The Reply.

We thank Drs Chiang and Gupta for their thoughtful comments on our paper relating to thromboxane A2 activation and thrombosis in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; coronavirus disease 2019 [COVID-19]) infection. We share the same concerns that there may be an overwhelming activation of this pathway that could overcome the inhibitory effects of aspirin on cyclooxygenase-1 and induce the converse process of “aspirin resistance.” Recently Chow et al reported that 23.7% of hospitalized patients received antecedent aspirin and after adjustment, aspirin use was associated with decreased risk of mechanical ventilation (adjusted hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.37-0.85, P = .007), admission to the intensive care unit (adjusted HR 0.57, 95% CI 0.38-0.85, P = .005), and in-hospital mortality (adjusted HR 0.53, 95% CI 0.31-0.90, P = .02). There were no differences in major bleeding (P = .69) or overt thrombosis (P = .82) between aspirin users and nonaspirin users. The National Institutes of Health Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-4) Program (N = 7000) started September 7, 2020, is testing placebo, aspirin 81 mg, apixaban 2.5 mg twice daily, or apixaban 5 mg orally twice daily. It would be ideal if current patients could be enrolled, and if not feasible, we advise aspirin 325 mg every day, and in higher-risk patients, apixaban 5 mg orally twice daily or enoxaparin 40 mg subcutaneously twice daily. Given the fatal nature of progressive COVID-19, we are uncomfortable with therapeutic nihilism outside of monitored placebo-controlled randomized trials. We look forward to the late results of ACTIV-4 and the development of novel agents such as ramatroban, which could address the inflammatory component of pathologic platelet-rich thrombosis in COVID-19. ,