By: Bisma T. Sekhery PharmD. Candidate c/o 2025

             COVID-19 has had a significant impact on the health, economic, and social aspects of life for every person. Currently, there is only one Food and Drug Administration (FDA)-approved treatment for COVID-19–remdesivir (Veklury®). The lack of approved therapies makes COVID-19 difficult to treat and increases overall mortality for geriatric patients and immunocompromised populations. Though recently approved, remdesivir, an antiviral which inhibits SARS-CoV-2 RNA-dependent RNA polymerase, which can potentially shorten the duration of infection, still holds the emergency authorization for treatment of COVID-19. ² Due to dexamethasone’s (Decadron®) mechanism of action, which involves reducing inflammation, many patients have been receiving this as adjunct to remdesivir.

Dexamethasone is an anti-inflammatory corticosteroid that decreases inflammation by reducing neutrophil migration, reducing production of inflammatory mediators and reversing increased capillary permeability. ³ It is commonly used as an immunosuppressant in several disease states. However, since dexamethasone can cause immunosuppression, there is a risk for secondary infections. Therefore, selecting the right dose is critical for all disease management. ¹

The use of dexamethasone in treatment of COVID-19 has been debated because of its negative effects, which occur due to prolonged use, higher doses, but there may be a benefit for the treatment of critically-ill COVID-19 patients. ² However, trials which have examined the efficacy of dexamethasone for the treatment of COVID-19 have shown improvement in the overall health of COVID-19 patients. According to the Infectious Disease Society of America Guidelines, initiating dexamethasone 6 mg IV/PO once daily is recommended in critically ill patients with COVID-19. ⁸ It is also recommended in patients with severe, but not critical COVID-19. To further support this recommendation, the National Institutes of Health (NIH) stated that hospitalized patients with COVID-19 should be given dexamethasone 6 mg once daily for ten days or until discharge. ⁸ In practice, providers often utilize higher dosing for dexamethasone. The dose can be as high as 20 mg IV twice daily. Higher dexamethasone dosing strategies are used in critically ill patients that have progressed to Acute Respiratory Distress Syndrome (ARDS) secondary to COVID-19. The exact benefit of adding a steroid to antiviral therapy for treatment is currently unknown, but there are trials currently underway. ⁸

The coDex, randomized, open-label clinical trial was carried out to assess the overall benefit of dexamethasone in moderate to severe ARDS secondary to COVID-19 by the Coalition COVID-19 in Brazil. Since the patients enrolled in the trial had progressed to ARDS, they all received higher doses of dexamethasone. Patients received either dexamethasone 20 mg IV for 5 days, followed by 10 mg dexamethasone IV for 5 days or until ICU discharge plus standard of care therapy or standard of care therapy alone. Standard of care entailed that the patient received IV fluids, remdesivir, and appropriate symptom management without dexamethasone. The primary outcome was number of ventilator-free days in the first 28 days after hospital admission. The secondary outcomes included all-cause mortality at 28 days, clinical status of patient, ICU- free days during the first 28 days, Sequential Organ Failure Assessment (SOFA) scores, as well as mechanical ventilation use at 28 days. ⁷

A total of 299 patients were followed in this trial. The primary endpoint yielded statistically significant results and showed that the mean number of ventilator-free days was 6.6 days in the dexamethasone group versus 4 days in the standard of care group (p= 0.04). The only statistically significant secondary endpoint showed that the mean SOFA score was 6.1 in the dexamethasone group versus 7.5 in the standard of care group (p = 0.004). There was no significant difference in the secondary endpoints including all-cause mortality and ICU-free days in the first 28 days. The difference in clinical status was nonremarkable. Patients in the dexamethasone group had a mean score of 5, while the standard of care group had a score of 5-6(p=0.07). Overall, this trial demonstrated that use of dexamethasone contributed to a greater number of ventilator-free days. This trial had several limitations–it was not blinded, severe cases of COVID-19 without progression to ARDS were not included, patients were only followed for 28 days, and men outnumbered women. Although the results show statistical significance, one must also question whether dexamethasone’s adverse effects outweigh its potential benefit in this cohort of patients. The trial’s results also demonstrated that incidences of insulin use, new infections, catheter associated UTI, and pneumonia were the same in the both the control group and dexamethasone group, which is promising. ⁷ Data showed a statistically significant improvement in ventilator-free days and the side effect occurrence was similar in the both of the groups.

While the benefit of dexamethasone is apparent in COVID-19patients with ARDS, its benefit when used in COVID-19 patients without ARDS remains unclear. In October 2020, the RECOVERY trial was completed and carried out by Nuffield Department of Population Heal that the University of Oxford. In this trial, 2,079 COVID-19 patients being treated with dexamethasone 6 mg IV for 10 days and 4,278 COVID-19 patients being treated with standard of care therapy were followed. The primary outcome was all-cause mortality at 28 days. Secondary outcomes included time (days) until discharge. Enrolled patients included those that had a confirmed diagnosis of COVID-19 and were hospitalized because of the virus. Mortality at 28 days from COVID-19 was 22.9 percent in the dexamethasone group versus 25 percent in the standard of care group (p=0.001). Dexamethasone’s benefit was seen mostly in patients who had invasive mechanical ventilation as well as patients on oxygen support without ventilation. Use of dexamethasone in patients with no respiratory support did not show any benefit. The mean duration of hospital stay was 12 days in the dexamethasone group versus 13 days in the standard of care group. Incidence of progression to mechanical ventilation was lower in the dexamethasone group compared to the standard of care group. ⁴ Limitations of this study included an unequal distribution of participants in both groups, that women comprised only 36 percent of enrolled patients, and that it was carried out for a short period of time.

Despite their limitations, the two trials discussed above provide important information about the use and efficacy of dexamethasone in treating COVID-19 patients. Since COVID-19 continues to be a threat and no statistically significant adverse effects were noted in both trials, use of dexamethasone is justified when treating COVID-19 patients in inpatient settings. Further clinical trials are necessary over longer periods of time to assess if there is a long-term benefit of dexamethasone use in the treatment of COVID-19.

References

1. Dexamethasone. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Rivewoods, IL. Accessed 8/20/2020
2. Patel SK, Saikumar G, Rana J, et al. Dexamethasone: A boon for critically ill COVID-19patients?. Travel Med Infect Dis. 2020;37:101844. doi:10.1016/j.tmaid.2020.101844
3. Prescott HC, Rice TW. Corticosteroids in COVID-19 ARDS: Evidence and Hope During the Pandemic. JAMA. 2020;324(13):1292–1295. doi:10.1001/jama.2020.16747
4. Horby P, Lim WS, et al. Dexamethasone in Hospitalized Patients with Covid-19 – Preliminary Report. N Engl J Med.2020. doi: 10.1056/NEJMoa2021436
5. Remdesvir. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Rivewoods, IL. Accessed 8/20/2020.
6. Siordia JA Jr, Bernaba M, Yoshino K, et al. Systematic and Statistical Review of Coronavirus Disease 19 Treatment Trials [published online ahead of print, 2020 Jul 15]. SN Compr Clin Med. 2020;1-12. doi:10.1007/s42399-020-00399-6
7. Tomazini BM, et al. Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients with Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial. JAMA. 2020 Sep 2;324(13):1–11. doi:10.1001/jama.2020.17021. Epub ahead of print. PMID: 32876695; PMCID: PMC7489411.
8. Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review. JAMA. 2020;324(8):782–793. doi:10.1001/jama.2020.12839

Published by Rho Chi Post