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

  1. Emilie Sbidian
  2. Julie Josse
  3. Guillaume Lemaitre
  4. Imke Meyer
  5. Mélodie Bernaux
  6. Alexandre Gramfort
  7. Nathanaël Lapidus
  8. Nicolas Paris
  9. Antoine Neuraz
  10. Ivan Lerner
  11. Nicolas Garcelon
  12. Bastien Rance
  13. Olivier Grisel
  14. Thomas Moreau
  15. Ali Bellamine
  16. Pierre Wolkenstein
  17. Gaël Varoquaux
  18. Eric Caumes
  19. Marc Lavielle
  20. Armand Mekontso Dessap
  21. Etienne Audureau
  22. AP-HP Covid CDR Initiative and ‘Entrepôt de Données de Santé’ AP-HP consortium

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Abstract

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 1 st , 2020 and April 6 th , 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

  • -

    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

  • -

    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

  • -

    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

  • -

    Our results suggest an excess risk of mortality in patients treated by a combination of HCQ and 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

    • Article activity feed

    1. ScreenIT

      SciScore for 10.1101/2020.06.16.20132597: (What is this?)

      Please note, not all rigor criteria are appropriate for all manuscripts.

      Table 1: Rigor

      Institutional Review Board Statementnot detected.
      Randomizationnot detected.
      Blindingnot detected.
      Power Analysisnot detected.
      Sex as a biological variablenot detected.

      Table 2: Resources

      Software and Algorithms
      SentencesResources
      Using data acquisition procedures previously detailed, we identified patients with a prescription of HCQ (ATC P01BA02), AZI (ATC J01FA10), steroids (ATC H02AB), and antithrombotic agents (heparin group, ATC B01AB) usually used for acute respiratory distress syndrome.14,15 Exposure to a HCQ/AZI combination was defined as a simultaneous prescription of the two treatments (within one day).
      ATC
      suggested: None

      Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

      Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
      Study’s limitations include the absence of direct, clinical information on regimen duration and dosages, and respiratory parameters of COVID-19 infection, including oxygen requirement, non-invasive or mechanical ventilation, which are potential confounders. However, we used biological parameters proxy to assess the severity of the COVID-19 infection including creatine, lymphocyte count and inflammatory markers (D-Dimer and C-Reactive protein) well known to be associated with severity of COVID-1921Yet, causal interpretation of our findings relying on retrospective evaluation of medical records should remain cautious considering the observational nature of the study design.

      Results from TrialIdentifier: No clinical trial numbers were referenced.

      Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

      Results from JetFighter: We did not find any issues relating to colormaps.

      Results from rtransparent:
      • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
      • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
      • No protocol registration statement was detected.

      About SciScore

      SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

    2. ScreenIT

      SciScore for 10.1101/2020.06.16.20132597: (What is this?)

      Please note, not all rigor criteria are appropriate for all manuscripts.

      Table 1: Rigor

      Institutional Review Board Statementnot detected.RandomizationAltogether , our findings further support the need to complete currently undergoing randomized clinical trials .Blindingnot detected.Power Analysisnot detected.Sex as a biological variablePatients 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 .

      Table 2: Resources

      Software and Algorithms
      SentencesResources
      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)
      ATE
      suggested: None
      Using data acquisition procedures previously detailed , we identified patients with a prescription of HCQ ( ATC P01BA02) , AZI ( ATC J01FA10)
      ATC
      suggested: None

      Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:

      • Study's limitations include the absence of direct, clinical information on regimen duration and dosages, and respiratory parameters of COVID-19 infection, including oxygen requirement, non-invasive or mechanical ventilation, which are potential confounders.
      • However, we used biological parameters proxy to assess the severity of the COVID-19 infection including creatine, lymphocyte count and inflammatory markers (D-Dimer and C-Reactive protein) well known to be associated with severity of COVID-19.

      Results from OddPub: We did not find a statement about open data. We also did not find a statement about open code. Researchers are encouraged to share open data when possible (see Nature blog).

      About SciScore

      SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore is not a substitute for expert review. SciScore checks for the presence and correctness of RRIDs (research resource identifiers) in the manuscript, and detects sentences that appear to be missing RRIDs. SciScore also checks to make sure that rigor criteria are addressed by authors. It does this by detecting sentences that discuss criteria such as blinding or power analysis. SciScore does not guarantee that the rigor criteria that it detects are appropriate for the particular study. Instead it assists authors, editors, and reviewers by drawing attention to sections of the manuscript that contain or should contain various rigor criteria and key resources. For details on the results shown here, including references cited, please follow this link.

    3. Version published to 10.1101/2020.06.16.20132597v1 on medRxiv