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
Emilie Sbidian, Julie Josse, Guillaume Lemaitre, Imke Meyer, Mélodie Bernaux, Alexandre Gramfort, Nathanaël Lapidus, Nicolas Paris, Antoine Neuraz, Ivan Lerner, Nicolas Garcelon, Bastien Rance, Olivier Grisel, Thomas Moreau, Ali Bellamine, Pierre Wolkenstein, Gaël Varoquaux, Eric Caumes, Marc Lavielle, Armand Mekontso Dessap, Etienne Audureau
doi:10.1101/2020.06.16.20132597
Data sharing The data are available on request.
Transparency The manuscript's guarantors (ES) affirm that this manuscript is an honest, accurate and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.
Abbreviations: SD, Standard deviation; HCQ:hydroxychloroquine, IQR : interquartile 25
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'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>',
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