Prophylaxis against covid-19: living systematic review and network meta-analysis
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Abstract
Updates
This is the second version (first update) of the living systematic review, replacing the previous version (available as a data supplement). When citing this paper please consider adding the version number and date of access for clarity.
Objective
To determine and compare the effects of drug prophylaxis on severe acute respiratory syndrome coronavirus virus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (covid-19).
Design
Living systematic review and network meta-analysis (NMA).
Data sources
WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature to 4 March 2022.
Study selection
Randomised trials in which people at risk of covid-19 were allocated to prophylaxis or no prophylaxis (standard care or placebo). Pairs of reviewers independently screened potentially eligible articles.
Methods
After duplicate data abstraction, we conducted random-effects bayesian network meta-analysis. We assessed risk of bias of the included studies using a modification of the Cochrane risk of bias 2.0 tool and assessed the certainty of the evidence using the grading of recommendations assessment, development and evaluation (GRADE) approach.
Results
The second iteration of this living NMA includes 32 randomised trials which enrolled 25 147 participants and addressed 21 different prophylactic drugs; adding 21 trials (66%), 18 162 participants (75%) and 16 (76%) prophylactic drugs. Of the 16 prophylactic drugs analysed, none provided convincing evidence of a reduction in the risk of laboratory confirmed SARS-CoV-2 infection. For admission to hospital and mortality outcomes, no prophylactic drug proved different than standard care or placebo. Hydroxychloroquine and vitamin C combined with zinc probably increase the risk of adverse effects leading to drug discontinuation—risk difference for hydroxychloroquine (RD) 6 more per 1000 (95% credible interval (CrI) 2 more to 10 more); for vitamin C combined with zinc, RD 69 more per 1000 (47 more to 90 more), moderate certainty evidence.
Conclusion
Much of the evidence remains very low certainty and we therefore anticipate future studies evaluating drugs for prophylaxis may change the results for SARS-CoV-2 infection, admission to hospital and mortality outcomes. Both hydroxychloroquine and vitamin C combined with zinc probably increase adverse effects.
Systematic review registration
This review was not registered. The protocol established a priori is included as a supplement.
Funding
This study was supported by the Canadian Institutes of Health Research (grant CIHR-IRSC:0579001321).
Article activity feed
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SciScore for 10.1101/2021.02.24.21250469: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources Risk of bias within individual studies For each eligible trial, following training and calibration exercises, reviewers used a revision of the Cochrane tool for assessing risk of bias in randomized trials (RoB 2.0)18 to rate trials at the outcome level as either at i) low risk of bias, ii) some concerns—probably low risk of bias, iii) some concerns—probably high risk of bias, or iv) high risk of bias, across the following domains: bias arising from the randomization process; bias due to departures from the intended intervention; bias due to missing outcome data; bias in measurement of … SciScore for 10.1101/2021.02.24.21250469: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources Risk of bias within individual studies For each eligible trial, following training and calibration exercises, reviewers used a revision of the Cochrane tool for assessing risk of bias in randomized trials (RoB 2.0)18 to rate trials at the outcome level as either at i) low risk of bias, ii) some concerns—probably low risk of bias, iii) some concerns—probably high risk of bias, or iv) high risk of bias, across the following domains: bias arising from the randomization process; bias due to departures from the intended intervention; bias due to missing outcome data; bias in measurement of the outcome; bias in selection of the reported results, including deviations from the registered protocol; bias arising from early termination for benefit; and bias arising from competing risks. Cochrane toolsuggested: NoneThe networkplot command of Stata version 15.1 (StataCorp, College Station, TX) provided software for network plots in which the inverse variance of the direct comparison determined the thickness of lines between nodes and the size of nodes. StataCorpsuggested: (Stata, RRID:SCR_012763)21 For all other outcomes, we performed random-effects bayesian meta-analysis using bayesmeta package in RStudio version 3.5.3 (R Studio, Boston, MA, USA). RStudiosuggested: (RStudio, RRID:SCR_000432)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Strengths and limitations of this review This, the first network meta-analysis published on prophylactic drugs for covid-19, incorporates the most up-to-date evidence on hydroxychloroquine, ivermectin with iotacarrageenan and ivermectin alone. It adds to our living systematic review on drugs for covid-19 and directly informs the WHO living guidelines, together constituting major innovations in the evidence ecosystem.5 The search strategy was comprehensive with explicit eligibility criteria, and no restrictions on the language of publication. To ensure expertise in all areas, our team includes clinical and methods experts who have undergone training and calibration exercises for all stages of the review process. In order to avoid spurious findings, we prespecified that we would only analyse drugs to which at least 100 people had been randomized or 20 events have been observed. The single trial that evaluated ramipril against standard care was therefore omitted from the network meta-analysis, necessitated by the priority to avoid issues that arise from network meta-analysis of sparse data (uninformative and implausible results).7 The GRADE approach provided the structure for rating certainty of evidence and interpreting the results considering absolute effects. To rate the GRADE domain of imprecision, we prespecified thresholds of effect that most would consider small but important. In the absence of empiric data, these thresholds represent our collective experience but are, to...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04422561 Completed Prophylactic Ivermectin in COVID-19 Contacts NCT04701710 Completed Prophylaxis Covid-19 in Healthcare Agents by Intensive Treat… NCT04329923 Terminated The PATCH Trial (Prevention And Treatment of COVID-19 With H… NCT04329923 Terminated The PATCH Trial (Prevention And Treatment of COVID-19 With H… NCT03201185102 Trial number did not resolve on clinicaltrials.gov. Is the number correct? NA NCT04328961 Completed Hydroxychloroquine for COVID-19 Post-exposure Prophylaxis (P… NCT04308668 Completed Post-exposure Prophylaxis / Preemptive Therapy for SARS-Coro… NCT04668469234 Trial number did not resolve on clinicaltrials.gov. Is the number correct? NA NCT04331834 Completed Pre-Exposure Prophylaxis With Hydroxychloroquine for High-Ri… NCT043040532525 Trial number did not resolve on clinicaltrials.gov. Is the number correct? NA NCT043284671483 Trial number did not resolve on clinicaltrials.gov. Is the number correct? NA NCT0442256138 Trial number did not resolve on clinicaltrials.gov. Is the number correct? NA Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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