Randomized Controlled Trials of Early Ambulatory Hydroxychloroquine in the Prevention of COVID-19 Infection, Hospitalization, and Death: Meta-Analysis
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Abstract
Objective
To determine if hydroxychloroquine (HCQ) reduces the incidence of new illness, hospitalization or death among outpatients at risk for or infected with SARS-CoV-2 (COVID-19).
Design
Systematic review and meta-analysis of randomized clinical trials.
Data sources
Search of MEDLINE, EMBASE, PubMed, medRxiv, PROSPERO, and the Cochrane Central Register of Controlled Trials. Also review of reference lists from recent meta-analyses.
Study selection
Randomized clinical trials in which participants were treated with HCQ or placebo/standard-of-care for pre-exposure prophylaxis, post-exposure prophylaxis, or outpatient therapy for COVID-19.
Methods
Two investigators independently extracted data on trial design and outcomes. Medication side effects and adverse reactions were also assessed. The primary outcome was COVID-19 hospitalization or death. When unavailable, new COVID-19 infection was used. We calculated random effects meta-analysis according to the method of DerSimonian and Laird. Heterogeneity between the studies was evaluated by calculation of Cochran Q and I 2 parameters. An Egger funnel plot was drawn to investigate publication bias. We also calculated the fixed effects meta-analysis summary of the five studies. All calculations were done in Excel, and results were considered to be statistically significant at a two-sided threshold of P=.05.
Results
Five randomized controlled clinical trials enrolling 5,577 patients were included. HCQ was associated with a 24% reduction in COVID-19 infection, hospitalization or death, P=.025 (RR, 0.76 [95% CI, 0.59 to 0.97]). No serious adverse cardiac events were reported. The most common side effects were gastrointestinal.
Conclusion
Hydroxychloroquine use in outpatients reduces the incidence of the composite outcome of COVID-19 infection, hospitalization, and death. Serious adverse events were not reported and cardiac arrhythmia was rare.
Systematic review registration
This review was not registered.
Article activity feed
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SciScore for 10.1101/2020.09.30.20204693: (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 We initially identified 90 results in PubMed, 13 results in medRxiv, 77 results in Medline/Embase, and 72 results in the Cochrane database. PubMedsuggested: (PubMed, RRID:SCR_004846)Cochranesuggested: (Cochrane Library, RRID:SCR_013000)All calculations were done in Excel, and we considered results to be statistically significant at a two-sided threshold of P=. Excelsuggested: NoneResults 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 …SciScore for 10.1101/2020.09.30.20204693: (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 We initially identified 90 results in PubMed, 13 results in medRxiv, 77 results in Medline/Embase, and 72 results in the Cochrane database. PubMedsuggested: (PubMed, RRID:SCR_004846)Cochranesuggested: (Cochrane Library, RRID:SCR_013000)All calculations were done in Excel, and we considered results to be statistically significant at a two-sided threshold of P=. Excelsuggested: NoneResults 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:Our meta-analysis has limitations common to evaluations of preliminary trials that themselves have shortcomings, including truncated sample sizes and lack of placebo control. The clinical trials used different measures to define the primary outcome. To address this limitation, we prioritized assessing COVID-19 death and hospitalization, which are meaningful clinical outcomes, and used the authors’ listed primary outcome when death or hospitalization were unavailable. Whether the degree of benefit for risk of developing COVID-19 illness compared to the risk of mortality or hospitalization are comparable in magnitude is a potential but minor limitation, in that combining them in meta-analysis averages the benefit over these various types of patient outcomes. If the meta-analysis demonstrated appreciable heterogeneity between these types of studies, their outcome differences might be an explanation. If the meta-analysis demonstrated a null or statistically insignificant result, it could be argued that the outcome differences counteracted each other. Neither of these circumstances occurred, thus the combination of risk reductions of the different but physiologic effects of HCQ remain an appropriate average representation of HCQ’s effectiveness. A second limitation is that we were unable to perform more robust analyses of the relationship between initiating HCQ treatment earlier and HCQ treatment effectiveness. In addition, the clinical settings of the trials varied, ranging from ...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04308668 Completed Post-exposure Prophylaxis / Preemptive Therapy for SARS-Coro… NCT04328467 Active, not recruiting Pre-exposure Prophylaxis for SARS-Coronavirus-2 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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