COVID-19 outcomes among hospitalized men with or without exposure to alpha-1-adrenergic receptor blocking agents

ImportanceAlpha-1-adrenergic receptor antagonists (1-blockers) can abrogate pro-inflammatory cytokines and may improve outcomes among patients with respiratory infections. Repurposing readily available drugs such as 1-blockers could augment the medical response to the COVID-19 pandemic. ObjectiveTo evaluate the association between 1-blocker exposure and COVID-19 mortality DesignReal-world evidence study SettingPatient level data with 32,355 records tested for SARS-CoV-2 at the Mount Sinai Health System including 8,442 laboratory-confirmed cases extracted from five member hospitals in the New York City metropolitan area. Participants2,627 men aged 45 or older admitted with COVID-19 between February 24 and May 31, 2020 Exposures1-blocker use as an outpatient or while admitted for COVID-19 Main Outcomes and MeasuresIn-hospital mortality ResultsMen exposed to 1-blockers (N=436) were older (median age 73 vs. 64 years, P<0.001) and more likely to have comorbidities than unexposed men (N=2,191). Overall, 758 (28.9%) patients died in hospital, 1,589 (60.5%) were discharged, and 280 (10.7%) were still hospitalized as of May 31, 2020. Outpatient exposure to 1-blockers was not associated with COVID-19 hospital outcomes, though there was a trend towards significance (OR 0.749, 95% CI 0.527-1.064; P=0.106). Conversely, inpatient use of 1-blockers was independently associated with improved in-hospital mortality in both multivariable logistic (OR 0.633, 95% CI 0.434-0.921; P=0.017) and Cox regression analyses (HR 0.721, 95% CI 0.572-0.908; P=0.006) adjusting for patient demographics, comorbidities, and baseline vitals and labs. Age-stratified analyses suggested greater benefit from inpatient 1-blocker use among younger age groups: Age 45-65 OR 0.384, 95% CI 0.164-0.896 (P=0.027); Age 55-75 OR 0.511, 95% CI 0.297-0.880 (P=0.015); Age 65-89 OR 0.810, 95% CI 0.509-1.289 (P=0.374). Conclusions and RelevanceInpatient 1-blocker use was independently associated with improved COVID-19 mortality among hospitalized men. Clinical trials to assess the therapeutic value of 1-blockers in COVID-19 are warranted.

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.