Drug Treatments For Covid-19: Living Systematic Review and Network Meta-Analysis

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article. Drug treatments for covid-19: living systematic review and network
BMJ: first published as 10.1136/bmj.m2980 on 30 July 2020. Downloaded from http://www.bmj.com/ on 16 July 2021 by guest. Protected by copyright.
Correspondence to: R Siemieniuk
reed.siemieniuk@medportal.ca meta-analysis
https://orcid.org/0000-0002-3725-3031
Cite this as: BMJ 2020;370:m2980 Reed AC Siemieniuk, 1 , * Jessica J Bartoszko, 1 , * Long Ge, 2 , * Dena Zeraatkar, 1 , * Ariel Izcovich, 3 Elena Kum, 1
http://dx.doi.org/10.1136/bmj.m2980 Hector Pardo-Hernandez, 4, 5 Anila Qasim, 1 Juan Pablo Díaz Martinez, 1 Bram Rochwerg, 1, 6
Accepted: 2319 March July 2020 2021
Francois Lamontagne, 7 Mi Ah Han, 8 Qin Liu, 9, 10 Arnav Agarwal, 1, 11 Thomas Agoritsas, 1, 12 Derek K Chu, 1,
Published: 30 July 2020 6
Rachel Couban, 13 Ellen Cusano, Andrea Darzi, 1 Tahira Devji, 1 Bo Fang, 9, 10 Carmen Fang, 15
Signe Agnes Flottorp, 16, 17 Farid Foroutan, 1, 18 Maryam Ghadimi, 1 Diane Heels-Ansdell, 1 Kimia Honarmand, 19
Liangying Hou, 2 Xiaorong Hou, 20 Quazi Ibrahim, 1 Assem Khamis, 33 Bonnie Lam, 1 Mark Loeb, 1, 6
Maura Marcucci, 1, 6 Shelley L McLeod, 21, 22 Sharhzad Motaghi, 1 Srinivas Murthy, 23 Reem A Mustafa, 1, 24
John D Neary, 6 Gabriel Rada, 25, 26 Irbaz Bin Riaz, 27 Behnam Sadeghirad, 1, 13 Nigar Sekercioglu, 1
Lulu Sheng, 9, 10 Ashwini Sreekanta, 1 Charlotte Switzer, 1 Britta Tendal, 28 Lehana Thabane, 1
George Tomlinson, 29 Tari Turner, 28 Per O Vandvik, 15 Robin WM Vernooij, 30, 31 Andrés Viteri-García, 25, 32
Ying Wang, 1 Liang Yao, 1 Zhikang Ye, 1 Gordon H Guyatt, 1, 6 Romina Brignardello-Petersen1
ABSTRACT (30 fewer per 1000, 46 fewer to 10 fewer, moderate
OBJECTIVE certainty) and may reduce length of hospital stay (4.3
To compare the effects of treatments for coronavirus days fewer, 8.1 fewer to 0.5 fewer, low certainty), but
disease 2019 (covid-19). whether or not they reduce mortality is uncertain (15
DESIGN fewer per 1000, 30 fewer to 6 more, low certainty).
Living systematic review and network meta-analysis. Janus kinase inhibitors may reduce mortality (50
DATA SOURCES fewer per 1000, 84 fewer to no difference, low
certainty), mechanical ventilation (46 fewer per 1000,
WHO covid-19 database, a comprehensive
74 fewer to 5 fewer, low certainty), and duration of
multilingual source of global covid-19 literature, up
mechanical ventilation (3.8 days fewer, 7.5 fewer to
to 1 March 2021 and six additional Chinese databases
0.1 fewer, moderate certainty). The impact of
up to 20 February 2021. Studies identified as of 12
remdesivir on mortality and most other outcomes is
February 2021 were included in the analysis.
uncertain. The effects of ivermectin were rated as
STUDY SELECTION
very low certainty for all critical outcomes, including
Randomised clinical trials in which people with
mortality. In patients with non-severe disease,
suspected, probable, or confirmed covid-19 were
colchicine may reduce mortality (78 fewer per 1000,
randomised to drug treatment or to standard care or
110 fewer to 9 fewer, low certainty) and mechanical
placebo. Pairs of reviewers independently screened
ventilation (57 fewer per 1000, 90 fewer to 3 more,
potentially eligible articles.
low certainty). Azithromycin, hydroxychloroquine,
METHODS
lopinavir-ritonavir, and interferon-beta do not appear
After duplicate data abstraction, a bayesian network to reduce risk of death or have an effect on any other
meta-analysis was conducted. Risk of bias of the patient-important outcome. The certainty in effects
included studies was assessed using a modification for all other interventions was low or very low.
of the Cochrane risk of bias 2.0 tool, and the certainty CONCLUSION
of the evidence using the grading of
Corticosteroids and interleukin-6 inhibitors probably
recommendations assessment, development, and
confer important benefits in patients with severe
evaluation (GRADE) approach. For each outcome,
covid-19. Janus kinase inhibitors appear to have
interventions were classified in groups from the most
promising benefits, but certainty is low. Azithromycin,
to the least beneficial or harmful following GRADE
hydroxychloroquine, lopinavir-ritonavir, and
guidance.
interferon-beta do not appear to have any important
RESULTS
benefits. Whether or not remdesivir, ivermectin, and
196 trials enrolling 76 767 patients were included; other drugs confer any patient-important benefit
111 (56.6%) trials and 35 098 (45.72%) patients are remains uncertain.
new from the previous iteration; 113 (57.7%) trials SYSTEMATIC REVIEW REGISTRATION
evaluating treatments with at least 100 patients or
This review was not registered. The protocol is
20 events met the threshold for inclusion in the
publicly available in the supplementary material.
analyses. Compared with standard care,
READERS’ NOTE
corticosteroids probably reduce death (risk difference
This article is a living systematic review that will be
20 fewer per 1000 patients, 95% credible interval 36
updated to reflect emerging evidence. Updates may
fewer to 3 fewer, moderate certainty), mechanical
occur for up to two years from the date of original
ventilation (25 fewer per 1000, 44 fewer to 1 fewer,
publication. This is the fourth version of the original
moderate certainty), and increase the number of days
article published on 30 July 2020 (BMJ
free from mechanical ventilation (2.6 more, 0.3 more
2020;370:m2980), and previous versions can be
to 5.0 more, moderate certainty). Interleukin-6
found as data supplements. When citing this paper
inhibitors probably reduce mechanical ventilation
the bmj | BMJ 2020;370:m2980 | doi: 10.1136/bmj.m2980 1

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please consider adding the version number and date of access for • Siemieniuk RAC, Bartoszko JJ, Ge L, et al. Drug treatments for covid-19:
clarity.
living systematic review and network meta-analysis [Update 3]. BMJ
Introduction 2020;370:m2980, doi:10.1136/bmj.m2980
As of 28 March 2021, more than 127 million people have been infected ‐ Review and network meta-analysis of all available randomised
with severe acute respiratory syndrome coronavirus virus 2 trials that assessed drug treatments for covid-19
(SARS-CoV-2), the virus responsible for coronavirus disease 2019 • MAGICapp (https://app.magicapp.org/#/guideline/nBkO1E)
(covid-19); of these, more than 2.7 million have died.1 Despite global
efforts to identify effective interventions for the prevention and ‐ Expanded version of the methods, processes, and results with
treatment of covid-19, which have resulted in 2800 trials completed multilayered recommendations, evidence summaries, and decision
or underway,2 evidence for effective treatment remains limited. aids for use on all devices
• Author website (https://www.covid19lnma.com)
Faced with the pressures of a global pandemic, healthcare workers
around the world are prescribing drugs off-label for which there is ‐ Interim updates will be available here
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 Methods
the challenges of interpreting the results from trials that are being A protocol provides the detailed methods of this systematic review,
published at a rate never encountered previously. This environment including all updates (see supplementary appendix). We report this
makes it necessary to produce well developed summaries that living systematic review following the guidelines of the preferred
distinguish more trustworthy evidence from less trustworthy reporting items for systematic reviews and meta-analyses (PRISMA)
evidence. checklist for network meta-analyses.11 A living systematic review
Living systematic reviews deal with the main limitation of traditional is a cumulative synthesis that is updated regularly as new evidence
reviews—that of providing an overview of the relevant evidence becomes available.12 The linked BMJ Rapid Recommendations
only at a specific time.4 This is crucial in the context of covid-19, in guideline panels approved all decisions relevant to data synthesis.
which the best evidence is constantly changing. The ability of a Eligibility criteria
living network meta-analysis to present a complete, broad, and
updated view of the evidence makes it the best type of evidence We included randomised clinical trials in people with suspected,
synthesis to inform the development of practice recommendations. probable, or confirmed covid-19 that compared drugs for treatment
Network meta-analysis, rather than pairwise meta-analysis, provides against one another or against no intervention, placebo, or standard
useful information about the comparative effectiveness of treatments care. We included trials regardless of publication status (peer
that have not been tested head to head. The lack of such direct reviewed, in press, or preprint) or language. No restrictions were
comparisons is certain to limit inferences in the covid-19 setting. applied based on severity of illness or setting and we included trials
Moreover, the incorporation of indirect evidence can strengthen of Chinese medicines if the drug comprised one or more specific
evidence in comparisons that were tested head to head.5 molecules with a defined molecular weight dosing.
In this living systematic review and network meta-analysis we We excluded randomised trials evaluating vaccination, blood
compare the effects of drug treatments for covid-19. This review is products and antibody-based antiviral therapies (such as
part of the BMJ Rapid Recommendations project, a collaborative virus-specific monoclonal antibodies), nutrition, traditional Chinese
effort from the MAGIC Evidence Ecosystem Foundation herbal or alternative medicines that include more than one molecule
(www.magicproject.org) and The BMJ.6 This living systematic review or a molecule without specific molecular weighted dosing, and
and network meta-analysis informs World Health Organization and non-drug supportive care interventions. Trials that evaluated these
BMJ Rapid Recommendations6 on covid-19 treatments, initiated to interventions were identified and categorised separately.
provide trustworthy, actionable, and living guidance to clinicians Information sources
and patients soon after new and potentially practice-changing
We perform daily searches from Monday to Friday in the World
evidence becomes available. The first covid-19 BMJ Rapid
Health Organization (WHO) covid-19 database for eligible studies
Recommendation considered the role of remdesivir.7 Subsequent
– a comprehensive multilingual source of global literature on
guidance addressed the role of hydroxychloroquine, corticosteroids,
covid-19. Prior to its merge with the WHO covid-19 database on 9
lopinavir-ritonavir, and updated guidance for remdesivir (box 1).8
October 2020, we performed daily searches from Monday to Friday
The latest recommendation covers ivermectin. This living network
in the US Centers for Disease Control and Prevention (CDC) COVID-19
meta-analysis is the fourth version. The previous versions are
Research Articles Downloadable Database for eligible studies.13 The
available in the supplementary material. Drugs for prophylaxis9 10
database includes, but is not limited to the following 25
and antibody-based treatments will be addressed separately.
bibliographic and grey literature sources: Medline (Ovid and
Box 1: Linked resources in this BMJ Rapid Recommendations cluster PubMed), PubMed Central, Embase, CAB Abstracts, Global Health,
PsycInfo, Cochrane Library, Scopus, Academic Search Complete,
• Siemieniuk R, Rochwerg B, Agoritsas T, et al. A living WHO guideline Africa Wide Information, CINAHL, ProQuest Central, SciFinder, the
on drugs for covid-19 [Update 3]. BMJ 2020;370:m3379, Virtual Health Library, LitCovid, WHO covid-19 website, CDC
doi:10.1136/bmj.m3379 covid-19 website, Eurosurveillance, China CDC Weekly, Homeland
‐ Living WHO BMJ Rapid Recommendations guidance on drugs for Security Digital Library, ClinicalTrials.gov, bioRxiv (preprints),
covid-19 medRxiv (preprints), chemRxiv (preprints), and SSRN (preprints).
• World Health Organization. Therapeutics and COVID-19. Living
The supplementary material contains the WHO literature search
strategy.
guideline. 31 March 2021. https://www.who.int/publica-
tions/i/item/therapeutics-and-covid-19-living-guideline. The daily searches are designed to match the update schedule of
the database and to capture eligible studies the day of or the day
2 the bmj | BMJ 2020;370:m2980 | doi: 10.1136/bmj.m2980

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after publication. To identify randomised trials, we filtered the because both may be surrogates for transmissibility, although this
results from the WHO’s database through a validated and highly is uncertain.18
sensitive machine learning model.14 We tracked preprints of
Mechanical ventilation includes both invasive and non-invasive
randomised trials for updates and through publication: when data
mechanical ventilation. We used a hierarchy for the outcome
was discrepant, we used the most recent data.
mechanical ventilation in which we preferentially used the total
In addition, we search six Chinese databases monthly: Wanfang, number of patients who received mechanical ventilation over the
Chinese Biomedical Literature, China National Knowledge study. We used the number of patients ventilated at the time point
Infrastructure, VIP, Chinese Medical Journal Net (preprints), and that the largest number of the patients were ventilated if the trial
ChinaXiv (preprints). We adapted the search terms for covid-19 reported the number of patients ventilated at specific timepoints.
developed by the CDC to the Chinese language. For the Chinese
Risk of bias within individual studies
literature search, we also included search terms for randomised
trials. The supplementary appendix includes the Chinese literature For each eligible trial, reviewers, following training and calibration
search strategy. exercises, used a revision of the Cochrane tool for assessing risk of
bias in randomised trials (RoB 2.0)19 to rate trials as either at (i) low
We monitor living evidence retrieval services on an ongoing basis.
risk of bias, (ii) some concerns—probably low risk of bias, (iii) some
These included the Living Overview of the Evidence (L-OVE)
concerns—probably high risk of bias, or (iv) high risk of bias, across
COVID-19 Repository by the Epistemonikos Foundation15 and the
the following domains: bias arising from the randomisation process;
Systematic and Living Map on COVID-19 Evidence by the Norwegian
bias owing to departures from the intended intervention; bias from
Institute of Public Health, in collaboration with the Cochrane Canada
missing outcome data; bias in measurement of the outcome; bias
Centre at McMaster University.16
in selection of the reported results, including deviations from the
We searched WHO information sources from 1 December 2019 to 1 registered protocol; bias due to competing risks; and bias arising
March 2021, and the Chinese literature from conception of the from early termination for benefit. We rated trials at high risk of
databases to 20 February 2021. bias overall if one or more domains were rated as probably high
risk of bias or as high risk of bias and as low risk of bias if all
Study selection
domains were rated as probably low risk of bias or low risk of bias.
Using a systematic review software, Covidence,17 pairs of reviewers, For ivermectin, the linked guideline panel also requested a review
following training and calibration exercises, independently screened of the study protocols to check that trial registration occurred prior
all titles and abstracts, followed by full texts of trials that were to patient recruitment. Reviewers resolved discrepancies by
identified as potentially eligible. A third reviewer adjudicated discussion and, when not possible, with adjudication by a third
conflicts. party.
Data collection Data synthesis
For each eligible trial, pairs of reviewers, following training and We conducted the network meta-analysis using a bayesian
calibration exercises, extracted data independently using a framework.20 In this report, we conducted a network meta-analysis
standardised, pilot tested data extraction form. Reviewers collected of drug treatments for covid-19 that included all patients, regardless
information on trial characteristics (trial registration, publication of severity of disease.
status, study status, design), patient characteristics (country, age,
sex, smoking habits, comorbidities, setting and type of care, and Summary measures
severity of covid-19 symptoms for studies of treatment), and We summarised the effect of interventions on dichotomous outcomes
outcomes of interest (means or medians and measures of variability using the odds ratio and corresponding 95% credible interval. For
for continuous outcomes and the number of participants analysed continuous outcomes, we used the mean difference and
and the number of participants who experienced an event for corresponding 95% credible interval in days for ICU length of stay,
dichotomous outcomes). Reviewers resolved discrepancies by length of hospital stay, and duration of mechanical ventilation
discussion and, when necessary, with adjudication by a third party. because we expected similar durations across randomised trials.
We updated the data collected from included preprints as soon as For time to symptom resolution and time to viral clearance, we first
the peer review publication became available. performed the analyses using the relative effect measure ratio of
means and corresponding 95% credible interval before calculating
Outcomes of interest were selected based on importance to patients
the mean difference in days because we expected substantial
and were informed by clinical expertise in the systematic review
variation between studies.21
team and in the linked guideline panel responsible for the WHO-BMJ
Rapid Recommendations.7 8 The panel includes unconflicted clinical Treatment nodes
and methodology experts, recruited to ensure global representation,
Treatments were grouped into common nodes based on molecule
and patient-partners. All panel members rated outcomes from 1 to
and not on dose or duration. For intervention arms with more than
9 based on importance to individual patients (9 being most
one drug, we created a separate node. Chloroquine and
important), and we included any outcome rated 7 or higher by any
hydroxychloroquine were included in the same node for covid-19
panel member. Selected outcomes included mortality (closest to 90
specific effects and separated for disease independent adverse
days), mechanical ventilation (total number of patients, over 90
effects. We drew network plots using the networkplot command of
days), adverse events leading to discontinuation (within 28 days),
Stata version 15.1 (StataCorp, College Station, TX), with thickness
viral clearance (closest to 7 days, 3 days either way), admission to
of lines between nodes and size of the nodes based on the inverse
hospital, duration of hospital stay, intensive care unit (ICU) length
of the variance of the direct comparison.22
of stay, duration of mechanical ventilation, time to symptom
resolution or clinical improvement, time to viral clearance, and
days free from mechanical ventilation (within 28 days). Viral
clearance at seven days and time to viral clearance were included

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Statistical analysis mechanical ventilation, duration of hospitalisation, and ICU length

of stay we used baseline risks from the International Severe Acute
For most outcomes, we conducted network meta-analyses and
Respiratory and Emerging Infection COVID-19 database.31 For all
pairwise meta-analyses using a bayesian framework with the same
other outcomes, we used the median from all studies in which
priors for the variance and effect parameters.20 In previous versions,
participants received standard of care to calculate the baseline risk
we used fixed effects for some outcomes because data was sparse
for each outcome, with each study weighed equally. We calculated
or dominated by a single trial. As per our protocol, we used random
absolute effects using the transitive risks model32 using R2jags
effects for all outcomes. We used a plausible prior for variance
package in R.33
parameter and a uniform prior for the effect parameter suggested
in a previous study based on empirical data.23 For all analyses, we For each outcome, we classified treatments in groups from the most
used three Markov chains with 100 000 iterations after an initial to the least effective using the minimally contextualised framework,
burn-in of 10 000 and a thinning of 10. We used node splitting which focuses on the treatment effect estimates and the certainty
models to assess local incoherence and to obtain indirect of the evidence.34
estimates.24 All network meta-analyses were performed using the
Subgroup and sensitivity analysis
gemtc package of R version 3.6.3 (RStudio, Boston, MA)25 and all
pairwise meta-analyses using the bayesmeta package.20 Subgroup analyses were performed for specific interventions of
interest at the direction of the linked WHO living guideline panel.
In the first iteration of this living network meta-analysis, some
In this iteration, we performed subgroup analyses for ivermectin
treatment nodes with few total participants and few total events
and interleukin-6 inhibitors for the pairwise comparison against
resulted in highly implausible and extremely imprecise effect
standard care. Previous iterations included subgroup analyses for
estimates. We therefore decided to include only treatments that
corticosteroids, hydroxychloroquine, lopinavir-ritonavir, and
included at least 100 patients or had at least 20 events, based on
remdesivir. The panel requested subgroup analyses by age (children
our impression of the minimum number of patients/events to
v non-elderly adults v elderly), severity (non-severe v severe v
possibly provide meaningful results.
critical), concomitant use of corticosteroids (for interleukin-6
Certainty of the evidence inhibitors), dose (for ivermectin; by cumulative dose and by single
v multiple dosing regimens), higher v lower C reactive protein (for
We assessed the certainty of evidence using the grading of
interleukin-6 inhibitors), and risk of bias (for ivermectin) for the
recommendations assessment, development and evaluation
following outcomes: adverse events leading to discontinuation,
(GRADE) approach for network meta-analysis.5 26 27 Two people
hospital admission (for ivermectin), mortality, and mechanical
with experience in using GRADE rated each domain for each
ventilation. We performed bayesian hierarchical meta-regression
comparison separately and resolved discrepancies by consensus.
with study as a random effect. Where possible, we performed within
We rated the certainty for each comparison and outcome as high,
rather than between trial analyses.
moderate, low, or very low, based on considerations of risk of bias,
inconsistency, indirectness, publication bias, intransitivity, Patient and public involvement
incoherence (difference between direct and indirect effects), and
Patients were involved in outcome selection, interpretation of
imprecision.27 We rated down for risk of bias if the interpretation
results, and the generation of parallel recommendations, as part of
of the effect would change if only studies at low risk of bias would
the BMJ Rapid Recommendations initiative.
have been considered. For example, if the credible interval of the
pooled effect from studies at low risk of bias would have crossed Results
the threshold for imprecision, we rated down for risk of bias.
After screening 31 848 titles and abstracts and 611 full texts, 206
Judgments of imprecision for this systematic review were made
unique randomised trials from 189 publications were identified that
using a minimally contextualised approach, with a null effect as
evaluated drug treatments as of 1 March 2021 (fig 1). A table of
the threshold of importance.28 The minimally contextualised
excluded full texts is provided in the supplementary appendix.
approach considers only whether credible intervals include the null
Searches of living evidence retrieval services identified 84
effect and thus does not consider whether plausible effects, captured
publications of eligible randomised trials, which were reconciled
by credible intervals, include both important and trivial effects.28
with our formal search strategy when necessary. One hundred and
To evaluate certainty of no benefit (or no effect), we used a 2% risk
thirty randomised trials have been published in peer reviewed
difference threshold of the 95% credible interval for mortality and
journals, 53 as preprints, 17 within three meta-analyses, three as
mechanical ventilation. In other words, if the entire 95% credible
correspondence from study authors, one as a presentation, one as
interval was within 2% of the null effect, we would not rate down
a conference abstract and one as a clinical trial registry reporting
for imprecision. We decided on this preliminary threshold based
results. Most of the trials were registered (181/206; 88%), published
on a survey of the authors. Interim updates and additional study
in English (197/206; 96%), and evaluated treatment in patients
data will be posted on our website (www.covid19lnma.com).
admitted to hospital with covid-19 (168/206; 82%). China, Iran,
Interpretation of results Brazil, United States and Spain were the five most common countries
in which randomised trials were conducted. Eighty-four different
To facilitate interpretation of the results, we calculated absolute
drug treatments were evaluated. The five most common drug
effects for outcomes in which the summary measure was an odds
treatments evaluated, based on number of randomised trials, were
ratio or ratio of means. When available, we inferred baseline risk
(hydroxy)chloroquine (37/206; 18%), ivermectin (16/206, 7.8%),
in the usual care group for each outcome from representative
corticosteroids (14/206; 6.8%), lopinavir-ritonavir (14/206, 6.8%)
observational data (supplementary material). For mortality, we
and interleukin-6 inhibitors (tocilizumab and sarilumab) (11/206;
used data from the CDC on patients who were hospitalised with
5.3%).
covid-19.29 30 For mechanical ventilation, duration of invasive

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Fig 1 | Study selection
One hundred and ninety six randomised trials that evaluated drug that evaluated different durations or doses of the same drug, because
treatments were identified up until the date of analysis (12 February both arms would have been classified within the same treatment
2021) (table 1; supplementary appendix).35 -211 Several of these trials node; two trials145 146 with insufficient data; and ten
could not be included in the analysis: nine trials69 77 90 129 130 158 181 212 trials38 56 87 101 172 192 198 204 209 211 that reported no outcomes of

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interest. Of the remaining 175 trials, we analysed 113 (69.8%) presents the characteristics of the 196 included studies. Additional
reporting on treatments with at least 100 patients or 20 events to study characteristics, outcome data, and risk of bias assessments
avoid implausible and extremely imprecise estimates. Table 1 for each study are available in the supplementary appendix.
Table 1 | Study characteristics. Values are numbers (percentages) of studies unless stated otherwise
Characteristic
Registered 175 (89.3%)
Publication status:
Preprint 52 (26.5%)
Published 121 (61.7%)
Unpublished 23 (11.7%)
Median (SD) No of patients 87.5 (145.2)
Country:
China 38 (19.4%)
Iran 28 (14.3%)
Brazil 26 (13.3%)
United States 26 (13.3%)
Spain 19 (9.7%)
Intensity of care:
Outpatient 33 (16.8%)
Inpatient 156 (79.6%)
ICU 8 (4.1%)
Severity:
Mild/moderate 57 (29.1%)
Severe/critical 35 (17.9%)
Median (SD) percentage of patients mechanically ventilated at baseline 3.9 (37.7)
Table 2 describes the 10 randomised trials that were identified after

the data analysis and that will be included in the next update.213 -222
Table 2 | Randomised trials identified after data analysis, which will be included in the next update
Study Publication status, registration No No of participants Treatments
Yadegarinia 2020213 Published, NR 34 Umifenovir; standard care
Balykova 2020214 Published, NCT04542694 39 Favipiravir; standard care
Thomas 2021215 Published, NCT04342728 214 Zinc, ascorbic acid; zinc; ascorbic acid; standard
care
Baratt-Due 2021217 Preprint, NCT04321616 185 Hydroxychloroquine; remdesivir; standard care
Purwati 2021222 Published, INA-TX6YYSS 754 Lopinavir-ritonavir, azithromycin;
lopinavir-ritonavir, doxycycline;
hydroxychloroquine, azithromycin
Jamaati 2021219 Published, IRCT20151227025726N17 50 Dexamethasone; standard care
Migled 2020220 Published, NR 60 Methisoprinol; standard care
Balykova 2020216 Published, NR 200 Favipiravir; standard care
Patel 2021221 Published, ACTRN12620000454976 33 Zinc; placebo
Cadegiani 2021218 Published, NR 236 Proxalutamide; placebo
Of the randomised trials included in the analyses, eight did not were allocated by preference; the authors shared outcome data with
have publicly accessible protocols or registrations. Of the trials with us among patients who were truly randomised.64
publicly accessible protocols or registrations, 79 reported results
Thirty five studies were initially posted as preprints and
for one or more of our outcomes of interest that were not prespecified
subsequently published after peer review. The supplementary
in protocols or registrations. No other discrepancies between the
material presents the differences between study preprint and peer
reporting of our outcomes of interest in trial reports and protocols
reviewed publications. Eighteen studies had discrepancies in
or registrations were noted. One trial did not stratify reporting of
outcome reporting between the preprint and peer-reviewed
outcomes for those who were truly randomised versus those who
publication. Fourteen studies had discrepancies with patient

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baseline characteristics. Six studies had discrepancies in reporting judged at low risk of bias in all domains. All other studies had
that led to changes in risk of bias ratings. No substantive differences probably high or high risk of bias in at least one of the domains.
were found for 11 studies.
Effects of the interventions
All analyses reached convergence based on trace plots and a
The supplementary material presents the network plots depicting
Brooks-Gelman-Rubin statistic less than 1.05, except comparisons
the interventions included in the network meta-analysis of each
including umifenovir for mortality because no patients randomised
outcome. Figure 2 presents a summary of the effects of the
to either of these drugs died, interleukin-6 inhibitors and
interventions on the outcomes. The supplementary appendix also
doxycycline with ivermectin for adverse events, proxalutamide for
presents detailed relative and absolute effect estimates and certainty
hospital admission, and sulodexide for clinically important bleeding.
of the evidence for all comparisons and outcomes. We did not detect
Risk of bias in included studies statistical incoherence in any of the network meta-analyses.
The supplementary material presents the assessment of risk of bias
of the included studies for each outcome. Thirty-seven studies were

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Fig 2 | Summary of effects compared with standard care
Mortality hundred and one trials with 67 491 participants met the threshold
of analysing treatments with a minimum of 100 patients or 20 events
One hundred and forty eight randomised trials including 71 468
and were included in the network meta-analysis (supplementary
participants reported mortality (supplementary appendix). One
appendix). Figure 3 shows the network plot for mortality, with each

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edge representing a direct comparison between two interventions. with non-severe disease; odds ratio 0.37, 0.13 to 0.92; low certainty),
The most common interventions were standard care/placebo (95 and janus kinase (JAK) inhibitors (baricitinib and ruxolitinib, odds
trials, 36 166 participants), hydroxychloroquine (33 trials, 4902 ratio 0.58, 0.33 to 1.00; low certainty). Patients randomised to
participants), remdesivir (4 trials, 3826 participants), azithromycin (odds ratio 0.97, 0.78 to 1.19; low certainty),
lopinavir-ritonavir (7 trials, 3557 participants), interleukin-6 hydroxychloroquine (odds ratio 1.09, 0.93 to 1.27; moderate certainty
inhibitors (9 trials, 3642 participants), azithromycin (6 trials, 2982 of no benefit), lopinavir-ritonavir (odds ratio 1.02, 0.85 to 1.23; low
participants), and corticosteroids (11 trials, 2975 participants). certainty), full dose anticoagulation (odds ratio 0.98, 0.72 to 1.32;
Random effects network meta-analysis showed that corticosteroids low certainty), and interferon beta (odds ratio 0.99, 0.71 to 1.26; low
probably reduce deaths compared with standard care (odds ratio certainty) did not have a lower risk of death than those randomised
0.83, 95% credible interval 0.69 to 0.98; moderate certainty) (fig 2). to standard care. Although the 95% credible intervals did not include
Evidence was less certain for remdesivir (odds ratio 0.90, 0.72 to harm for ivermectin and recombinant human granulocyte colony
1.11; low certainty), interleukin-6 inhibitors (odds ratio 0.87, 0.74 stimulating factor (rhG-CSF), the evidence was very low certainty
to 1.05; low certainty), colchicine (evidence primarily from patients because of risk of bias and extremely low total number of events.
Fig 3 | Network plot for mortality. The size of the circles is proportional to the number of patients randomised to that intervention and the size of the lines is proportional to
the inverse of the standard error of the effect estimate.
Mechanical ventilation low certainty). Patients randomised to several interventions did not
have a lower chance of mechanical ventilation compared to standard
Eighty seven randomised trials including 56 560 participants
care: hydroxychloroquine (odds ratio 1.15, 0.92 to 1.46; low
reported mechanical ventilation (supplementary appendix). Sixty
certainty), azithromycin (odds ratio 0.95, 0.69 to 1.28),
six trials with 55 174 participants met the threshold of analysing
lopinavir-ritonavir (odds ratio 1.10, 0.84 to 1.42; low certainty). The
treatments with a minimum of 100 patients or 20 events and were
effect of ivermectin was very uncertain (odds ratio 0.51, 0.13 to 1.86;
included in the network meta-analysis (supplementary appendix).
very low certainty).
The most common interventions were standard care (64 trials, 30
339 participants), remdesivir (4 trials, 3433 participants), Adverse events leading to discontinuation
hydroxychloroquine (11 trials, 3155 participants), lopinavir-ritonavir
Fifty nine randomised trials including 10 314 participants reported
(4 trials, 3086 participants), interleukin-6 inhibitors (9 trials, 3056
adverse effects leading to discontinuation of the study drug
participants), and corticosteroids (8 trials, 2425 participants).
(supplementary appendix). Twenty five trials with 6999 participants
Random effects network meta-analysis showed that, compared with met the threshold of analysing treatments with a minimum of 100
standard care, two interventions probably reduce risk of mechanical patients or 20 events and were included in the network
ventilation: corticosteroids (odds ratio 0.76, 0.59 to 0.99; moderate meta-analysis (supplementary appendix). The most common
certainty) and interleukin-6 inhibitors (odds ratio 0.72, 0.57 to 0.90; interventions were standard care (24 trials, 2866 participants),
moderate certainty) (fig 2). Treatments that may reduce mechanical hydroxychloroquine (8 trials, 893 participants), and remdesivir (2
ventilation, with lower certainty, were remdesivir (odds ratio 0.75, trials, 699 participants). Moderate certainty evidence showed that
0.52 to 0.98; low certainty), JAK inhibitors (odds ratio 0.57, 0.33 to remdesivir did not result in a substantial increase in adverse effects
0.95; low certainty), and colchicine (odds ratio 0.48, 0.21 to 1.03; leading to drug discontinuation compared with standard care (odds

RESEARCH
ratio 1.00, 0.36 to 4.06). Certainty in evidence for all of the other ICU length of stay
interventions was low or very low (fig 2).
Fourteen randomised trials including 1784 participants reported
Viral clearance at 7 days (± 3 days) length of ICU stay (supplementary appendix). Three interventions
had at least 100 patients including standard care (3 trials, 609
Forty three randomised trials including 5136 participants measured
participants), interleukin-6 inhibitors (2 trials, 598 participants),
viral clearance with polymerase chain reaction cut-off points
and corticosteroids (1 trial, 278 participants). Most of these trials
(supplementary appendix). Thirty one trials with 4383 participants
did not report estimates of variance. Therefore, we did not perform
met the threshold of analysing treatments with a minimum of 100
a meta-analysis (fig 2). The REMAP-CAP trial found a large reduction
patients or 20 events and were included in the network
in median duration of ICU stay with interleukin-6 inhibitors (−9
meta-analysis (supplementary appendix). The most common
days).93
interventions were standard care (29 trials, 1741 participants),
hydroxychloroquine (10 trials, 756 participants), lopinavir-ritonavir Duration of mechanical ventilation
(6 trials, 450 participants), and ivermectin (7 trials, 291 participants).
Thirteen randomised trials including 1138 participants reported
We did not find evidence that any of the interventions increased
duration of mechanical ventilation (supplementary appendix). Four
the rate of viral clearance: hydroxychloroquine (odds ratio 1.01,
trials with 966 participants met the threshold of analysing
0.69 to 1.56; very low certainty), lopinavir-ritonavir (odds ratio 0.92,
treatments with a minimum of 100 patients and were included in
0.50 to 1.49; very low certainty), ivermectin (odds ratio 1.62, 0.95 to
the network meta-analysis (supplementary appendix). The included
2.86; low certainty), and remdesivir (odds ratio 1.06, 0.35 to 3.20)
(fig 2).
remdesivir (2 trials, 194 participants), corticosteroids (1 trial, 151
Admission to hospital participants), and JAK inhibitors (1 trial, 100 participants). JAK
inhibitors probably reduce the duration of mechanical ventilation
Sixteen randomised trials including 8307 participants reported
(−3.8 days, −7.5 to −0.1, moderate certainty). There was no
admission to hospital among outpatients at baseline (supplementary
convincing evidence that corticosteroids (mean difference −1.4 days,
appendix). Nine trials with 7655 participants met the threshold of
−3.2 to 0.4; low certainty) or remdesivir (mean difference −1.4 days,
analysing treatments with a minimum of 100 patients or 20 events
−3.2 to 1.5; low certainty) reduce duration of mechanical ventilation
and were included in the network meta-analysis (supplementary
(fig 2).
appendix). The most common interventions were standard care (9
trials, 3603 participants), colchicine (1 trial, 2235 participants), Ventilator-free days
hydroxychloroquine (4 trials, 668 participants), and
Ten randomised trials including 2495 participants reported
lopinavir-ritonavir (1 trial, 244 participants). There was insufficient
ventilator-free days (supplementary appendix). Seven studies with
evidence to know if any of the interventions reduce hospitalisation
1835 participants met the threshold of analysing treatments with a
(fig 2).
minimum of 100 patients and were included in the network
Venous thromboembolism meta-analysis (supplementary appendix). The most common
Two trials including a total of 2523 participants43 126 reported venous
interleukin-6 inhibitors (3 trials, 652 participants), azithromycin (2
thromboembolism in patients who received full dose anticoagulation
trials, 155 participants), and corticosteroids (1 trial, 151 participants).
versus prophylactic dose anticoagulation (odds ratio 0.57, 0.21 to
Compared with standard care, corticosteroids probably increase
1.73; low certainty).
ventilator-free days (mean difference 2.6 days, 0.3 to 4.9; moderate
Clinically important bleeding certainty). There was no evidence that interleukin-6 inhibitors (low
Two trials including 2523 participants43 126 reported clinically certainty), hydroxychloroquine (very low certainty), or azithromycin
important bleeding in patients who received full dose (very low certainty) increase ventilator-free days (fig 2).
anticoagulation versus prophylactic dose anticoagulation (odds Time to symptom resolution
ratio 2.00, 0.70 to 5.98; low certainty).
Fifty nine randomised trials including 9846 participants reported
Duration of hospital stay time to symptom resolution (supplementary appendix). Thirty one
Eighty two randomised trials including 54 277 participants reported trials including 7639 participants met the threshold of analysing
duration of hospital stay (supplementary appendix). Fifty eight treatments with a minimum of 100 patients and were included in
trials with 52 518 participants met the threshold of analysing the network meta-analysis (supplementary appendix). The most
treatments with a minimum of 100 patients and were included in common interventions were standard care (29 trials, 3155
the network meta-analysis (supplementary appendix). The most participants), remdesivir (3 trials, 1083 participants), interleukin-6
common interventions were standard care (56 trials, 29 443 inhibitors (5 trials, 1070 participants), hydroxychloroquine (9 trials,
participants), interleukin-6 inhibitors (9 trials, 3583 participants), 706 participants), and JAK inhibitors (2 trials, 535 participants).
remdesivir (4 trials, 3826 participants), hydroxychloroquine (12 Favipiravir may reduce time to symptom resolution (ratio of mean
trials, 3226 participants), azithromycin (3 trials, 2780 participants), days between intervention and standard care 0.62, 0.48 to 0.81; low
and corticosteroids (5 trials, 2669 participants). Compared with certainty). The 95% credible interval for all other interventions
standard care, duration of hospitalisation was shorter in patients included no effect, and certainty was low or very low for all
who received interleukin-6 inhibitors (mean difference −4.5 days, interventions except remdesivir (ratio of mean days between
−6.7 to −2.3; low certainty), colchicine (mean difference −1.7 days, intervention and standard care, 0.82, 0.64 to 1.06; moderate
−2.8 to −0.7; low certainty), and favipiravir (mean difference −1.3 certainty) (fig 2).
days, −2.4 to −0.1; low certainty). There was no evidence that any Time to viral clearance
of the other interventions reduce length of stay, but certainty was
Thirty-five randomised trials including 2933 participants reported
low or very low (fig 2).
time to viral clearance (supplementary appendix). Thirteen trials

RESEARCH
including 1444 participants met the threshold of analysing These results were driven in large part by the COLCORONA study,185
treatments with at least 100 patients and were included in the which enrolled outpatients with non-severe disease. The RECOVERY
network meta-analysis (supplementary appendix). The treatments trial randomised 11 162 inpatients to colchicine or standard care
analysed include standard care (12 trials, 485 participants), and was not included in this analysis because the study was
hydroxychloroquine (7 trials, 482 participants), favipiravir (4 trials, published after conducting the analysis. Colchicine did not appear
243 participants), and ivermectin (3 trials, 234 participants). The to have an effect on mortality in the RECOVERY trial, which was
95% credible interval for all other interventions included no effect, limited to inpatients with mostly severe or critical disease.224
and certainty was low or very low for all interventions (fig 2). Substantial uncertainty about the effect of colchicine on patients
with non-severe disease remains.
Subgroups
Several small trials have examined the effect of ivermectin, and the
Previous iterations of this living systematic review explored
pooled result suggests a possible reduction in mortality. However,
subgroup effects for remdesivir, lopinavir-ritonavir,
the data are limited by extremely few events (very serious
hydroxychloroquine, and corticosteroids. In this iteration, we
imprecision) and serious risk of bias (several of the studies were
explored subgroup effects for ivermectin and interleukin-6 inhibitors
not pre-registered prior to enrolling patients or were not adequately
(supplementary material). For ivermectin, there was no difference
blinded). The effect of ivermectin on all other outcomes was similarly
in relative effects for any of the subgroups tested, including
uncertain, with 95% credible intervals that include substantial
cumulative dose, single versus multiple doses of ivermectin, or risk
harm.
of bias. There was insufficient information to examine the effect of
age or severity of illness. For interleukin-6 inhibitors, there was no Two trials examined the effect of JAK inhibitors and appear to show
difference in relative effects between sarilumab and tocilizumab, promising results. JAK inhibitors may reduce mortality, mechanical
by disease severity, or concomitant corticosteroid use on mortality, ventilation, and duration of hospitalisation. They probably reduce
mechanical ventilation, or adverse effects. There was insufficient the duration of mechanical ventilation. Further trials are needed to
information to examine the effect of age on any of these outcomes. confirm these promising effects.
There was also no credible effect difference between patients with
Full dose anticoagulation did not appear to show any important
higher versus lower C reactive protein on a composite of mortality
effect. A separate meta-analysis of four trials that examined full
and mechanical ventilation.
dose anticoagulation versus prophylactic dose anticoagulation
Discussion appeared to show a reduction in mortality in patients with severe
but not critical illness43; but these trials are not yet published in
This living systematic review and network meta-analysis provides
full and the data available is insufficient to judge whether or not it
a comprehensive overview of the evidence for drug treatments of
is a credible subgroup effect.
covid-19 up to 12 February 2021 and a comprehensive list of drug
trials to 1 March 2021. There are now more than 200 randomised Several interventions do not appear to have important impact on
trials examining many different interventions for treating covid-19, any patient-important outcomes, including angiotensin-converting
and, as a result, the certainty in evidence for multiple interventions enzyme inhibitors, azithromycin, hydroxychloroquine,
is improving. interferon-beta, lopinavir-ritonavir, vitamin C, and vitamin D. For
other interventions, there remains substantial uncertainty.
Corticosteroids probably reduce the risk of death and mechanical
ventilation and probably increase ventilator-free days. The evidence Compared with the second iteration, there are several important
for corticosteroids comes primarily from patients who are hypoxic updates (box 2). We now have evidence from several large-scale
and admitted to hospital. Whether corticosteroids have any international trials on azithromycin, interleukin-6 inhibitors, full
important effect on patients with non-severe disease remains dose anticoagulation, and colchicine.
uncertain.
Box 2: Summary of changes since last iteration
Interleukin-6 inhibitors are likely to have some benefits, although
the evidence regarding their impact on mortality remains of low • One hundred and eleven additional randomised trials (35 038
certainty. Other meta-analyses using fixed effects (that is, they do participants)
not consider between-trial heterogeneity) found a significant • Angiotensin-converting enzyme inhibitors, anakinra, full dose
mortality reduction.105 223 Interleukin-6 inhibitors probably reduce anticoagulation, ivermectin, ivermectin plus doxycycline, JAK
risk of mechanical ventilation and may reduce duration of inhibitors, lopinavir-ritonavir plus interferon-beta, peginterferon
hospitalisation. The evidence for interleukin-6 inhibitors comes lambda, proxalutamide, sulodexide, vitamin C, and vitamin D are new
interventions included in the analyses, but certainty is low or very low
primarily from patients who are admitted to hospital and are
for the effects of the most of these interventions
hypoxic. The use (or not) of corticosteroids, and baseline C reactive
• New evidence suggests that azithromycin may not have an impact on
protein levels did not appear to modify their effects, however data
available for subgroup analyses was limited. any patient-important outcome, when combined with usual care.
• New evidence suggests that interleukin-6 inhibitors probably reduce
Whether or not remdesivir has any effect on mortality remains mechanical ventilation (moderate certainty) and may reduce duration
uncertain. If one believes the subgroup effect previously reported, of hospitalisation (low certainty).
remdesivir may reduce or have no effect mortality in patients with • New evidence suggests that JAK inhibitors probably reduce duration
less severe disease and may increase or have no effect on mortality of mechanical ventilation (moderate certainty) and may reduce
in patients with critical illness. The subgroup effect however has mortality (low certainty), mechanical ventilation (low certainty), and
only moderate credibility and whether or not remdesivir reduces duration of hospitalisation (low certainty).
or increases mortality in any subgroup is uncertain. Remdesivir • New evidence suggests that colchicine may reduce mortality (low
may reduce risk of mechanical ventilation. certainty) and mechanical ventilation (low certainty) in outpatients
Evidence from our analyses suggests that colchicine may reduce with non-severe disease, however our analysis does not include recent
mortality, mechanical ventilation, and duration of hospitalisation.

RESEARCH
Our living systematic review and network meta-analysis will

evidence from the RECOVERY trial, which did not find any effect on
continue to inform the development of the WHO living guidelines
mortality in hospitalised patients.
and BMJ Rapid Recommendations.6 -8 An important difference in
• There is some new evidence on ivermectin and ivermectin plus
the methods for assessing the certainty of the evidence does,
doxycycline, however whether or not they have an important impact
however, exist between the two. In this living systematic review
on any patient-important outcome remains very uncertain.
and network meta-analysis, we use a minimally contextualised
• Evidence for other interventions is similar to the previous version
approach for rating the certainty of the evidence, whereas the
guideline panels use a fully contextualised approach in which the
Strengths and limitations of this review thresholds of importance of magnitudes of effects depend on all
Our search strategy and eligibility criteria were comprehensive, other outcomes and factors involved in the decision.28 The
without restrictions on language of publication or publication status. contextualisation explains differences in the certainty of the
To ensure expertise in all areas, our team is composed of clinical evidence between the two.
and methods experts who have undergone training and calibration To date, we are aware of two other similar efforts to ours.228 229 Our
exercises for all stages of the review process. To minimise problems intention is different in that the results fully inform clinical decision
with counterintuitive results, we anticipated challenges that arise making for the associated living guidance.6 We also include a more
in network meta-analysis when data are sparse.225 Many of the comprehensive search for the evidence and several differences in
results for comparisons with sparse data were uninformative and analytical methods, which we believe are best suited for this
were sometimes implausible. For that reason, we decided to report evidence. For example, some others use fixed rather than random
evidence on treatments for which at least 100 people were effects meta-analysis and provide estimates for pairwise
randomised or for which there were at least 20 events. comparisons only. It is also important to evaluate the reproducibility
The main limitation of the data is that only thirty-seven studies were and replicability of findings from different scientific approaches.
judged to be at low risk of bias. The primary limitation of the We will periodically update this living systematic review and
evidence is lack of blinding, which might introduce bias through network meta-analysis. The changes from each version will be
differences in co-interventions between randomised groups. We highlighted for readers and the most updated version will be the
chose to consider the treatment arms that did not receive an active one available in the publication platform. Previous versions will be
experimental drug (that is, placebo or standard care) within the archived in the supplementary material. This living systematic
same node: it is possible that the unblinded standard care groups review and network meta-analysis will also be accompanied by an
received systematically different co-interventions than groups interactive infographic and a website for users to access the most
randomised to receive a placebo. Direct comparisons in which the updated results in a user-friendly format (magicapp.org).
evidence is dominated by unblinded studies were rated down,
consistent with GRADE, for risk of bias and that is reflected in the Conclusions
rating of the quality of evidence from the network estimate.226 Many Evidence from this living systematic review and network
of the data also had reporting concerns. For some outcomes, the meta-analysis suggests that corticosteroids probably reduce
method in which the researchers measured and reported outcomes mortality, mechanical ventilation, and ventilator-free days in
proved inconsistent across studies. This led the team to propose a patients with severe covid-19. Remdesivir may reduce the need for
hierarchy for the outcome mechanical ventilation, as described in mechanical ventilation but does not appear to have an impact on
the methods. mortality. Interleukin-6 inhibitors (sarilumab and tocilizumab)
probably reduce mechanical ventilation and ICU length of stay, and
The living nature of our systematic review and network
may reduce duration of hospitalisation. JAK inhibitors (baricitinib
meta-analysis could conceivably (at least temporarily) amplify
and ruxolitinib) may reduce mortality, mechanical ventilation,
publication bias, because studies with promising results are more
duration of hospitalisation. Azithromycin, hydroxychloroquine,
likely to be published and are published sooner than studies with
lopinavir-ritonavir, and interferon beta seem unlikely to have any
negative results. The inclusion of preprints, many of which have
benefits. The effects of many other drug interventions are currently
negative results, might reduce this risk. However, the inclusion of
highly uncertain (including ivermectin), and no definitive evidence
preprints in our network meta-analysis might introduce bias from
exists that these interventions result in important benefits and
simple errors and the reporting limitations of preprints. We include
harms for any outcomes.
preprints because of the urgent need for information and because
so many of the studies on covid-19 are published first as preprints. What is already known on this topic
So far, differences between preprints and peer reviewed publications
• Despite huge efforts to identify effective drug interventions for
have been mostly been limited to additional baseline patient
coronavirus disease 2019 (covid-19), evidence for effective treatment
information, clarification on study design, and outcomes reported
remains limited
in the peer reviewed publications. None of these changes would
have resulted in a meaningful change to pooled effect estimates or What this study adds
certainty for any outcome. • This living systematic review and network meta-analysis provides a
comprehensive overview and assessment of the evidence published
It is possible that we did not detect important subgroup as of 1 March 2021 and will be updated periodically
modification.227 For example, the RECOVERY trial suggested that
• The certainty of the evidence for most interventions is low or very low,
patients with more severe disease might obtain a greater benefit
103 including ivermectin
from dexamethasone than patients with less severe disease. Full
• In patients with severe covid-19, glucocorticoids probably decrease
dose anticoagulation may be beneficial in patients with severe but
mortality, mechanical ventilation.
not critical disease, and harmful in patients with critical disease.
However, these subgroup effects only have moderate credibility at • In patients with severe covid-19, interleukin-6 inhibitors probably
best. Users should carefully consider the characteristics of the reduce mechanical ventilation and ICU length of stay, and may improve
patients included in the trials for each intervention. ventilator-free days and duration of hospitalisation.

RESEARCH
AUTHOR AFFILIATIONS 30
Department of Nephrology and Hypertension, University Medical Center Utrecht,
1
Department of Health Research Methods, Evidence, and Impact, McMaster University, Utrecht, Netherlands
1280 Main St W, Hamilton, ON L8S 4L8, Canada 31
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht,
2
Evidence Based Social Science Research Center, School of Public Health, Lanzhou Utrecht University, Utrecht, Netherlands
University, Lanzhou, Gansu, China 32
Centro de Investigación de Salud Pública y Epidemiología Clínica (CISPEC), Facultad
3
Servicio de Clinica Médica del Hospital Alemán, Buenos Aires, Argentina de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
33
4
Iberoamerican Cochrane Centre, Sant Pau Biomedical Research Institute (IIB Sant Wolfson Palliative Care Research Centre, Hull York Medical School, Hull, UK
Pau), Barcelona, Spain *
Joint first authors
5
CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain Contributors: RACS, JJB, LG, and DZ contributed equally to the systematic review and are joint first
6 authors. RACS, JJB, DZ, EK, LG, and RB-P were the core team leading the systematic review. JJB, RC,
Department of Medicine, McMaster University, Hamilton, ON, Canada SAF, MG, RWMV, SM, YW, ZY, CS, LY, QL, XH, LS, BF, and AV-G identified and selected the studies.
7 DZ, EK, NS, RWMV, AA, YW, KH, HP-H, MAH, CF, SLM, QL, AS, AQ, LY, BL, MG, EC, and FF collected
Department of Medicine and Centre de recherche du CHU de Sherbrooke, Sherbrooke, the data. LG, AK, AQ, JPDM, BS, LH, QI, DH-A, GHG, GT, and LT analysed the data. RB-P, HPH, AI, RAM,
Quebec, Canada TD, NS, and DC assessed the certainty of the evidence. SLM, FL, BR, TA, POV, GHG, MM, JDN, ML, TT,
BT, FF, and GR provided advice at different stages. RACS, RB-P, and GHG drafted the manuscript. All
8 authors approved the final version of the manuscript. RACS is the guarantor. The corresponding author
Department of Preventive Medicine, College of Medicine, Chosun University, Gwangju, attests that all listed authors meet authorship criteria and that no others meeting the criteria have been
Republic of Korea omitted.
9
Cochrane China Network Affiliate, Chongqing Medical University, Chongqing, China Funder: This study was supported by the Canadian Institutes of Health Research CIHR-IRSC:057900132
and Coronavirus Rapid Research Funding Opportunity - OV2170359.
10
School of Public Health and Management, Chongqing Medical University, Chongqing,
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icm-
China je.org/coi_disclosure.pdf and declare: support from the Canadian Institutes of Health Research; no
11 financial relationships with any organisations that might have an interest in the submitted work in the
Department of Medicine, University of Toronto, Toronto, ON, Canada previous three years; no other relationships or activities that could appear to have influenced the
12 submitted work.
Division of General Internal Medicine & Division of Clinical Epidemiology, University
Hospitals of Geneva, Geneva, Switzerland Ethical approval: Not applicable. All the work was developed using published data.
13 Data sharing: No additional data available.

Department of Anesthesia, McMaster University, Hamilton, ON, Canada
14 RACS affirms that this manuscript is an honest, accurate, and transparent account of the study being
Department of Medicine, University of Calgary, Calgary, AB, Canada reported; that no important aspects of the study have been omitted; and that any discrepancies from
15 the study as planned have been explained.
William Osler Health Network, Toronto, ON, Canada
Dissemination to participants and related patient and public communities: The infographic and MAGICapp
16 decision aids (available at www.magicapp.org/) were created to facilitate conversations between
Norwegian Institute of Public Health, Oslo, Norway healthcare providers and patients or their surrogates. The MAGICapp decision aids were co-created
17 with people who have lived experience of covid-19.
Institute of Health and Society, University of Oslo, Oslo, Norway
18 Provenance and peer review: Not commissioned; externally peer reviewed.
Ted Rogers Center for Heart Research, Toronto General Hospital, ON, Canada
19
We thank Kevin Cheung and Paul Alexander (who was an author in the previous version of this review)
Department of Medicine, Western University, London, ON, Canada for input and early contributions.
20 1 John Hopkins University. Coronavirus Resource Center 2020 https://coronavirus.jhu.edu/map.html.

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Drug Treatments For Covid-19: Living Systematic Review and Network Meta-Analysis

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Drug Treatments For Covid-19: Living Systematic Review and Network Meta-Analysis

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RESEARCH

the bmj | BMJ 2020;370:m2980 | doi: 10.1136/bmj.m2980 1

2 the bmj | BMJ 2020;370:m2980 | doi: 10.1136/bmj.m2980

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Statistical analysis mechanical ventilation, duration of hospitalisation, and ICU length

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Fig 1 | Study selection

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Table 2 describes the 10 randomised trials that were identified after

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Fig 2 | Summary of effects compared with standard care

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Our living systematic review and network meta-analysis will

12 the bmj | BMJ 2020;370:m2980 | doi: 10.1136/bmj.m2980

13 Data sharing: No additional data available.

20 1 John Hopkins University. Coronavirus Resource Center 2020 https://coronavirus.jhu.edu/map.html.

the bmj | BMJ 2020;370:m2980 | doi: 10.1136/bmj.m2980 13

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