Lack of efficacy of hydroxychloroquine and azithromycin in patients hospitalized for COVID-19 pneumonia: A retrospective study

DOI record: { "DOI": "10.1371/journal.pone.0252388", "ISSN": [ "1932-6203" ], "URL": "http://dx.doi.org/10.1371/journal.pone.0252388", "abstract": "<jats:sec id=\"sec001\">\n<jats:title>Background</jats:title>\n<jats:p>Hydroxychloroquine combined with azithromycin (HCQ/AZI) has initially been used against coronavirus disease-2019 (COVID-19). In this retrospective study, we assessed the clinical effects of HCQ/AZI, with a 28-days follow-up.</jats:p>\n</jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods</jats:title>\n<jats:p>In a registry-study which included patients hospitalized for COVID-19 between March 15 and April 2, 2020, we compared patients who received HCQ/AZI to those who did not, regarding a composite outcome of mortality and mechanical ventilation with a 28-days follow-up. QT was monitored for patients treated with HCQ/AZI. Were excluded patients in intensive care units, palliative care and ventilated within 24 hours of admission. Three analyses were performed to adjust for selection bias: propensity score matching, multivariable survival, and inverse probability score weighting (IPSW) analyses.</jats:p>\n</jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results</jats:title>\n<jats:p>Overall, 203 patients were included: 60 patients treated by HCQ/AZI and 143 control patients. During the 28-days follow-up, 32 (16.3%) patients presented the primary outcome and 23 (12.3%) patients died. Propensity-score matching identified 52 unique pairs of patients with similar characteristics. In the matched cohort (n = 104), HCQ/AZI was not associated with the primary composite outcome (log-rank p-value = 0.16). In the overall cohort (n = 203), survival and IPSW analyses also found no benefit from HCQ/AZI. In the HCQ/AZI group, 11 (18.3%) patients prolonged QT interval duration, requiring treatment cessation.</jats:p>\n</jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusions</jats:title>\n<jats:p>HCQ/AZI combination therapy was not associated with lower in-hospital mortality and mechanical ventilation rate, with a 28-days follow-up. In the HCQ/AZI group, 18.3% of patients presented a prolonged QT interval requiring treatment cessation, however, control group was not monitored for this adverse event, making comparison impossible.</jats:p>\n</jats:sec>", "author": [ { "affiliation": [], "family": "Saib", "given": "Anis", "sequence": "first" }, { "affiliation": [], "family": "Amara", "given": "Walid", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0002-4057-3765", "affiliation": [], "authenticated-orcid": true, "family": "Wang", "given": "Pascal", "sequence": "additional" }, { "affiliation": [], "family": "Cattan", "given": "Simon", "sequence": "additional" }, { "affiliation": [], "family": "Dellal", "given": "Azeddine", "sequence": "additional" }, { "affiliation": [], "family": "Regaieg", "given": "Kais", "sequence": "additional" }, { "affiliation": [], "family": "Nahon", "given": "Stephane", "sequence": "additional" }, { "affiliation": [], "family": "Nallet", "given": "Olivier", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0002-6014-6269", "affiliation": [], "authenticated-orcid": true, "family": "Nguyen", "given": "Lee S.", "sequence": "additional" } ], "container-title": "PLOS ONE", "container-title-short": "PLoS ONE", "content-domain": { "crossmark-restriction": false, "domain": [ "www.plosone.org" ] }, "created": { "date-parts": [ [ 2021, 6, 9 ] ], "date-time": "2021-06-09T18:11:20Z", "timestamp": 1623262280000 }, "deposited": { "date-parts": [ [ 2021, 6, 9 ] ], "date-time": "2021-06-09T18:11:47Z", "timestamp": 1623262307000 }, "editor": [ { "affiliation": [], "family": "Cortegiani", "given": "Andrea", "sequence": "first" } ], "indexed": { "date-parts": [ [ 2023, 10, 12 ] ], "date-time": "2023-10-12T00:59:58Z", "timestamp": 1697072398745 }, "is-referenced-by-count": 5, "issue": "6", "issued": { "date-parts": [ [ 2021, 6, 9 ] ] }, "journal-issue": { "issue": "6", "published-online": { "date-parts": [ [ 2021, 6, 9 ] ] } }, "language": "en", "license": [ { "URL": "http://creativecommons.org/licenses/by/4.0/", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2021, 6, 9 ] ], "date-time": "2021-06-09T00:00:00Z", "timestamp": 1623196800000 } } ], "link": [ { "URL": "https://dx.plos.org/10.1371/journal.pone.0252388", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "340", "original-title": [], "page": "e0252388", "prefix": "10.1371", "published": { "date-parts": [ [ 2021, 6, 9 ] ] }, "published-online": { "date-parts": [ [ 2021, 6, 9 ] ] }, "publisher": "Public Library of Science (PLoS)", "reference": [ { "article-title": "Use of Hydroxychloroquine and Chloroquine During the COVID-19 Pandemic: What Every Clinician Should Know", "author": "J Yazdany", "journal-title": "Ann Intern Med", "key": "pone.0252388.ref001", "year": "2020" }, { "article-title": "In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).", "author": "X Yao", "first-page": "ciaa237", "journal-title": "Clinical Infectious Diseases", "key": "pone.0252388.ref002", "year": "2020" }, { "DOI": "10.1038/s41422-020-0282-0", "article-title": "Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.", "author": "M Wang", "doi-asserted-by": "crossref", "first-page": "269", "issue": "3", "journal-title": "Cell Res", "key": "pone.0252388.ref003", "volume": "30", "year": "2020" }, { "article-title": "Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial", "author": "P Gautret", "journal-title": "Int J Antimicrob Agents", "key": "pone.0252388.ref004", "year": "2020" }, { "DOI": "10.1016/j.jcrc.2020.06.019", "article-title": "Update I. A systematic review on the efficacy and safety of chloroquine/hydroxychloroquine for COVID-19", "author": "A Cortegiani", "doi-asserted-by": "crossref", "first-page": "176", "journal-title": "Journal of Critical Care", "key": "pone.0252388.ref005", "volume": "59", "year": "2020" }, { "DOI": "10.1056/NEJMoa2022926", "article-title": "Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19.", "doi-asserted-by": "crossref", "first-page": "2030", "issue": "21", "journal-title": "New England Journal of Medicine", "key": "pone.0252388.ref006", "volume": "383", "year": "2020" }, { "DOI": "10.1056/NEJMoa2023184", "article-title": "Repurposed Antiviral Drugs for Covid-19—Interim WHO Solidarity Trial Results", "author": "WST Consortium", "doi-asserted-by": "crossref", "first-page": "497", "issue": "6", "journal-title": "New England Journal of Medicine", "key": "pone.0252388.ref007", "volume": "384", "year": "2020" }, { "key": "pone.0252388.ref008", "unstructured": "Décret n° 2020–314 du 25 mars 2020 complétant le décret n° 2020–293 du 23 mars 2020 prescrivant les mesures générales nécessaires pour faire face à l’épidémie de covid-19 dans le cadre de l’état d’urgence sanitaire, (2020/03/25/, 2020)." }, { "article-title": "Cardiovascular Toxicities Associated with Hydroxychloroquine and Azithromycin: An Analysis of the World Health Organization Pharmacovigilance Database", "author": "LS Nguyen", "journal-title": "Circulation", "key": "pone.0252388.ref009", "year": "2020" }, { "DOI": "10.1161/JAHA.116.003264", "article-title": "Which QT Correction Formulae to Use for QT Monitoring?", "author": "B Vandenberk", "doi-asserted-by": "crossref", "issue": "6", "journal-title": "JAHA", "key": "pone.0252388.ref010", "volume": "5", "year": "2016" }, { "DOI": "10.1185/03007995.2013.840568", "article-title": "QT interval prolongation and the risk of torsades de pointes: essentials for clinicians.", "author": "KE Trinkley", "doi-asserted-by": "crossref", "first-page": "1719", "issue": "12", "journal-title": "Current Medical Research and Opinion", "key": "pone.0252388.ref011", "volume": "29", "year": "2013" }, { "DOI": "10.1177/0962280215584401", "article-title": "The performance of inverse probability of treatment weighting and full matching on the propensity score in the presence of model misspecification when estimating the effect of treatment on survival outcomes.", "author": "PC Austin", "doi-asserted-by": "crossref", "first-page": "1654", "issue": "4", "journal-title": "Stat Methods Med Res", "key": "pone.0252388.ref012", "volume": "26", "year": "2017" }, { "DOI": "10.1002/sim.1903", "article-title": "Stratification and weighting via the propensity score in estimation of causal treatment effects: a comparative study.", "author": "JK Lunceford", "doi-asserted-by": "crossref", "first-page": "2937", "issue": "19", "journal-title": "Statistics in Medicine", "key": "pone.0252388.ref013", "volume": "23", "year": "2004" }, { "DOI": "10.1007/s00134-018-5442-z", "article-title": "Percutaneous versus surgical femoro-femoral veno-arterial ECMO: a propensity score matched study.", "author": "P Danial", "doi-asserted-by": "crossref", "first-page": "2153", "issue": "12", "journal-title": "Intensive care medicine.", "key": "pone.0252388.ref014", "volume": "44", "year": "2018" }, { "DOI": "10.1111/ajt.15849", "article-title": "Quadritherapy vs standard tritherapy immunosuppressant regimen after heart transplantation: A propensity score-matched cohort analysis.", "author": "LS Nguyen", "doi-asserted-by": "crossref", "first-page": "2791", "issue": "10", "journal-title": "American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons", "key": "pone.0252388.ref015", "volume": "20", "year": "2020" }, { "article-title": "Effect of Tocilizumab in Hospitalized Patients with Severe COVID-19 Pneumonia: A Case-Control Cohort Study.", "author": "B Rossi", "issue": "10", "journal-title": "Pharmaceuticals (Basel, Switzerland).", "key": "pone.0252388.ref016", "volume": "13", "year": "2020" }, { "article-title": "Clinical Characteristics of Coronavirus Disease 2019 in China.", "author": "W-j Guan", "journal-title": "New England Journal of Medicine.", "key": "pone.0252388.ref017", "year": "2020" }, { "DOI": "10.1016/S0140-6736(20)30566-3", "article-title": "Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study", "author": "F Zhou", "doi-asserted-by": "crossref", "first-page": "1054", "issue": "10229", "journal-title": "The Lancet", "key": "pone.0252388.ref018", "volume": "395", "year": "2020" }, { "DOI": "10.1001/jama.2020.1585", "article-title": "Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China.", "author": "D Wang", "doi-asserted-by": "crossref", "first-page": "1061", "issue": "11", "journal-title": "JAMA.", "key": "pone.0252388.ref019", "volume": "323", "year": "2020" }, { "article-title": "Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study", "author": "X Yang", "issue": "0", "journal-title": "The Lancet Respiratory Medicine", "key": "pone.0252388.ref020", "volume": "0", "year": "2020" }, { "article-title": "Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19", "author": "J Geleris", "journal-title": "New England Journal of Medicine", "key": "pone.0252388.ref021", "year": "2020" }, { "DOI": "10.1016/j.tmaid.2020.101663", "article-title": "Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study.", "author": "P Gautret", "doi-asserted-by": "crossref", "first-page": "101663", "journal-title": "Travel Medicine and Infectious Disease", "key": "pone.0252388.ref022", "year": "2020" }, { "article-title": "No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for COVID-19 infection with oxygen requirement: results of a study using routinely collected data to emulate a target trial.", "author": "M Mahevas", "first-page": "2020", "journal-title": "medRxiv.", "key": "pone.0252388.ref023", "year": "2020" }, { "DOI": "10.1001/jama.2020.8630", "article-title": "Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State", "author": "ES Rosenberg", "doi-asserted-by": "crossref", "first-page": "2493", "issue": "24", "journal-title": "JAMA", "key": "pone.0252388.ref024", "volume": "323", "year": "2020" }, { "DOI": "10.1056/NEJMoa2022926", "article-title": "Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19.", "author": "group Rc", "doi-asserted-by": "crossref", "first-page": "2030", "issue": "21", "journal-title": "New England Journal of Medicine", "key": "pone.0252388.ref025", "volume": "383", "year": "2020" }, { "DOI": "10.1056/NEJMoa2019014", "article-title": "Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19.", "author": "AB Cavalcanti", "doi-asserted-by": "crossref", "first-page": "2041", "issue": "21", "journal-title": "New England Journal of Medicine.", "key": "pone.0252388.ref026", "volume": "383", "year": "2020" }, { "DOI": "10.1093/rheumatology/kel402", "article-title": "Heart conduction disorders related to antimalarials toxicity: an analysis of electrocardiograms in 85 patients treated with hydroxychloroquine for connective tissue diseases.", "author": "N Costedoat-Chalumeau", "doi-asserted-by": "crossref", "first-page": "808", "issue": "5", "journal-title": "Rheumatology", "key": "pone.0252388.ref027", "volume": "46", "year": "2007" }, { "DOI": "10.1016/j.hrthm.2015.05.027", "article-title": "Hydroxychloroquine reduces heart rate by modulating the hyperpolarization-activated current If: Novel electrophysiological insights and therapeutic potential", "author": "RA Capel", "doi-asserted-by": "crossref", "first-page": "2186", "issue": "10", "journal-title": "Heart Rhythm", "key": "pone.0252388.ref028", "volume": "12", "year": "2015" }, { "DOI": "10.1155/2018/1574806", "article-title": "Risk Evaluation of Azithromycin-Induced QT Prolongation in Real-World Practice.", "author": "Y Choi", "doi-asserted-by": "crossref", "first-page": "1", "journal-title": "BioMed Research International", "key": "pone.0252388.ref029", "volume": "2018", "year": "2018" }, { "article-title": "Azithromycin and the Risk of Cardiovascular Death", "author": "WA Ray", "journal-title": "The New England Journal of Medicine", "key": "pone.0252388.ref030", "volume": "10", "year": "2012" }, { "DOI": "10.1371/journal.pone.0208321", "article-title": "Interleukin-6 inhibition of hERG underlies risk for acquired long QT in cardiac and systemic inflammation", "author": "AS Aromolaran", "doi-asserted-by": "crossref", "first-page": "e0208321", "issue": "12", "journal-title": "PLoS ONE", "key": "pone.0252388.ref031", "volume": "13", "year": "2018" }, { "DOI": "10.1016/S0140-6736(20)31528-2", "article-title": "Retraction and republication: cardiac toxicity of hydroxychloroquine in COVID-19", "author": "C Funck-Brentano", "doi-asserted-by": "crossref", "first-page": "e2", "issue": "10245", "journal-title": "Lancet (London, England).", "key": "pone.0252388.ref032", "volume": "396", "year": "2020" } ], "reference-count": 32, "references-count": 32, "relation": {}, "resource": { "primary": { "URL": "https://dx.plos.org/10.1371/journal.pone.0252388" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [ "Multidisciplinary" ], "subtitle": [], "title": "Lack of efficacy of hydroxychloroquine and azithromycin in patients hospitalized for COVID-19 pneumonia: A retrospective study", "type": "journal-article", "update-policy": "http://dx.doi.org/10.1371/journal.pone.corrections_policy", "volume": "16" }