4 Discussion
death, critically ill, respiratory failure, stroke, venous thromboembolism, reduced overall illness, platelet aggregation
PERIPHERAL ARTERIAL DISEASE, CRITICALLY ILL, RESPIRATORY FAILURE, STROKE, DISEASE, COVID-19 INFECTION, ADHESION, EVENTS, COMPLICATIONS, INFLUENZA
In this RCT involving 98 hospitalized patients with confirmed COVID-19, an FDA-approved standard therapeutic-dose of Aggrenox in addition to the SOC treatment did not result in significantly reduced overall illness severity on the COVID ordinal scale, all-cause mortality, or respiratory failure as compared to the patients only receiving SOC treatment. Our results refute our hypothesis that use of Aggrenox as an adjunctive therapy improves outcomes for hospitalized SARS-CoV-2 infected patients at standard dose compared with SOC treatment alone. However, as fewer instances of these outcomes occurred in patients taking Aggrenox, additional studies utilizing adenosine augmenting therapies appear warranted in the treatment of COVID-19 moving forward.Our overall hypothesis is primarily based on the scientific premise that dipyridamole (DIP) increases extracellular adenosine, a potent immunoregulatory nucleoside that interferes with inflammatory processes by modulating the biosynthesis and release of proinflammatory cytokines, slowing down the oxidative activity, preventing platelet aggregation, and reducing neutrophils adhesion and degranulation. Specifically, DIP blocks intracellular uptake of extracellularly- generated adenosine thereby increasing extracellular adenosine. This results in the up-regulation of adenosine A2A receptors (A2AR) signaling which exerts anti-inflammatory and anti-thrombotic effects through cAMP [COVID-19 induces venous and arterial micro- and macrothrombotic events resulting in complications such as venous thromboembolism, peripheral arterial disease and stroke [ATTAC-19 is the first RCT to investigate the role of Aggrenox in improving patient outcomes after COVID-19. Our results showed that in patients hospitalized with COVID-19, Aggrenox was not associated with statistically significant reductions in 28-day mortality or in the risk of progressing to invasive mechanical ventilation or death. Therefore, results from the current trial do not justify the additional use of Aggrenox on top of SOC practice for hospitalized COVID-19 patients.A number of potential hypotheses may explain our results. First, despite the controversial results demonstrated in the recent literature on in-hospital aspirin, earlier use of anti-inflammatory and anti-platelet drugs, such as Aggrenox at the beginning of symptoms may be more beneficial for moderately to critically ill patients. Preexisting aspirin prescription among COVID-19-positive veterans was found to result in a statistically and clinically significant decreases in overall mortality at 14-days (OR [95% CI]: 0.38 [0.32,0.46] and at 30-days (OR [95% CI]: 0.38 [0.33, 0.45]) [Secondly, although DIP has demonstrated the ability to indirectly reduce many of the pathogenic mechanisms of COVID-19 in other settings, such as influenza [Currently, improving vaccination rates remains the most effective method of preventing widespread viral dissemination and global morbidity and mortality due to COVID-19 infection. However, emerging data demonstrates waning immunity just 6 months after vaccination, illustrating the importance of continuing to identify prognostic markers of disease severity for earlier interventions and resource allocation as well as further examination of possible drug therapies [