Effectiveness of remdesivir with and without dexamethasone in hospitalized patients with COVID-19

Garibaldi et al., medRxiv, doi:10.1101/2020.11.19.20234153, Nov 2020

https://c19early.org/garibaldi.html

Retrospective 303 remdesivir patients and 303 matched controls showing significantly faster clinical improvement, and lower (but not statistically significant) mortality.

Gérard, Zhou, Wu, Kamo, Choi, Kim show increased risk of acute kidney injury with remdesivir. Leo, Briciu, Muntean, Petrov show increased risk of liver injury with remdesivir.

Remdesivir efficacy disappears with longer followup. Mixed-effects meta-regression of efficacy as a function of followup duration across all remdesivir studies shows decreasing efficacy with longer followup11. This may reflect antiviral efficacy being offset by serious adverse effects of treatment.

Standard of Care (SOC) for COVID-19 in the study country, the USA, is very poor with very low average efficacy for approved treatments12. Only expensive, high-profit treatments were approved. Low-cost treatments were excluded, reducing the probability of treatment—especially early—due to access and cost barriers, and eliminating complementary and synergistic benefits seen with many low-cost treatments.

Important missing comments or errors? Let us know.

risk of death, 20.0% lower, HR 0.80, p = 0.44, treatment 23 of 303 (7.6%), control 45 of 303 (14.9%), adjusted per study, day 28.

risk of no improvement, 35.0% better, RR 0.65, p < 0.001, treatment 52 of 303 (17.2%), control 80 of 303 (26.4%), NNT 11, adjusted per study, day 28.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

1. Gérard et al., Remdesivir and Acute Renal Failure: A Potential Safety Signal From Disproportionality Analysis of the WHO Safety Database, Clinical Pharmacology & Therapeutics, doi:10.1002/cpt.2145.wiley.com, doi.org.

2. Zhou et al., Acute Kidney Injury and Drugs Prescribed for COVID-19 in Diabetes Patients: A Real-World Disproportionality Analysis, Frontiers in Pharmacology, doi:10.3389/fphar.2022.833679.frontiersin.org, doi.org.

3. Wu et al., Acute Kidney Injury Associated With Remdesivir: A Comprehensive Pharmacovigilance Analysis of COVID-19 Reports in FAERS, Frontiers in Pharmacology, doi:10.3389/fphar.2022.692828.frontiersin.org, doi.org.

4. Kamo et al., Association of Antiviral Drugs for the Treatment of COVID-19 With Acute Renal Failure, In Vivo, doi:10.21873/invivo.13637.iiarjournals.org, doi.org.

5. Choi et al., Comparative effectiveness of combination therapy with nirmatrelvir–ritonavir and remdesivir versus monotherapy with remdesivir or nirmatrelvir–ritonavir in patients hospitalised with COVID-19: a target trial emulation study, The Lancet Infectious Diseases, doi:10.1016/S1473-3099(24)00353-0.sciencedirect.com, doi.org.

6. Kim et al., Investigating the Safety Profile of Fast‐Track COVID‐19 Drugs Using the FDA Adverse Event Reporting System Database: A Comparative Observational Study, Pharmacoepidemiology and Drug Safety, doi:10.1002/pds.70043.wiley.com, doi.org.

7. Leo et al., Hepatocellular liver injury in hospitalized patients affected by COVID-19: Presence of different risk factors at different time points, Digestive and Liver Disease, doi:10.1016/j.dld.2021.12.014.sciencedirect.com, doi.org.

8. Briciu et al., Evolving Clinical Manifestations and Outcomes in COVID-19 Patients: A Comparative Analysis of SARS-CoV-2 Variant Waves in a Romanian Hospital Setting, Pathogens, doi:10.3390/pathogens12121453.mdpi.com, doi.org.

9. Muntean et al., Effects of COVID-19 on the Liver and Mortality in Patients with SARS-CoV-2 Pneumonia Caused by Delta and Non-Delta Variants: An Analysis in a Single Centre, Pharmaceuticals, doi:10.3390/ph17010003.mdpi.com, doi.org.

10. Petrov et al., The Effect of Potentially Hepatotoxic Medicinal Products on Alanine Transaminase Levels in COVID-19 Patients: A Case–Control Study, Safety and Risk of Pharmacotherapy, doi:10.30895/2312-7821-2025-458.risksafety.ru, doi.org.

11. c19early.org, c19early.org/smeta.html.c19early.org/smeta.html.

12. c19early.org (B), c19early.org/soc/usa.html.c19early.org/soc/usa.html.

Garibaldi et al., 20 Nov 2020, retrospective, USA, preprint, 10 authors.

This Paper Remdesivir All

Effectiveness of remdesivir with and without dexamethasone in hospitalized patients with COVID-19

MD MEHP Brian T Garibaldi, MS Kunbo Wang, MD Matthew L Robinson, PhD Scott L Zeger, PhD Karen Bandeen Roche, PhD Mei-Cheng Wang, MD G Caleb Alexander, MD Amita Gupta, MD MPH Robert Bollinger, PhD Yanxun Xu

doi:10.1101/2020.11.19.20234153

Rationale: Remdesivir and dexamethasone reduced the severity of COVID-19 in clinical trials. However, their individual or combined effectiveness in clinical practice remains unknown. Objectives: To examine the effectiveness of remdesivir with or without dexamethasone. Methods: We conducted a multicenter, retrospective cohort study between March 4 and August 29, 2020. Eligible COVID cases were hospitalized patients treated with remdesivir with or without dexamethasone. We applied a Cox proportional hazards model with propensity score matching to estimate the effect of these treatments on clinical improvement by 28 days (discharge or a 2-point decrease in WHO severity score) and 28-day mortality. Measurements and Main Results: Of 2485 COVID-19 patients admitted between March 4 and August 29, 2020, 342 received remdesivir and 157 received remdesivir plus dexamethasone. Median age was 60 years; 45% were female; 81% were non-white. Remdesivir recipients on room air or nasal cannula oxygen had a faster time to clinical improvement (median 5.0 days [IQR 4.0, 8.0], remdesivir vs. 7.0 days [IQR 5.0, 12.0], control; adjusted hazard ratio (aHR) 1.55 [1.28; 1.87]), yet those requiring higher levels of respiratory support did not benefit. Remdesivir recipients had lower, but statistically insignificant, 28-day mortality (7.6% [23 deaths], remdesivir vs. 14.9% [45 deaths], control). Adding dexamethasone trended toward lower 28-day mortality compared to remdesivir alone (5.1% [8 deaths] vs. 9.2% [17 deaths]; aHR 0.14 [0.02; 1.03]). Conclusions: Remdesivir offered a significantly faster time to clinical improvement among a cohort of predominantly non-white patients hospitalized with COVID-19, particularly with mildmoderate disease. Remdesivir plus dexamethasone may reduce mortality.

References

Beigel, Tomashek, Dodd, Remdesivir for the Treatment of Covid-19 -Preliminary Report, New Engl J Med

Chastain, Osae, Henao-Martínez, Franco-Paredes, Chastain et al., Racial Disproportionality in Covid Clinical Trials, New Engl J Med

Davis, Mccreary, Pogue, That Escalated Quickly: Remdesivir's Place in Therapy for COVID-19, Infect Dis Ther

Garibaldi, Fiksel, Muschelli, Patient trajectories and risk factors for severe outcomes among persons hospitalized for COVID-19 in the Maryland/DC region, medRxiv

Goldman, Lye, Hui, Remdesivir for 5 or 10 Days in Patients with Severe Covid-19, N Engl J Med

Hernán, Brumback, Robins, Marginal structural models to estimate the causal effect of zidovudine on the survival of HIV-positive men, Epidemiology

Horby, Lim, Emberson, Dexamethasone in Hospitalized Patients with Covid-19 -Preliminary Report, N Engl J Med

Ison, Wolfe, Boucher, Emergency Use Authorization of Remdesivir: The Need for a Transparent Distribution Process, JAMA

Jorgensen, Kebriaei, Dresser, Remdesivir: Review of Pharmacology, Preclinical Data, and Emerging Clinical Experience for COVID-19, Pharmacotherapy

Kabpw, Remdesivir Could Be in Short Supply. Here's a Fix, The New York Times

Lu, Propensity score matching with time-dependent covariates, Biometrics

Mulangu, Dodd, Davey, A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics, N Engl J Med

Shah, Sachdeva, Dodiuk-Gad, COVID-19 and racial disparities, Journal of the American Academy of Dermatology

Spinner, Gottlieb, Criner, Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial, JAMA

Tchesnokov, Feng, Porter, Götte, Mechanism of Inhibition of Ebola Virus RNA-Dependent RNA Polymerase by Remdesivir, Viruses

Wang, Cao, Zhang, Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res

Wang, Zhang, Du, Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial, Lancet

Williamson, Feldmann, Schwarz, Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2, Nature

Xie, Bowe, Li, Xian, Yan et al., Risk of death among users of Proton Pump Inhibitors: a longitudinal observational cohort study of United States veterans, BMJ Open

DOI record: { "DOI": "10.1101/2020.11.19.20234153", "URL": "http://dx.doi.org/10.1101/2020.11.19.20234153", "abstract": "ABSTRACTRationaleRemdesivir and dexamethasone reduced the severity of COVID-19 in clinical trials. However, their individual or combined effectiveness in clinical practice remains unknown.ObjectivesTo examine the effectiveness of remdesivir with or without dexamethasone.MethodsWe conducted a multicenter, retrospective cohort study between March 4 and August 29, 2020. Eligible COVID cases were hospitalized patients treated with remdesivir with or without dexamethasone. We applied a Cox proportional hazards model with propensity score matching to estimate the effect of these treatments on clinical improvement by 28 days (discharge or a 2-point decrease in WHO severity score) and 28-day mortality.Measurements and Main ResultsOf 2485 COVID-19 patients admitted between March 4 and August 29, 2020, 342 received remdesivir and 157 received remdesivir plus dexamethasone. Median age was 60 years; 45% were female; 81% were non-white. Remdesivir recipients on room air or nasal cannula oxygen had a faster time to clinical improvement (median 5.0 days [IQR 4.0, 8.0], remdesivir vs. 7.0 days [IQR 5.0, 12.0], control; adjusted hazard ratio (aHR) 1.55 [1.28; 1.87]), yet those requiring higher levels of respiratory support did not benefit. Remdesivir recipients had lower, but statistically insignificant, 28-day mortality (7.6% [23 deaths], remdesivir vs. 14.9% [45 deaths], control). Adding dexamethasone trended toward lower 28-day mortality compared to remdesivir alone (5.1% [8 deaths] vs. 9.2% [17 deaths]; aHR 0.14 [0.02; 1.03]).ConclusionsRemdesivir offered a significantly faster time to clinical improvement among a cohort of predominantly non-white patients hospitalized with COVID-19, particularly with mild-moderate disease. 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Late treatment
is less effective

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