients who received oxygen only, dexamethasone reduced deaths by one-fifth (RR 0.80; 95% CI, 0.67-0.96; P = .0021).

“Since the appearance of COVID-19 6 months ago, the search has been on for treatments that can improve survival, particularly in the sickest patients,” Martin Landray, MB, ChB, PhD, FRCP, FHEA, FASN, FBPhD, FESC, professor of medicine and epidemiology in the Nuffield Department of Population Health of the University of Oxford, commented in a press release.³ “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.”

In the large, randomized, controlled trial, investigators set out to evaluate a range of potential therapies for COVID-19, including low-dose dexamethasone. Over 11,500 patients had been enrolled to the trial, across 175 National Health Service (NHS) hospitals throughout the United Kingdom. To be eligible for enrollment, patients had to have clinically suspected or laboratory confirmed COVID-19 infection. Initially, they had to be 18 years or older, but the age restriction was lifted on May 9, 2020. Patients could not have a medical history that could put them at significant risk upon trial participation, in the opinion of the attending clinician. Notably, patients who were pregnant or were breast feeding could still participate on the trial.

A total of 6425 patients underwent randomization to either dexamethasone plus usual care (n = 2104) or usual care alone (n = 4321). Additional results indicated that in all participants, the overall 28-day mortality was 21.6% with dexamethasone plus usual care versus 24.6% with standard care (RR, 0.83; 95% CI, 0.74-0.92; P <.001). The 28-day mortality in those who did not receive respiratory support, the rates were 17.0% and 13.2% in the dexamethasone and comparator arms, respectively (RR, 1.22; 95% CI, 0.93-1.61; P = .14). In sum, the greatest absolute reductions in mortality were observed in the patients who were most ill.

Some limitations to this research are that several patients were excluded because dexamethasone was either unavailable at the hospital at the time of trial enrollment or it was considered to be contraindicated by the managing clinician. Notably, it is not certain how many patients were excluded from the analysis and how that exclusion might impact the findings from the trial.

Additionally, because the trial was open label, all participants were aware of which arm they were in, which could potentially result in biased results. Because mortality is an objective outcome, it is unlikely to be subject to any bias. However, results could be biased with regard to the amount of care provided to a group receiving steroids in that they receive higher quality care compared with those who are not, for example.

The WHO also acknowledged this research and issued a press release stating that the investigators involved shared their initial insights about the data with the organization. “We are looking forward to the full data analysis in the coming days,” the release reads. “WHO will coordinate a meta-analysis to increase our overall understanding of this intervention.”

Notably, 19 hours after the data were released, the UK government granted immediate authorization to the NHS to utilize dexamethasone in all hospitalized patients with COVID-19 who require oxygen, including those on ventilators, in the United Kingdom.⁴

To ensure supply to the drug, the government has purchased additional stocks ahead of time in the event of a positive trial outcome; from stockpiles alone, there is enough drug supply available to treat over 200,000 patients in need, according to a recent press release. “Guided by the science, the UK is leading the way in the global fight against coronavirus—with the best clinical trials, the best vaccine development, and the best immunology research in the world,” Health Secretary Matt Hancock stated in the release.

The government has also added dexamethasone to its parallel export list,⁵ which prohibits companies from purchasing medicines intended for patients within the United Kingdom and selling them at a higher price in another country. The intention of this effort is to protect the drug supply for patients within the country by way of taking regulatory action on those who do not honor the restrictions in place.

In the United States, hospitals have already begun to treat the patients with COVID-19 who are most ill with dexamethasone, rather than waiting for confirmation of the preliminary data yielded from the study. “It almost feels unethical not to use the drug,” Kartik Cherabuddi, MD, FACP, an infectious disease specialist at the University of Florida’s (UF) Medical School commented to Reuters.⁶

Because of the increased use of the drug in hospitals, supplies are starting to take a hit. The FDA added dexamethasone to their current drug shortages list on their website,⁷ and group drug purchaser Vizient, which supplies medicine to approximately half of US hospitals, confirmed that there has been a 610% increase in demand by its member hospitals for dexamethasone.⁸ As a result, fill rates for the product dropped to 54% for Vizient member hospitals.

Dan Kistner, PharmD, group senior vice president of Pharmacy Solutions for Vizient, commented in a press release that he remains optimistic that manufacturers and distributors of the drug will be able to quickly adjust to increase its availability and adequately manage allocations, as needed. However, this underscores the need for manufacturers to build “additional resiliency into pharmaceutical inventory capacity” in light of rapidly changing demand.

Notably, because the endorsements for dexamethasone follow the FDA’s retraction of its emergency use authorization for hydroxychloroquine for COVID-19, some are still hesitant to trust that dexamethasone is considered a breakthrough in the fight against the virus.

An issue often faced with steroids is that they are known to lead to immune suppression, which could potentially complicate the recovery process of those who have been infected with the virus. Because of this challenge, physicians at Northwell hospitals, for example, are using steroids on a case-by-case basis, according to Thomas McGinn, MD, MPH, of Feinstein Institutes for Medical Research, Northwell Health.

“Across the country now intensivists have been using it based on their judgment calls. If this is legitimate, you may find...instead of say, 5 out of 10 intensive-care COVID patients getting it, maybe everybody would get it,” McGinn told Reuters._⁹

References

1. WHO welcomes preliminary results about dexamethasone use in treating critically ill COVID-19 patients. News release. World Health Organization. June 16, 2020. Accessed July 7, 2020. bit.ly/3eaaVRP.
2. Horby P, Lim WS, Emberson J, et al. Effect of dexamethasone in hospitalized patients with COVID-19: preliminary report. MedRxIv. Published online June 22, 2020. doi:10.1101/2020.06.22.20137273
3. Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of COVID-19. News release. University of Oxford. June 16, 2020. Accessed July 6, 2020. bit.ly/2O603K2.
4. World first coronavirus treatment approved for NHS use by government. News release. June 16, 2020. Accessed July 6, 2020. bit.ly/2WeKFQj.
5. Medicines that you cannot export from the UK or hoard. Guidance. Updated June 15, 2020. Accessed July 6, 2020. bit.ly/2VZpIZo.
6. US hospitals in hard hit regions step up use of steroids on sickest COVID-19 patients. News release. Reuters. June 19, 2020. Accessed, July 6, 2020. reut.rs/2ZNhBjH.
7. FDA Drug Shortages. FDA. Updated June 18, 2020. Accessed July 6, 2020. bit.ly/3gyGm9S.
8. Vizient data show 610% increase in demand for dexamethasone after study shows effectiveness for patients severely ill with COVID-19. News release. Vizient, Inc. June 25, 2020. Accessed July 6, 2020. bwnews.pr/3293Crp.
9. Steroid drug hailed as ‘breakthrough’ for seriously ill COVID-19 patients. News release. Reuters. June 16, 2020. Accessed July 6, 2020. bit.ly/38C62jr.