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

Liam Rose; Laura Graham; Allison Koenecke; Michael Powell; Ruoxuan Xiong; Zhu Shen; Kenneth W Kinzler; Chetan Bettegowda; Bert Vogelstein; Susan Athey; Joshua T Vogelstein; Maximilian F Konig; Todd H Wagner

doi:10.1101/2020.12.18.20248346

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

medRxiv [Preprint]. 2021 Feb 11:2020.12.18.20248346. doi: 10.1101/2020.12.18.20248346.

Authors

Liam Rose¹, Laura Graham¹, Allison Koenecke², Michael Powell³, Ruoxuan Xiong⁴, Zhu Shen⁵, Kenneth W Kinzler⁶, Chetan Bettegowda^{6

7}, Bert Vogelstein⁶, Susan Athey⁸, Joshua T Vogelstein^{3

9}, Maximilian F Konig^{6

10}, Todd H Wagner^{1

11}

Affiliations

¹ VA Health Economics Resource Center, Palo Alto VA, Menlo Park, CA, USA.
² Institute for Computational & Mathematical Engineering, Stanford University, Stanford, CA, USA.
³ Department of Biomedical Engineering, Institute for Computational Medicine, The Johns Hopkins University, Baltimore, MD, USA.
⁴ Management Science & Engineering, Stanford University, Stanford, CA, USA.
⁵ Department of Statistics, Stanford University, Stanford, CA, USA.
⁶ Ludwig Center, Lustgarten Laboratory, and the Howard Hughes Medical Institute at The Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA.
⁷ The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁸ Stanford Graduate School of Business, Stanford University, Stanford, CA, USA.
⁹ Department of Biostatistics, The Johns Hopkins Bloomberg School of Public Health at The Johns Hopkins University, Baltimore, MD, USA.
¹⁰ Division of Rheumatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, US.
¹¹ Department of Surgery, Stanford University, Stanford, CA, USA.

Abstract

Effective therapies for coronavirus disease 2019 (COVID-19) are urgently needed, and preclinical data suggest alpha-1 adrenergic receptor antagonists (α₁-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 α₁-AR antagonists and likelihood of death due to COVID-19 during hospitalization. Having an active prescription for any α₁-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 to 0.85; p ≤ 0.001) and death within 28 days of admission (relative risk reduction 17%; odds ratio 0.74; 95% CI 0.65 to 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 to 0.94; p = 0.028) compared to matched controls not on any α₁-AR antagonist at the time of admission. These findings suggest that use of α₁-AR antagonists may reduce mortality in COVID-19, supporting the need for randomized, placebo-controlled clinical trials in patients with early symptomatic infection.

Keywords: COVID-19; SARS-CoV-2; alpha-1 adrenergic receptor antagonist; catecholamine; doxazosin; hyperinflammation; in-hospital mortality; retrospective cohort study.

Publication types

Preprint

Grants and funding

T32 AR048522/AR/NIAMS NIH HHS/United States