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

Effective therapies for coronavirus disease 2019 (COVID-19) are urgently needed, and preclinical data suggest alpha-1 adrenergic receptor antagonists (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 1-AR antagonists and likelihood of death due to COVID-19 during hospitalization. Having an active prescription for any 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 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 1-AR antagonist at the time of admission. These findings suggest that use of 1-AR antagonists may reduce mortality in COVID-19, supporting the need for randomized, placebo-controlled clinical trials in patients with early symptomatic infection.

Targeting the catecholamine-cytokine axis to prevent SARS-CoV-2 cytokine storm syndrome

In Coronavirus disease 2019 (COVID-19), the initial viral-replication phase is often followed by a hyperinflammatory reaction in the lungs and other organ systems that leads to acute respiratory distress syndrome (ARDS), the need for mechanical ventilation, and death despite maximal supportive care. As no antiviral treatments have yet proven effective, efforts to prevent progression to the severe stages of COVID-19 without inhibiting antiviral immune responses are desperately needed. We have previously demonstrated that a common, inexpensive, and well-tolerated class of drugs called alpha-1 adrenergic receptor (1-AR) antagonists can prevent hyperinflammation ("cytokine storm") and death in mice. We here present clinical data that supports the use of 1-AR antagonists in the prevention of severe complications of pneumonia, ARDS, and COVID-19.