Randomized Controlled Trials of Early Ambulatory Hydroxychloroquine in the Prevention of COVID-19 Infection, Hospitalization, and Death: Meta-Analysis

DOI record: { "DOI": "10.1101/2020.09.30.20204693", "URL": "http://dx.doi.org/10.1101/2020.09.30.20204693", "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>", "accepted": { "date-parts": [ [ 2020, 9, 30 ] ] }, "author": [ { "affiliation": [], "family": "Ladapo", "given": "Joseph A.", "sequence": "first" }, { "affiliation": [], "family": "McKinnon", "given": "John E.", "sequence": "additional" }, { "affiliation": [], "family": "McCullough", "given": "Peter A.", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0001-5337-3941", "affiliation": [], "authenticated-orcid": false, "family": "Risch", "given": "Harvey A.", "sequence": "additional" } ], "container-title": [], "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2020, 10, 1 ] ], "date-time": "2020-10-01T03:55:35Z", "timestamp": 1601524535000 }, "deposited": { "date-parts": [ [ 2022, 11, 21 ] ], "date-time": "2022-11-21T13:28:40Z", "timestamp": 1669037320000 }, "group-title": "Infectious Diseases (except HIV/AIDS)", "indexed": { "date-parts": [ [ 2023, 11, 29 ] ], "date-time": "2023-11-29T13:39:45Z", "timestamp": 1701265185482 }, "institution": [ { "name": "medRxiv" } ], "is-referenced-by-count": 15, "issued": { "date-parts": [ [ 2020, 9, 30 ] ] }, "link": [ { "URL": "https://syndication.highwire.org/content/doi/10.1101/2020.09.30.20204693", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "246", "original-title": [], "posted": { "date-parts": [ [ 2020, 9, 30 ] ] }, "prefix": "10.1101", "published": { "date-parts": [ [ 2020, 9, 30 ] ] }, "publisher": "Cold Spring Harbor Laboratory", "reference": [ { "key": "2021021707251007000_2020.09.30.20204693v1.1", "unstructured": "RECOVERY Collaborative Group, Horby P , Lim WS , et al. Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report. N Engl J Med 2020 Jul 17:EJMoa2021436. https://www.nejm.org/doi/10.1056/NEJMoa2021436" }, { "DOI": "10.1016/j.nmni.2020.100707", "doi-asserted-by": "crossref", "key": "2021021707251007000_2020.09.30.20204693v1.2", "unstructured": "02 Brouqui P , Giraud-Gatineau A , Raoult D. Remdesivir investigational trials in COVID-19: a critical reappraisal. New Microbes New Infect 2020 Jun 7;100707. https://doi.org/10.1016/j.nmni.2020.100707" }, { "DOI": "10.1371/journal.ppat.1001176", "doi-asserted-by": "publisher", "key": "2021021707251007000_2020.09.30.20204693v1.3" }, { "key": "2021021707251007000_2020.09.30.20204693v1.4", "unstructured": "Barbosa Esper R , Souza da Silva R , Teiichi Costa Oikawa F , et al. Empirical treatment with hydroxychloroquine and azithromycin for suspected cases of COVID-19 followed-up by telemedicine. April 15, 2020. Accessed April 30, 2020. https://pgibertie.files.wordpress.com/2020/04/2020.04.15-journal-manuscript-final.pdf" }, { "DOI": "10.21203/rs.3.rs-70219/v2", "doi-asserted-by": "crossref", "key": "2021021707251007000_2020.09.30.20204693v1.5", "unstructured": "Heras E , Garibaldi P , Boix M , et al. COVID-19 mortality risk factors in older people in a long-term care center. Preprints September 9, 2020. https://doi.org/10.21203/rs.3.rs-70219/v2" }, { "DOI": "10.1101/2020.08.20.20178772", "doi-asserted-by": "crossref", "key": "2021021707251007000_2020.09.30.20204693v1.6", "unstructured": "Ip A , Ahn J , Zhou Y , et al. Hydroxychloroquine in the treatment of outpatients with mildly symptomatic COVID-19: A multi-center observational study. Preprints August 25, 2020. https://doi.org/10.1101/2020.08.20.20178772" }, { "key": "2021021707251007000_2020.09.30.20204693v1.7", "unstructured": "Lagier JC , Million M , Gautret P , et al. Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: A retrospective analysis. Travel Med Infect Dis 2020 Jun 25:101791. https://www.sciencedirect.com/science/article/pii/S1477893920302817" }, { "DOI": "10.1016/j.ijantimicag.2020.106219", "doi-asserted-by": "crossref", "key": "2021021707251007000_2020.09.30.20204693v1.8", "unstructured": "Ly TDA , Zanini D , Laforge V , et al. Pattern of SARS-CoV-2 infection among dependant elderly residents living in retirement homes in Marseille, France, March-June 2020. Preprints August 20,2020. https://www.mediterranee-infection.com/wp-content/uploads/2020/08/Abstract-COVID-EHPAD.pdf" }, { "DOI": "10.1101/2020.09.09.20184143", "doi-asserted-by": "crossref", "key": "2021021707251007000_2020.09.30.20204693v1.9", "unstructured": "Sulaiman T , Mohana A , Alawdah L , et al. The effect of early hydroxychloroquine-based therapy in COVID-19 patients in ambulatory care settings: A nationwide prospective cohort study. Preprints September 13, 2020. https://doi.org/10.1101/2020.09.09.20184143" }, { "DOI": "10.1101/2020.07.20.20157651", "doi-asserted-by": "crossref", "key": "2021021707251007000_2020.09.30.20204693v1.10", "unstructured": "Mitjà O , Ubals M , Corbacho-Monné M , et al. A cluster-randomized trial of hydroxychloroquine as prevention of COVID-19 transmission and disease. Preprints July 26, 2020. https://doi.org/10.1101/2020.07.20.20157651" }, { "DOI": "10.1093/cid/ciaa1009", "doi-asserted-by": "crossref", "key": "2021021707251007000_2020.09.30.20204693v1.11", "unstructured": "Mitjà O , Corbacho-Monné M , Ubals M , et al. Hydroxychloroquine for early treatment of adults with mild COVID-19: A randomized-controlled trial. Clin Infect Dis 2020 Jul 16:ciaa1009. https://doi.org/10.1093/cid/ciaa1009" }, { "key": "2021021707251007000_2020.09.30.20204693v1.12", "unstructured": "Skipper CP , Pastick KA , Engen NW , et al. Hydroxychloroquine in nonhospitalized adults with early COVID-19: A randomized trial. Ann Intern Med 2020 Jul 16:M20–4207. https://www.acpjournals.org/doi/10.7326/M20-4207" }, { "DOI": "10.1101/2020.09.18.20197327", "doi-asserted-by": "crossref", "key": "2021021707251007000_2020.09.30.20204693v1.13", "unstructured": "Rajasingham R , Bangdiwala AS , Nicol MR , et al. Hydroxychloroquine as pre-exposure prophylaxis for COVID-19 in healthcare workers: a randomized trial. 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