Randomized Controlled Trials of Early Ambulatory Hydroxychloroquine in the Prevention of COVID-19 Infection, Hospitalization, and Death: Meta-Analysis
MD, PhD Joseph A Ladapo, MD, MSc John E Mckinnon, MD, MPH Peter A Mccullough, MD, PhD Harvey A Risch
doi:10.1101/2020.09.30.20204693
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
Conflicts of Interest Dr. Risch acknowledges past advisory consulting work with two of the more than 50 manufacturers of hydroxychloroquine, azithromycin and doxycycline. This past work was not related to any of these medications and was completed more than two years ago. He has no ongoing, planned or projected relationships with any of these companies, nor any other potential conflicts-of-interest to disclose. None of the other authors have any potential conflicts of interest to disclose.
Key Messages Box: What is already known on this topic • Various government, clinical and research entities have been trying to evaluate the degree of benefit of hydroxychloroquine in early COVID-19 outpatient treatment. • Seven nonrandomized but controlled clinical trials to date have shown significant reductions in hospitalization and mortality with early ambulatory hydroxychloroquine use, but individual randomized outpatient trials have not shown statistical significance of benefit with these or other outcomes.
What this study adds • The five outpatient randomized controlled studies to date examining new infection, hospitalization or mortality together show statistically significant evidence of reduced risk, RR=0.76 (95% CI 0.59 to 0.97). • No serious adverse cardiac events were reported in any of the studies. • The combined literature of seven nonrandomized controlled trials and five randomized controlled trials provides substantial and statistically significant evidence of benefit..
References
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'abstract': '<jats:title>Abstract</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>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).</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>Systematic '
'review and meta-analysis of randomized clinical '
'trials.</jats:p></jats:sec><jats:sec><jats:title>Data sources</jats:title><jats:p>Search of '
'MEDLINE, EMBASE, PubMed, medRxiv, PROSPERO, and the Cochrane Central Register of Controlled '
'Trials. Also review of reference lists from recent '
'meta-analyses.</jats:p></jats:sec><jats:sec><jats:title>Study '
'selection</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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<jats:sup>2</jats:sup>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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Systematic review '
'registration</jats:title><jats:p>This review was not registered.</jats:p></jats:sec>',
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