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Objective To compare the effects of treatments for coronavirus disease 2019 (covid-19).
Design Living systematic review and network meta-analysis.
Data sources WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, up to 1 March 2021 and six additional Chinese databases up to 20 February 2021. Studies identified as of 12 February 2021 were included in the analysis.
Study selection Randomised clinical trials in which people with suspected, probable, or confirmed covid-19 were randomised to drug treatment or to standard care or placebo. Pairs of reviewers independently screened potentially eligible articles.
Methods After duplicate data abstraction, a bayesian network meta-analysis was conducted. Risk of bias of the included studies was assessed using a modification of the Cochrane risk of bias 2.0 tool, and the certainty of the evidence using the grading of recommendations assessment, development, and evaluation (GRADE) approach. For each outcome, interventions were classified in groups from the most to the least beneficial or harmful following GRADE guidance.
Results 196 trials enrolling 76 767 patients were included; 111 (56.6%) trials and 35 098 (45.72%) patients are new from the previous iteration; 113 (57.7%) trials evaluating treatments with at least 100 patients or 20 events met the threshold for inclusion in the analyses. Compared with standard care, corticosteroids probably reduce death (risk difference 20 fewer per 1000 patients, 95% credible interval 36 fewer to 3 fewer, moderate certainty), mechanical ventilation (25 fewer per 1000, 44 fewer to 1 fewer, moderate certainty), and increase the number of days free from mechanical ventilation (2.6 more, 0.3 more to 5.0 more, moderate certainty). Interleukin-6 inhibitors probably reduce mechanical ventilation (30 fewer per 1000, 46 fewer to 10 fewer, moderate certainty) and may reduce length of hospital stay (4.3 days fewer, 8.1 fewer to 0.5 fewer, low certainty), but whether or not they reduce mortality is uncertain (15 fewer per 1000, 30 fewer to 6 more, low certainty). Janus kinase inhibitors may reduce mortality (50 fewer per 1000, 84 fewer to no difference, low certainty), mechanical ventilation (46 fewer per 1000, 74 fewer to 5 fewer, low certainty), and duration of mechanical ventilation (3.8 days fewer, 7.5 fewer to 0.1 fewer, moderate certainty). The impact of remdesivir on mortality and most other outcomes is uncertain. The effects of ivermectin were rated as very low certainty for all critical outcomes, including mortality. In patients with non-severe disease, colchicine may reduce mortality (78 fewer per 1000, 110 fewer to 9 fewer, low certainty) and mechanical ventilation (57 fewer per 1000, 90 fewer to 3 more, low certainty). Azithromycin, hydroxychloroquine, lopinavir-ritonavir, and interferon-beta do not appear to reduce risk of death or have an effect on any other patient-important outcome. The certainty in effects for all other interventions was low or very low.
Conclusion Corticosteroids and interleukin-6 inhibitors probably confer important benefits in patients with severe covid-19. Janus kinase inhibitors appear to have promising benefits, but certainty is low. Azithromycin, hydroxychloroquine, lopinavir-ritonavir, and interferon-beta do not appear to have any important benefits. Whether or not remdesivir, ivermectin, and other drugs confer any patient-important benefit remains uncertain.
Systematic review registration This review was not registered. The protocol is publicly available in the supplementary material.
Readers’ note This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication. This is the fourth version of the original article published on 30 July 2020 (BMJ 2020;370:m2980), and previous versions can be found as data supplements. When citing this paper please consider adding the version number and date of access for clarity.
As of 28 March 2021, more than 127 million people have been infected with severe acute respiratory syndrome coronavirus virus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (covid-19); of these, more than 2.7 million have died.1 Despite global efforts to identify effective interventions for the prevention and treatment of covid-19, which have resulted in 2800 trials completed or underway,2 evidence for effective treatment remains limited.
Faced with the pressures of a global pandemic, healthcare workers around the world are prescribing drugs off-label for which there is only very low quality evidence. Timely evidence summaries and associated guidelines could ameliorate the problem.3 Clinicians, patients, guideline bodies, and government agencies are also facing the challenges of interpreting the results from trials that are being published at a rate never encountered previously. This environment makes it necessary to produce well developed summaries that distinguish more trustworthy evidence from less trustworthy evidence.
Living systematic reviews deal with the main limitation of traditional reviews—that of providing an overview of the relevant evidence only at a specific time.4 This is crucial in the context of covid-19, in which the best evidence is constantly changing. The ability of a living network meta-analysis to present a complete, broad, and updated view of the evidence makes it the best type of evidence synthesis to inform the development of practice recommendations. Network meta-analysis, rather than pairwise meta-analysis, provides useful information about the comparative effectiveness of treatments that have not been tested head to head. The lack of such direct comparisons is certain to limit inferences in the covid-19 setting. Moreover, the incorporation of indirect evidence can strengthen evidence in comparisons that were tested head to head.5
In this living systematic review and network meta-analysis we compare the effects of drug treatments for covid-19. This review is part of the BMJ Rapid Recommendations project, a collaborative effort from the MAGIC Evidence Ecosystem Foundation (www.magicproject.org) and The BMJ.6 This living systematic review and network meta-analysis informs World Health Organization and BMJ Rapid Recommendations6 on covid-19 treatments, initiated to provide trustworthy, actionable, and living guidance to clinicians and patients soon after new and potentially practice-changing evidence becomes available. The first covid-19 BMJ Rapid Recommendation considered the role of remdesivir.7 Subsequent guidance addressed the role of hydroxychloroquine, corticosteroids, lopinavir-ritonavir, and updated guidance for remdesivir (box 1).8 The latest recommendation covers ivermectin. This living network meta-analysis is the fourth version. The previous versions are available in the supplementary material. Drugs for prophylaxis910 and antibody-based treatments will be addressed separately.
Créditos: Comité científico Covid