Association between benzodiazepine receptor agonist use and mortality in patients hospitalised for COVID-19: a multicentre observational study

  1. N. Hoertel
  2. M. Sánchez-Rico
  3. E. Gulbins
  4. J. Kornhuber
  5. R. Vernet
  6. N. Beeker
  7. A. Neuraz
  8. C. Blanco
  9. M. Olfson
  10. G. Airagnes
  11. C. Lemogne
  12. J. M. Alvarado
  13. M. Arnaout
  14. C. Cougoule
  15. P. Meneton
  16. F. Limosin

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Abstract

Aims

To examine the association between benzodiazepine receptor agonist (BZRA) use and mortality in patients hospitalised for coronavirus disease 2019 (COVID-19).

Methods

A multicentre observational study was performed at Greater Paris University hospitals. The sample involved 14 381 patients hospitalised for COVID-19. A total of 686 (4.8%) inpatients received a BZRA at hospital admission at a mean daily diazepam-equivalent dose of 19.7 mg (standard deviation ( s.d. ) = 25.4). The study baseline was the date of admission, and the primary endpoint was death. We compared this endpoint between patients who received BZRAs and those who did not in time-to-event analyses adjusted for sociodemographic characteristics, medical comorbidities and other medications. The primary analysis was a Cox regression model with inverse probability weighting (IPW).

Results

Over a mean follow-up of 14.5 days ( s.d. = 18.1), the primary endpoint occurred in 186 patients (27.1%) who received BZRAs and in 1134 patients (8.3%) who did not. There was a significant association between BZRA use and increased mortality both in the crude analysis (hazard ratio (HR) = 3.20; 95% confidence interval (CI) = 2.74–3.74; p < 0.01) and in the IPW analysis (HR = 1.61; 95% CI = 1.31–1.98, p < 0.01), with a significant dose-dependent relationship (HR = 1.55; 95% CI = 1.08–2.22; p = 0.02). This association remained significant in sensitivity analyses. Exploratory analyses indicate that most BZRAs may be associated with an increased mortality among patients hospitalised for COVID-19, except for diazepam, which may be associated with a reduced mortality compared with any other BZRA treatment.

Conclusions

BZRA use may be associated with an increased mortality among patients hospitalised for COVID-19, suggesting the potential benefit of decreasing dose or tapering off gradually these medications when possible.

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  1. Version published to 10.1017/s2045796021000743
  2. ScreenIT

    SciScore for 10.1101/2021.02.18.21252004: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: This observational study using routinely collected data received approval from the Institutional Review Board of the AP-HP clinical data warehouse (decision CSE-20-20_COVID19, IRB00011591).
    Consent: AP-HP clinical Data Warehouse initiatives ensure patient information and informed consent regarding the different approved studies through a transparency portal in accordance with European Regulation on data protection and authorization n°1980120 from National Commission for Information Technology and Civil Liberties (CNIL).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    All analyses were conducted in R software version 2.4.3 (R Project for Statistical Computing).
    R Project for Statistical
    suggested: (R Project for Statistical Computing, RRID:SCR_001905)

    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:
    Our study has several limitations. First, there are two possible major inherent biases in observational studies: unmeasured confounding and confounding by indication. We tried to minimize the effects of confounding in several different ways. First, we used an analysis with inverse probability weighting to minimize the effects of confounding by indication (19,28). Second, we performed multiple sensitivity analyses, which showed similar results. Finally, although some amount of unmeasured confounding may remain, our analyses adjusted for numerous potential confounders. Other limitations include missing data for some baseline characteristic variables (i.e., 11.5%), which might be explained by the overwhelming of all hospital units during the COVID-19 peak incidence, and different results might have been observed during a lower COVID-19 incidence period. However, imputation of missing data did not alter the significance of our results. Second, inflation of type I error might have occurred in secondary analyses due to multiple testing. Third, our study cannot establish a causal relationship between BZRA use and increased mortality. Finally, despite the multicenter design, our results may not be generalizable to outpatients or other regions. In this multicenter observational retrospective study, benzodiazepine receptor agonist use was significantly and substantially associated with increased mortality among adult patients hospitalized for COVID-19, with a significant dose-dependent...

    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.

  3. Version published to 10.1101/2021.02.18.21252004v1 on medRxiv