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Review Suggests Which COVID-19 Patients Should Get Remdesivir
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Mark Mascolini
Download the PDF here
Analyzing already-extensive literature on remdesivir, 3 US experts propose that in-hospital COVID-19 patients requiring low-flow supplemental oxygen will benefit most from this nucleoside analog prodrug with activity against coronaviruses [1]. If initial remdesivir availability allows, they suggest hospitalized patients breathing ambient air should be next in line to get remdesivir. "Overall," the authors conclude, "remdesivir is a well-tolerated therapeutic agent with demonstrable benefits in the treatment of COVID-19."
Findings of several randomized remdesivir trials have already appeared, note pharmacology and clinical experts from the University of California, Los Angeles, the University of Pittsburgh, and the University of Michigan. But "available observational and prospective data are conflicting," they write, "requiring clinicians to critically evaluate and reconcile results to determine patient populations that may optimally benefit from remdesivir therapy, especially while the drug supply is scarce."
To assist in that endeavor, the researchers analyze data on remdesivir for COVID-19 that became available from January 1, 2020 through May 31, 2020. In studies considered, people could receive remdesivir through compassionate use programs or in a clinical trial. The largest completed compassionate use analysis involved 61 patients in the United States, Europe, Canada, and Japan [2]. Twelve of 12 people (100%) requiring low-flow oxygen improved, compared with 5 of 7 (71%) receiving noninvasive ventilation and 16 of 34 (47%) needing mechanical ventilation. The authors of this review believe the cumulative improvement incidence of 84% through 28 days of follow-up is overstated because it does not include people who died as "not improved." And because the analysis had no control group, "it is difficult to interpret or draw any meaningful conclusions from this data set." At the time of this review, clinical outcomes were not available for more than 2000 patients who received remdesivir through compassionate use or expanded access sponsored by Gilead Sciences, remdesivir's maker.
The first double-blind placebo-controlled trial of remdesivir in adults with severe COVID-19 randomized 158 participants in China to remdesivir and 78 to placebo [3]. An intention-to-treat analysis discerned no difference in time to clinical improvement with remdesivir versus placebo. Post hoc (initially not planned) analysis of the subgroup enrolled within 10 days of symptom onset found shorter median time to improvement with remdesivir than with placebo (median 18 versus 23 days, hazard ratio 1.52, 95% confidence interval [CI] 0.95 to 2.42). The review authors believe findings do not support remdesivir use in patients with severe COVID-19, "but the potential effect of symptom duration on efficacy warranted further study."
Preliminary analysis of data from the 1063-person ACTT-1 randomized, double-blind, placebo-controlled trial determined that remdesivir cut recovery time in the overall study population by 4 days (rate ratio for recovery 1.32 , 95% CI 1.12 to 1.55, P < 0.001) with the greatest benefit derived by people requiring low-flow oxygen at baseline (rate ratio 1.47, 95% CI 1.17 to 1.84) [4].
The SIMPLE-1 trial compared 5- and 10-day remdesivir courses in 397 patients with an oxygen saturation at or below 94% on ambient air or requiring supplemental oxygen [5]. After adjustment for baseline differences in clinical status, this study found no difference between the 5- and 10-day courses in 14-day clinical status improvement on a 7-point ordinal scale (P = 0.14). And the longer course did not significantly improve time to clinical improvement, time to recovery, or death.
The review authors reach the following conclusions about four COVID-19 populations [1]:
Patients admitted to the hospital but not requiring supplemental oxygen
"While . . . data support a small benefit of remdesivir in this patient population in terms of time to clinical improvement, there does not appear to be a difference in progression of severity of disease or death, likely because of the low incidence rate of these end points in mild-moderately ill patients."
Patients requiring supplemental low-flow oxygen
"Data demonstrate a clinically meaningful benefit of remdesivir in patients requiring low-flow supplemental oxygen at baseline."
Patients requiring high-flow nasal cannula or noninvasive ventilation
"Taken together, these data [from ACTT-1 and SIMPLE-1] do not support a clinically meaningful benefit of remdesivir in patients requiring high-flow oxygen support on noninvasive ventilation."
Patients requiring invasive mechanical ventilation
"In both ACTT-1 and SIMPLE-1, remdesivir failed to demonstrate any benefit in patients requiring mechanical ventilation and/or receiving ECMO [extracorporeal membrane oxygenation]."
These reviewers stress that "while it appears progression of disease plays an important role in the efficacy of remdesivir, the amount of time from onset of symptoms does not." Based on available evidence, they recommend a 5-day course of remdesivir for all patients.
Scrutinizing safety data from available studies, the authors conclude that remdesivir is generally well tolerated and has adverse event rates similar to those seen with placebo.
References
1. Davis MR, McCreary EK, Pogue JM, et al. That escalated quickly: remdesivir's place in therapy for COVID-19. Infect Dis Ther. 2020 Jul 10. https://doi.org/10.1007/s40121-020-00318-1
2. Grein J, Ohmagari N, Shin D, et al. Compassionate use of remdesivir for patients with severe Covid-19. N Engl J Med. 2020;382:2327-2336. https://www.nejm.org/doi/full/10.1056/NEJMoa2007016
3. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395:1569-1578. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31022-9/fulltext
4. NIH clinical trial shows remdesivir accelerates recovery from advanced COVID-19. News releases. April 29, 2020. https://www.niaid.nih.gov/news-events/nih-clinical-trial-shows-remdesivir-accelerates-recovery-advanced-covid-19
5. Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 days in patients with severe Covid-19. N Engl J Med. 2020. https://doi.org/10.1056/nejmoa2015301
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