An updated systematic review and network meta-analysis of 25 randomized trials assessing the efficacy and safety of treatments in COVID-19 disease

  • Alhassane Diallo
    INSERM, CIC 1411, CHU of Montpellier, St. Eloi Hospital, University of Montpellier, France.
    https://orcid.org/0000-0002-1666-8641
  • Miguel Carlos-Bolumbu
    Urgences Réanimation Centre Hospitalier Sud Essonnes CHSE, Paris, France.
  • Marie Traoré
    Service de Rhumatologie, APHP Henry Mondor, Paris, France.
    https://orcid.org/0000-0003-2196-6720
  • Mamadou Hassimiou Diallo
    Hôpitaux Universitaires Pitié Salpêtrière – Charles Foix, Unité de Recherche Clinique Salpêtrière – Charles Foix, Paris, France.
    https://orcid.org/0000-0002-4098-277X
  • Christophe Jedrecy
    Urgences Réanimation Centre Hospitalier Sud Essonnes CHSE, Paris, France.

ABSTRACT

To date, there is no definite effective treatment for the COVID-19 pandemic. We performed an update network meta-analysis to compare and rank COVID-19 treatments according to their efficacy and safety. Literature search was performed from MEDLINE and CENTRAL databases from inception to September 5, 2020. Randomized clinical trials (RCTs) which compared the effect of any pharmacological drugs versus standard care or placebo 28-day after hospitalization in adult patients with COVID-19 disease were included. Risk ratio (RR) and 95% CI were calculated for 28-day all-cause mortality, clinical improvement, any adverse event (AEs), and viral clearance. A total of 25 RCTs, evaluating 17 different treatments, and 11,597 participants were analyzed. Remdesivir for 10-day compared to standard care (RR 0.69, 95% CI [0.48–0.99]), and a low dose compared to a high dose of HCQ (0.38, [0.17–0.89]) were associated with a lower risk of death. A total of 2,766 patients experienced clinical improvement, a 5-day course of remdesivir was associated with a higher frequency of clinical improvement compared to standard care (RR 1.21, 95% CI [1.00–1.47]). Compared to standard care, remdesivir for both 5 and 10 days, lopinavir/ritonavir, and dexamethasone reduced the risk of any severe AEs by 52% (0.48, 0.34–0.67), 24% (0.77, 0.63–0.92), 40% (0.60, 0.37–0.98), and 50% (0.50, 0.25–0.98) respectively. In this study of hospitalized patients with COVID-19, administration of remdesivir for 10-day compared to standard care was associated with lower 28-day all-cause mortality and serious AEs, and higher clinical improvement rate.

REFERENCES

Johns Hopkins University [Internet]. Coronavirus Resource Center. COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU). Accessed 1 September 2020. Available from: https://coronavirus.jhu.edu/map.html

Dyall J, Gross R, Kindrachuk J, et al. Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current therapeutic options and potential targets for novel therapies. Drugs 2017;77:1935‑66. DOI: https://doi.org/10.1007/s40265-017-0830-1

Million M, Gautret P, Colson P, et al. Clinical efficacy of chloroquine derivatives in COVID-19 infection: Comparative meta-analysis between the big data and the real world. New Microbes New Infect 2020;38:100709. DOI: https://doi.org/10.1016/j.nmni.2020.100709

Singh AK, Singh A, Singh R, Misra A. Hydroxychloroquine in patients with COVID-19: A systematic review and meta-analysis. Diabetes Metab Syndr Clin Res Rev 2020;14:589‑96. DOI: https://doi.org/10.1016/j.dsx.2020.05.017

Fiolet T, Guihur A, Rebeaud ME, et al. Effect of hydroxychloroquine with or without azithromycin on the mortality of coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis. Clin Microbiol Infect 2021;27:19-27. DOI: https://doi.org/10.1016/j.cmi.2020.08.022

The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JAC, Murthy S, et al. Association between administration of systemic corticosteroids and mortality among critically Ill patients with COVID-19: A meta-analysis. JAMA 2020;324:1330-41.

Alhassane D, Traoré M, Carlos-Bolumbo M, et al. Efficacy and safety data of treatments for novel coronavirus pneumonia (SARS-Cov-2): A systematic review and network meta-analysis of randomized trials. J Infect Dis Epidemiol 2020;6:151. DOI: https://doi.org/10.23937/2474-3658/1510151

Sterne AC, Page MG, Elbers RG, et al. RoB 2: A revised tool for assessing risk of bias in randomized trials. BMJ 2019;366 14898.

Schwarzer G, Carpenter JR, Rücker G. Meta-analysis with R. Cham: Springer. 2015 DOI: https://doi.org/10.1007/978-3-319-21416-0

Huang M, Tang T, Pang P, et al. Treating COVID-19 with chloroquine. J Mol Cell Biol 2020;12:322‑5. DOI: https://doi.org/10.1093/jmcb/mjaa014

Chen J, Liu D, Liu L, et al. [A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19)].[Article in Chinese]. Zhejiang Da Xue Xue Bao Yi Xue Ban 2020;49:215-9.

Chen Z, Hu J, Zhang Z, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv 2020. doi: 10.1101/2020.03.22.20040758 DOI: https://doi.org/10.1101/2020.03.22.20040758

Chen C, Zhang Y, Huang J, et al. Favipiravir versus arbidol for COVID-19: A randomized clinical trial. medRxiv 2020. doi: 10.1101/2020.03.17.20037432 DOI: https://doi.org/10.1101/2020.03.17.20037432

Li Y, Xie Z, Lin W, et al. An exploratory randomized controlled study on the efficacy and safety of lopinavir/ritonavir or arbidol treating adult patients hospitalized with mild/moderate COVID-19 (ELACOI). medRxiv 2020. doi:10.1101/2020.03.19.20038984 DOI: https://doi.org/10.1101/2020.03.19.20038984

Li L, Zhang W, Hu Y, et al. Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: A randomized clinical trial. JAMA 2020;324:460-70. DOI: https://doi.org/10.1001/jama.2020.10044

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;383:1827-37. DOI: https://doi.org/10.1056/NEJMoa2015301

Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ 2020;369:m1849. DOI: https://doi.org/10.1136/bmj.m1849

Cao B, Wang Y, Wen D, et al. A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 2020;382:1787‑99. DOI: https://doi.org/10.1056/NEJMc2008043

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;395:1569‑78.

Borba MGS, Val FFA, Sampaio VS, et al. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection: A randomized clinical trial. JAMA Netw Open 2020;3:e208857. DOI: https://doi.org/10.1001/jamanetworkopen.2020.8857

Hung IF-N, Lung K-C, Tso EY-K, et al. Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet 2020;395:1695‑704.

Cavalcanti AB, Zampieri FG, Rosa RG, et al. Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19. N Engl J Med 2020;383:e119. DOI: https://doi.org/10.1056/NEJMx200021

Cao Y, Wei J, Zou L, et al. Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial. J Allergy Clin Immunol 2020;146:137-46.e3. DOI: https://doi.org/10.1016/j.jaci.2020.05.019

Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19 — Preliminary report. N Engl J Med 2020;383:992-4. DOI: https://doi.org/10.1056/NEJMoa2007764

Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: A randomized clinical trial. JAMA 2020;324:1048-57. DOI: https://doi.org/10.1001/jama.2020.16349

Miller J, Bruen C, Schnaus M, et al. Auxora versus standard of care for the treatment of severe or critical COVID-19 pneumonia: results from a randomized controlled trial. Crit Care 2020;24:502. DOI: https://doi.org/10.1186/s13054-020-03220-x

Tomazini BM, Maia IS, Cavalcanti AB, 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;324:1307-16. DOI: https://doi.org/10.1001/jama.2020.17021

The RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19 – Preliminary report. N Engl J Med 2020;NEJMoa2021436.

Dequin P-F, Heming N, Meziani F, et al. Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19: A randomized clinical trial. JAMA 2020;324:1298-306. DOI: https://doi.org/10.1001/jama.2020.16761

The Writing Committee for the REMAP-CAP Investigators, Angus DC, Derde L, et al. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: The REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial. JAMA 2020;324:1317-29.

Deftereos SG, Giannopoulos G, Vrachatis DA, et al. Effect of colchicine vs standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: The GRECCO-19 randomized clinical trial. JAMA Netw Open 2020;3:e2013136. DOI: https://doi.org/10.1001/jamanetworkopen.2020.13136

Arshad S, Kilgore P, Chaudhry ZS, et al. Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19. Int J Infect Dis 2020;97:396-403. DOI: https://doi.org/10.1016/j.ijid.2020.06.099

Rosenberg ES, Dufort EM, Udo T, et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State. JAMA 2020;323:2493. DOI: https://doi.org/10.1001/jama.2020.8630

Mahévas M, Tran V-T, Roumier M, et al. Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data. BMJ 2020;369:m1844.

Sbidian E, Josse J, Lemaitre G, et al. Hydroxychloroquine with or without azithromycin and in-hospital mortality or discharge in patients hospitalized for COVID-19 infection: a cohort study of 4,642 in-patients in France. medRxiv 2020. doi: 10.1101/2020.06.16.20132597 DOI: https://doi.org/10.1101/2020.06.16.20132597

Lagier J-C, Million M, Gautret P, et al. Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: A retrospective analysis. Travel Med Infect Dis 2020;36:101791. DOI: https://doi.org/10.1016/j.tmaid.2020.101791

Cortegiani A, Ippolito M, Ingoglia G, et al. Update I. A systematic review on the efficacy and safety of chloroquine/hydroxychloroquine for COVID-19. J Crit Care 2020;59:176-90. DOI: https://doi.org/10.1016/j.jcrc.2020.06.019

Boulware DR, Pullen MF, Bangdiwala AS, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19. N Engl J Med 2020;383:517‑25. DOI: https://doi.org/10.1056/NEJMc2023617