Episode 9 - COVID-19 Series: Part 3 - Current Treatment Options

Network Five Emergency Medicine

Theme:
COVID-19.

Participants:

Dr Matthew O'Sullivan (infectious diseases specialist), Prof. Sanjay Swaminathan (immunologist), Dr George Zhou (intensivist), Ali Sayeed (ICU registrar), Dr James Tadros (ED consultant), Dr Pramod Chandru (ED consultant), Harry Hong, Samoda Wilegoda Mudalige, Shreyas Iyer, Kit Rowe, and Caroline Tyers.

Discussion:
Ansems, K., Grundeis, F., Dahms, K., Mikolajewska, A., Thieme, V., & Piechotta, V. et al. (2021). Remdesivir for the treatment of COVID-19. Cochrane Database Of Systematic Reviews, 2021(8). https://doi.org/10.1002/14651858.cd014962.

Presenter - Ali Sayeed, ICU Registrar at Westmead Hospital.

Summary:

• Remdesivir is a small molecule pro-drug that inhibits viral replication via its inhibition of RNA polymerase - In Australia, it has been provisionally approved by the TGA for its use in COVID-19.
• The theory behind using Remdesivir is really in the early stages of COVID-19 pneumonitis (by reducing the viral load and thereby preventing the augmentation of the inflammatory response).
• This was a systematic review with included meta-analyses looking at the use of Remdesivir in COVID-19 compared with placebo or standard care.
• It included only randomised control trials, with the primary outcomes being all-cause mortality, changes in clinical status (such as time to liberation from mechanical intervention) and adverse events.
• The 5 studies analysed for this review were: the Beigel study (ACTT-1 trial) which enrolled 1,000 patients, the Spinner trial which had 600 patients, the Wang trial with 230 patients, the Mahajan trial with 82 patients, and the WHO Solidarity trial with over 5,000 patients.
• Remdesivir was found to have little to no impact on all-cause mortality at 28 days.
• The duration to liberation from non-invasive and invasive mechanical ventilation was found to be 17 days in the Remdesivir group compared with 20 days in the control group in the Beigel study, and 7 days in the Remdesivir group compared with 15 days in the control group in the Wang study, although neither of these results were statistically significant.
• The Beigel study demonstrated a difference in time to recovery in the Remdesivir group compared with the placebo group, with a median difference of 5 days (however it is unclear whether this result was statistically significant).
• The significant heterogeneity in study protocols, methodology, subgroups and settings made it very difficult to compare these studies statistically.

Take-Home Points:

• Remdesivir likely has very limited or no effect on hard outcomes in COVID-19 (in particular on mortality).
• The benefit of Remdesivir is not constant across disease severities; if there is a benefit it is likely to be a subset of patients (which appears to be those on low-flow oxygen).
• It does not appear to affect hospital length of stay (there is not sufficient evidence to suggest it does).
• All outcomes were based on low certainty evidence, and it is unlikely that there will be further evidence on Remdesivir alone to come, as most patients will be receiving combination therapy in ongoing studies.
• Of all the treatment modalities that we have for COVID-19, Remdesivir appears to be the one that has the least impact, but it was the one that was available first, and has very few side effects.
• At present in NSW, COVID-19 patients requiring oxygen are being treated with a combination of Dexamethasone, Remdesivir and Baracitinib (or Tocilizumab).

References:

• Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al. Remdesivir for the treatment of COVID-19 – final report. New England Journal of Medicine 2020;383:1813-26.[DOI: 10.1056/NEJMoa2007764].
• Spinner CD, Gottlieb RL, Criner GJ, Arribas Lopez JR, Cattelan AM, Soriano Viladomiu A, et al. Effect of remdesivirvs standard care on clinical status at 11 days in patientswith moderate COVID-19: a randomised clinical trial. JAMA2020;324(11):1048-57. [DOI: 10.1001/jama.2020.16349] [PMID:32821939].
• Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. The Lancet2020;395(10236):1569-78. [CLINICALTRIALS.GOV: NCT04257656][DOI: 10.1016/s0140-6736(20)31022-9].
• Mahajan L, Singh AP, GiSy. Clinical outcomes of using Remdesivir in patients with moderate to severe COVID-19: a prospective randomised study. Indian Journal of Anaesthesia2021;65:41-6. [DOI: 10.4103/ija.IJA_149_21].
• WHO Solidarity Trial Consortium. Repurposed antiviral drugs for COVID-19 - interim WHO solidarity trial results. New England Journal of Medicine 2021;384(8):497-511. [CLINICALTRIALS.GOV:NCT04315948] [DOI: 10.1056/NEJMoa2023184] [EUCTR:EUCTR2020-001366-11] [ISRCTN: ISRCTN83971151].
• Living Guidelines [Internet]. Caring for people with COVID-19. 2021 [cited 16 September 2021]. Available from: https://covid19evidence.net.au/#living-guidelines.
• The RECOVERY Collaborative Group. Dexamethasone in Hospitalized Patients with Covid-19. New England Journal of Medicine [Internet]. 2021 [cited 16 September 2021];384(8):693-704. Available from: https://www.nejm.org/doi/full/10.1056/NEJMoa2021436.
• Kalil AC, Patterson TF, Mehta AK, Tomashek KM, et al. Baricitinib plus Remdesivir for Hospitalized Adults with COVID-19. N Engl J Med 2021; 384:795-807.
• Gupta A, Gonzalez-Rojas Y, Juarez E, Crespo Casal M, Moya J, Falci DR, Sarkis E, Solis J, Zheng H, Scott N, Cathcart AL, Hebner CM, Sager J, Mogalian E, Tipple C, Peppercorn A, Alexander E, Pang PS, Free A, Brinson C, Aldinger M, Shapiro AE. Early COVID-19 Treatment with SARS-CoV-2 Neutralizing Antibody Sotrovimab [Internet]. medRxiv; May 2021 [cited 16 September 2021]. Available from: https://www.medrxiv.org/content/10.1101/2021.05.27.21257096v1.
• Tomazini B, Maia I, Cavalcanti A, Berwanger O, Rosa R, Veiga V et al. Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19. JAMA [Internet]. 2020 [cited 16 September 2021];324(13):1307. Available from: https://jamanetwork.com/journals/jama/fullarticle/2770277.
• Hasan MJ, Rabbani R, Anam AM, Huq SMR, Polash MMI, Nessa SST, Bachar SC. Impact of high dose Baracitinib in severe COVID-19 pneumonia: a prospective cohort study in Bangladesh. BMC Infect Dis. May 2021; 21(1): 427. Available from: https://pubmed.ncbi.nlm.nih.gov/33962573/.

Kit's Corner

• Signbank [Internet]. Auslan.org.au. 2021 [cited 01 October 2021]. Available from: https://www.auslan.org.au/dictionary/words/COVID-19-1.html.

Credits:
This episode was produced by the ­­­­Emergency Medicine Training Network 5 with the assistance of Dr Kavita Varshney and, Deepa Dasgupta.

Music/Sound Effects

• Angel by Ikson | https://youtube.com/ikson, Music promoted by