Hydroxychloroquine with or without azithromycin and in-hospital mortality or discharge in patients hospitalized for COVID-19 infection: a cohort study of 4,642 in-patients in France

{ 'institution': [{'name': 'medRxiv'}], 'indexed': {'date-parts': [[2024, 2, 8]], 'date-time': '2024-02-08T18:04:24Z', 'timestamp': 1707415464202}, 'posted': {'date-parts': [[2020, 6, 19]]}, 'group-title': 'Pharmacology and Therapeutics', 'reference-count': 31, 'publisher': 'Cold Spring Harbor Laboratory', 'content-domain': {'domain': [], 'crossmark-restriction': False}, 'accepted': {'date-parts': [[2020, 6, 19]]}, 'abstract': '<jats:title>Abstract</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>To ' 'assess the clinical effectiveness of oral hydroxychloroquine (HCQ) with or without ' 'azithromycin (AZI) in preventing death or leading to hospital ' 'discharge.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>Retrospective ' 'cohort study.</jats:p></jats:sec><jats:sec><jats:title>Setting</jats:title><jats:p>An ' 'analysis of data from electronic medical records and administrative claim data from the ' 'French Assistance Publique - Hôpitaux de Paris (AP-HP) data warehouse, in 39 public ' 'hospitals, Ile-de-France, ' 'France.</jats:p></jats:sec><jats:sec><jats:title>Participants</jats:title><jats:p>All adult ' 'inpatients with at least one PCR-documented SARS-CoV-2 RNA from a nasopharyngeal sample ' 'between February 1<jats:sup>st</jats:sup>, 2020 and April 6<jats:sup>th</jats:sup>, 2020 were ' 'eligible for analysis. The study population was restricted to patients who did not receive ' 'COVID-19 treatments assessed in ongoing trials, including antivirals and immunosuppressive ' 'drugs. End of follow-up was defined as the date of death, discharge home, day 28 after ' 'admission, whichever occurred first, or administrative censoring on May 4, ' '2020.</jats:p></jats:sec><jats:sec><jats:title>Intervention</jats:title><jats:p>Patients were ' 'further classified into 3 groups: (i) receiving HCQ alone, (ii) receiving HCQ together with ' 'AZI, and (iii) receiving neither HCQ nor AZI. Exposure to a HCQ/AZI combination was defined ' 'as a simultaneous prescription of the 2 treatments (more or less one ' 'day).</jats:p></jats:sec><jats:sec><jats:title>Main outcome measures</jats:title><jats:p>The ' 'primary outcome was all-cause 28-day mortality as a time-to-event endpoint under a competing ' 'risks survival analysis framework. The secondary outcome was 28-day discharge home. Augmented ' 'inverse probability of treatment weighted (AIPTW) estimates of the average treatment effect ' '(ATE) were computed to account for ' 'confounding.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>A total of ' '4,642 patients (mean age: 66.1 ± 18; males: 2,738 (59%)) were included, of whom 623 (13.4%) ' 'received HCQ alone, 227 (5.9%) received HCQ plus AZI, and 3,792 (81.7%) neither drug. ' 'Patients receiving ‘HCQ alone’ or ‘HCQ plus AZI’ were more likely younger, males, current ' 'smokers and overall presented with slightly more co-morbidities (obesity, diabetes, any ' 'chronic pulmonary diseases, liver diseases), while no major difference was apparent in ' 'biological parameters. After accounting for confounding, no statistically significant ' 'difference was observed between the ‘HCQ’ and ‘Neither drug’ groups for 28-day mortality: ' 'AIPTW absolute difference in ATE was +1.24% (−5.63 to 8.12), ratio in ATE 1.05 (0.77 to ' '1.33). 28-day discharge rates were statistically significantly higher in the ‘HCQ’ group: ' 'AIPTW absolute difference in ATE (+11.1% [3.30 to 18.9]), ratio in ATE (1.25 [1.07 to 1.42]). ' 'As for the ‘HCQ+AZI’ vs neither drug, trends for significant differences and ratios in AIPTW ' 'ATE were found suggesting higher mortality rates in the former group (difference in ATE ' '+9.83% [-0.51 to 20.17], ratio in ATE 1.40 [0.98 to ' '1.81];p=0.062).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Using ' 'a large non-selected population of inpatients hospitalized for COVID-19 infection in 39 ' 'hospitals in France and robust methodological approaches, we found no evidence for efficacy ' 'of HCQ or HCQ combined with AZI on 28-day mortality. Our results suggested a possible excess ' 'risk of mortality associated with HCQ combined with AZI, but not with HCQ alone. ' 'Significantly higher rates of discharge home were observed in patients treated by HCQ, a ' 'novel finding warranting further confirmation in replicative studies. Altogether, our ' 'findings further support the need to complete currently undergoing randomized clinical ' 'trials.</jats:p></jats:sec><jats:sec><jats:title>WHAT THIS PAPER ' 'ADDS?</jats:title><jats:sec><jats:title>What is already known on this ' 'subject</jats:title><jats:list ' 'list-type="simple"><jats:list-item><jats:label>-</jats:label><jats:p>The use of ' 'Hydroxychloroquine (HCQ) or HCQ with azithromycin (AZI) has been associated with viral load ' 'reduction at 6 days in COVID-19 infected ' 'patients</jats:p></jats:list-item><jats:list-item><jats:label>-</jats:label><jats:p>No ' 'difference between HCQ and no-HCQ groups in terms of risk of death or need for mechanical ' 'ventilation was found in two large cohorts of hospitalized COVID-19 infected ' 'patients</jats:p></jats:list-item></jats:list></jats:sec><jats:sec><jats:title>What this ' 'study adds</jats:title><jats:list ' 'list-type="simple"><jats:list-item><jats:label>-</jats:label><jats:p>Using a large ' 'non-selected population of inpatients hospitalized for COVID-19 infection in 39 hospitals in ' 'France and robust methodological approaches, we found no evidence for efficacy of HCQ on ' '28-day ' 'mortality</jats:p></jats:list-item><jats:list-item><jats:label>-</jats:label><jats:p>Our ' 'results suggest an excess risk of mortality in patients treated by a combination of HCQ and ' 'AZI, but not with HCQ ' 'alone</jats:p></jats:list-item><jats:list-item><jats:label>-</jats:label><jats:p>Significantly ' 'higher rates of discharge home were observed in patients treated by HCQ, a novel finding ' 'warranting further confirmation in replicative ' 'studies</jats:p></jats:list-item></jats:list></jats:sec></jats:sec>', 'DOI': '10.1101/2020.06.16.20132597', 'type': 'posted-content', 'created': {'date-parts': [[2020, 6, 19]], 'date-time': '2020-06-19T18:25:13Z', 'timestamp': 1592591113000}, 'source': 'Crossref', 'is-referenced-by-count': 18, 'title': 'Hydroxychloroquine with or without azithromycin and in-hospital mortality or discharge in ' 'patients hospitalized for COVID-19 infection: a cohort study of 4,642 in-patients in France', 'prefix': '10.1101', 'author': [ { 'ORCID': 'http://orcid.org/0000-0002-1267-5270', 'authenticated-orcid': False, 'given': 'Emilie', 'family': 'Sbidian', 'sequence': 'first', 'affiliation': []}, {'given': 'Julie', 'family': 'Josse', 'sequence': 'additional', 'affiliation': []}, {'given': 'Guillaume', 'family': 'Lemaitre', 'sequence': 'additional', 'affiliation': []}, {'given': 'Imke', 'family': 'Meyer', 'sequence': 'additional', 'affiliation': []}, {'given': 'Mélodie', 'family': 'Bernaux', 'sequence': 'additional', 'affiliation': []}, {'given': 'Alexandre', 'family': 'Gramfort', 'sequence': 'additional', 'affiliation': []}, {'given': 'Nathanaël', 'family': 'Lapidus', 'sequence': 'additional', 'affiliation': []}, {'given': 'Nicolas', 'family': 'Paris', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0001-7142-6728', 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