The Association Between Alpha-1 Adrenergic Receptor Antagonists and In-Hospital Mortality From COVID-19

  1. Liam Rose
  2. Laura Graham
  3. Allison Koenecke
  4. Michael Powell
  5. Ruoxuan Xiong
  6. Zhu Shen
  7. Brett Mench
  8. Kenneth W. Kinzler
  9. Chetan Bettegowda
  10. Bert Vogelstein
  11. Susan Athey
  12. Joshua T. Vogelstein
  13. Maximilian F. Konig
  14. Todd H. Wagner

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Abstract

Effective therapies for coronavirus disease 2019 (COVID-19) are urgently needed, and pre-clinical data suggest alpha-1 adrenergic receptor antagonists (α 1 -AR antagonists) may be effective in reducing mortality related to hyperinflammation independent of etiology. Using a retrospective cohort design with patients in the Department of Veterans Affairs healthcare system, we use doubly robust regression and matching to estimate the association between baseline use of α 1 -AR antagonists and likelihood of death due to COVID-19 during hospitalization. Having an active prescription for any α 1 -AR antagonist (tamsulosin, silodosin, prazosin, terazosin, doxazosin, or alfuzosin) at the time of admission had a significant negative association with in-hospital mortality (relative risk reduction 18%; odds ratio 0.73; 95% CI 0.63–0.85; p ≤ 0.001) and death within 28 days of admission (relative risk reduction 17%; odds ratio 0.74; 95% CI 0.65–0.84; p ≤ 0.001). In a subset of patients on doxazosin specifically, an inhibitor of all three alpha-1 adrenergic receptors, we observed a relative risk reduction for death of 74% (odds ratio 0.23; 95% CI 0.03–0.94; p = 0.028) compared to matched controls not on any α 1 -AR antagonist at the time of admission. These findings suggest that use of α 1 -AR antagonists may reduce mortality in COVID-19, supporting the need for randomized, placebo-controlled clinical trials in patients with early symptomatic infection.

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  1. Version published to 10.3389/fmed.2021.637647
  2. ScreenIT

    SciScore for 10.1101/2020.12.18.20248346: (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 variableBecause over 90% of α1-AR antagonist users in the analysis were older men, we excluded women to reduce unmeasured confounding unrelated to COVID-19, specifically with respect to respiratory conditions.

    Table 2: Resources

    No key resources detected.

    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:
    This study has important strengths and weaknesses. We have focused on mortality as a definitive clinical outcome, thereby avoiding process measures, such as use of mechanical ventilators or admission to an ICU, that are subject to local and individual practice patterns and would be biased if clinicians or hospitals changed their practices in unobserved ways. Another strength is our use of information prior to the COVID-19 admission for risk adjustment. One limitation in this study was the exclusion of women which was required due to limitations in samples size since α1-AR antagonists are most commonly used to treat benign prostatic hyperplasia and 90% of patients in the VA system are men (26). A second limitation, best addressed in prospective clinical trials, was our inability to examine dose effects given our sample size. Our results suggest that inhibition of catecholamine signaling with doxazosin (and other α1-AR antagonists) may reduce in-hospital and 28-day mortality in patients with COVID-19 and highlight the need for randomized placebo-controlled clinical trials to examine the efficacy of α1-AR antagonists for improving survival and preventing adverse outcomes from COVID-19. Importantly, α1-AR antagonists are inexpensive, administered orally, do not require refrigeration, and have a well-established safety profile. Thus, if trials confirm these results, α1-AR antagonists could be widely deployed to reduce mortality from inflammatory injury. Importantly, α1-AR antagoni...

    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 10.1101/2020.12.18.20248346v2 on medRxiv
  4. Version published to 10.1101/2020.12.18.20248346v1 on medRxiv