Abstract
Effective therapies for coronavirus disease 2019 (COVID-19) are urgently needed, and pre-clinical 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 0.63–0.85; 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 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.
Highlights
The viral replication phase in Coronavirus disease 2019 (COVID-19) can be followed by a hyperinflammatory host immune response, hereafter referred to as COVID-19-associated hyperinflammation, which can lead to acute respiratory distress syndrome (ARDS), multiorgan dysfunction, and death despite maximal supportive care [1,2,3,4]
To the extent we can measure COVID-19 severity at time of admission, we find that this cohort was not operationally different from the main cohort based on vital signs at time of admission (Supplementary Figure 1)
The sample contained 25,130 patients with COVID-19, with 5,600 patients taking any α1-adrenergic receptors (ARs) antagonist at time of admission. Of those taking α1-AR antagonists, 73% of patients were on tamsulosin (n = 4,078), 12% on terazosin (n = 679), 10% on prazosin (n = 581), 4% on doxazosin (n = 215), 3% on alfuzosin (n = 186), and
Summary
The viral replication phase in Coronavirus disease 2019 (COVID-19) can be followed by a hyperinflammatory host immune response, hereafter referred to as COVID-19-associated hyperinflammation, which can lead to acute respiratory distress syndrome (ARDS), multiorgan dysfunction, and death despite maximal supportive care [1,2,3,4]. Cells of the innate and adaptive immune system (phagocytes, lymphocytes) are capable of producing catecholamines de novo and signal in an autocrine/paracrine self-regulatory fashion [9, 11]. Beyond their well-established role in neurotransmission and physiological fight-or-flight responses, catecholamines have been shown to amplify immune responses and enhance acute inflammatory injury in vitro and in vivo by increasing cytokine production in immune cells (e.g., IL-6, TNFα, MIP-2) [8, 10,11,12]. The risk of progression to mechanical ventilation and death was significantly reduced in a retrospective analysis of >300,000 patients hospitalized with pneumonia who were prescribed α1-AR antagonists prior to their index admission, suggesting that baseline inhibition of catecholamine signaling may improve clinical outcomes in acute lower respiratory tract infection or inflammation [13]. We hypothesized that early treatment with α1-AR antagonists can improve mortality and ameliorate disease in patients with symptomatic SARS-CoV-2 infection [14], but data demonstrating the efficacy of α1-AR antagonists in COVID-19 is lacking
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