Annals for Hospitalists Inpatient Notes - Remdesivir—Making Sense of Emerging Evidence
Authors: Megan Rose Curtis, Paul Sax
Journal: Annals of Internal Medicine (2020)

Web Exclusives15 December 2020Annals for Hospitalists Inpatient Notes - Remdesivir—Making Sense of Emerging EvidenceFREEMegan Rose Curtis, MD, MS and Paul Sax, MDMegan Rose Curtis, MD, MSFrom Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (M.R.C., P.S.).Search for more papers by this author and Paul Sax, MDFrom Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (M.R.C., P.S.).Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M20-7498 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Should hospitalists prescribe remdesivir to all patients hospitalized with coronavirus disease 2019 (COVID-19)? In this article, we will attempt to answer that question by going through the emerging evidence and developing a construct to guide the clinical use of this medication.In May, investigators published the ACTT-1 (Adaptive COVID-19 Treatment Trial), which showed improved time to recovery among patients receiving remdesivir and prompted the U.S. Food and Drug Administration to issue an Emergency Use Authorization for it. This randomized, double-blind, placebo-controlled trial compared 10 days of remdesivir with placebo in 1062 patients hospitalized with COVID-19 in 60 sites across the United States, Europe, and Asia. The median time from symptom onset to randomization was 9 days, and 25% were enrolled within 6 days of symptom onset. More than 90% of patients had severe disease (defined as respiratory rate ≥24 breaths/min, oxygen saturation ≤94% on ambient air requiring supplemental oxygen, or mechanical ventilation).The final report of ACTT-1 showed that remdesivir shortened recovery time compared with placebo (median, 10 vs. 15 days) (1). Serious events were reported more frequently in the placebo group than in the remdesivir group (31.6% vs. 24.6%), suggesting that remdesivir may prevent the progression to more severe disease. The mortality rate by day 29 was lower in the remdesivir group than in the placebo group (11.4% vs. 15.2%), although this was not statistically significant. Among patients receiving oxygen by nasal cannula, remdesivir did significantly reduce mortality, by about one third (4% vs. 12.7%; hazard ratio, 0.3 [95% CI, 0.14 to 0.64]).The SIMPLE study, published shortly thereafter, provided additional support for remdesivir (2). This randomized, open-label, phase 3 trial evaluated remdesivir use among 584 patients hospitalized with moderate COVID-19 (defined as oxygen saturation >94% on ambient air) in the United States, Europe, and Asia. Participants were randomly assigned in a 1:1:1 ratio to receive a 10-day course of remdesivir, a 5-day course of remdesivir, or placebo. The 5-day group (but not the 10-day group) showed improved clinical status versus placebo, as measured by a 7-point ordinal scale (odds ratio, 1.65 [CI, 1.09 to 2.48]).The first randomized trial of remdesivir, done in Wuhan, China, was underpowered because of decreasing numbers of COVID-19 at the time of the study. However, among patients with fewer than 10 days of symptoms, there was a faster time to clinical improvement with remdesivir (3). These findings were not statistically significant, but they do corroborate the notion that remdesivir is most effective when initiated early.Digesting these data, we can assemble a basic construct for the clinical use of remdesivir. Remdesivir reduces viral replication, which benefits patients who are early in the course of their disease. This fits with our understanding of other antivirals for respiratory infections, analogous to the illness-shortening effects of oseltamivir when initiated shortly after the onset of symptoms of influenza. In contrast, in ACTT-1, remdesivir did not improve outcomes in those most severely ill with COVID-19, including those requiring high-flow oxygen, mechanical ventilation, or extracorporeal membrane oxygenation. It has been widely postulated that, in these severe cases, the host's immune response becomes the major pathologic driver of disease, with viral replication becoming less important. The RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial reinforced this construct by showing a mortality benefit of dexamethasone treatment among patients requiring supplemental oxygen or mechanical ventilation (4). Using this construct, remdesivir would be favored for patients with moderate disease, early in the course, and dexamethasone would be used for patients with severe disease, later in the course.Now, with the release of the much-anticipated World Health Organization's SOLIDARITY Trial as a non–peer-reviewed preprint, we may need to revisit this construct (5). The SOLIDARITY trial compared several interventions (including remdesivir) in patients with COVID-19. Among 2743 patients receiving remdesivir and 2708 control participants, no clinical differences in mortality, need for assisted ventilation, or duration of hospital stay were shown. More important, the preprint does not report the time from symptom onset to initiation of treatment in these patients.There are a few other idiosyncrasies in the remdesivir data. The drug unexpectedly failed to reduce viral loads in respiratory specimens in the underpowered Wuhan study. Furthermore, the open-label SIMPLE trial showed no statistical difference between the 10-day remdesivir group and the standard care group, a curious finding in light of the beneficial effect seen with 5 days of treatment (2, 3). However, neither these observations nor the preliminary results of the SOLIDARITY trial necessarily negate the benefits seen in ACTT-1 or the 5-day group of SIMPLE.Given the safety of remdesivir, and the lack of other treatment options, we recommend prescribing remdesivir to most patients hospitalized with COVID-19. Whenever possible, treatment should be started early, with a focus on patients requiring supplemental oxygen or those at high risk for disease progression. Whether remdesivir provides any benefit in the context of dexamethasone therapy—which is now standard of care for those with severe disease—remains unknown.Additional studies of remdesivir, including the full release of the SOLIDARITY trial results, are sure to refine the role of this medication in the treatment of patients hospitalized with COVID-19. In the meantime, 1 thing is undeniable—we desperately need more effective therapeutics because the death toll from COVID-19, especially in our most vulnerable patients, continues to climb.References1. Beigel JH, Tomashek KM, Dodd LE, et al; ACTT-1 Study Group Members. Remdesivir for the treatment of Covid-19—final report. N Engl J Med. 2020. [PMID: 32445440] doi:10.1056/NEJMoa2007764 CrossrefGoogle Scholar2. Spinner CD, Gottlieb RL, Criner GJ, et al; GS-US-540-5774 Investigators. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial. JAMA. 2020;324:1048-1057. [PMID: 32821939] doi:10.1001/jama.2020.16349 CrossrefMedlineGoogle Scholar3. 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. [PMID: 32423584] doi:10.1016/S0140-6736(20)31022-9 CrossrefMedlineGoogle Scholar4. Horby P, Lim WS, Emberson JR, et al; RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19—preliminary report. N Engl J Med. 2020. [PMID: 32678530] doi:10.1056/NEJMoa2021436 Google Scholar5. WHO Solidarity trial consortium, Pan H, Peto R, et al. Repurposed antiviral drugs for COVID-19—interim WHO SOLIDARITY trial results. medRxiv. Preprint posted online 15 October 2020. doi:10.1101/2020.10.15.20209817 Google Scholar Comments0 CommentsSign In to Submit A Comment Nora M Strong MD, MS; Robert G Badgett MDUniversity of Kansas School of Medicine14 January 2021 Stratifying Remdesivir Data for Further Clarity We commend the timely and succinct summary of the current remdesivir data provided by Curtis and Sax (1). This summary successfully proposes plausible explanations for variations in the data. This review has provided an overview of the current data quickly for an important and rapidly evolving topic. The public health crisis brought about by the COVID-19 epidemic led to a need for timely analysis and raises the question of whether methods of narrative and systematic reviews should at times be fused by the simple addition of a forest plot to a narrative review for clarity. The rationale is that while the narrative review of Curtis and Sax is can be produced much more quickly than the subsequent systematic review (2), there may be avoidable information loss in a narrative review without the structure of a forest plot. Inspection of a forest plot based on Curtis and Sax (3) raises two clinical questions. First, closer evaluation of the SOLIDARITY data, reveals a missing critical element: there is no separation of results for patients on low-flow vs. high-flow oxygen as performed in the ACTT-1 and Wuhan trials. This is critical since the low-flow oxygen patients specifically showed clear statistical benefit in the ACTT-1 trial. This may be diluting the potential benefit of remdesivir in the SOLIDARITY trial. Second, and more importantly, the proposed forest plot also shows that patients on high-flow oxygen or mechanical ventilation show a trend toward harm from remdesivir. This potential harm in the more severely ill patients could plausibly result from hepatotoxicity or nephrotoxicity in patients who are more critically ill and may already have very early organ dysfunction due to severe COVID. Based on inspection of the forest plot, we invite Curtis and Sax to comment on potentially restricting remdesivir use to patients on low-flow oxygen. We also suggest that authors presenting these highly effective narrative reviews consider including a forest plot for added clarity of effects. We found that enhancing the excellent analysis of Curtis and Sax with a forest plot was easy with a simple spreadsheet and free software. References Curtis MR, Sax P. Web Exclusive. Annals for Hospitalists Inpatient Notes - Remdesivir-Making Sense of Emerging Evidence. Ann Intern Med. 2020 Dec 15;173(12):HO2-HO3. doi: 7326/M20-7498 Kim MS, An MH, Kim WJ, Hwang TH. Comparative efficacy and safety of pharmacological interventions for the treatment of COVID-19: A systematic review and network meta-analysis. PLoS Med. 2020 Dec 30;17(12):e1003501. doi: 1371/journal.pmed.1003501 OpenMetaAnalysis Contributors. COVID-19 treatment with remdesivir. Version January 15, 2021. Available: http://openmetaanalysis.github.io/covid-19/remdesivir. Accessed 15 Jan 2021 Author, Article, and Disclosure InformationAffiliations: From Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (M.R.C., P.S.).Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M20-7498.Corresponding Author: Megan Rose Curtis, MD, MS, Harvard Medical School, 15 Francis Street, Boston, MA 02115; e-mail,[email protected]harvard.edu. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoAnnals for Hospitalists - 15 December 2020 David H. Wesorick and Vineet Chopra Metrics 15 December 2020Volume 173, Issue 12Page: HO2-HO3KeywordsCOVID-19DisclosureHospitalistsMortalityOxygenPatientsVentilatorsViral diseasesViral loadViral replication ePublished: 15 December 2020 Issue Published: 15 December 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...