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
Authors: Sbidian Emilie , Josse Julie , Lemaitre Guillaume , Meyer Imke , Bernaux Mélodie , Gramfort Alexandre , Lapidus Nathanaël , Paris Nicolas , Neuraz Antoine , Lerner Ivan , Garcelon Nicolas , Rance Bastien , Grisel Olivier , Moreau Thomas , Bellamine Ali , Wolkenstein Pierre , Varoquaux Gaël , Caumes Eric , Lavielle Marc , Dessap Armand Mekontso , Audureau Etienne ,   AP-HP Covid CDR Initiative and ‘Entrepôt de Données de Santé’ AP-HP consortium
Published: June 2020

Objective

To assess the clinical effectiveness of oral hydroxychloroquine (HCQ) with or without azithromycin (AZI) in preventing death or leading to hospital discharge.

Design

Retrospective cohort study.

Setting

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.

Participants

All adult inpatients with at least one PCR-documented SARS-CoV-2 RNA from a nasopharyngeal sample between February 1st, 2020 and April 6th, 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.

Intervention

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).

Main outcome measures

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.

Results

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).

Conclusions

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.

WHAT THIS PAPER ADDS?

What is already known on this subject

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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

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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

What this study adds

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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

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Our results suggest an excess risk of mortality in patients treated by a combination of HCQ and AZI, but not with HCQ alone

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Significantly higher rates of discharge home were observed in patients treated by HCQ, a novel finding warranting further confirmation in replicative studies