3.6.2. Aspirin and SARS-CoV-2 Infection

The global pandemic caused by SARS-CoV-2 has over 260 million confirmed cases and 5.2 million deaths worldwide (November 2021) [137]. The clinical presentation of SARS-CoV-2 infection is variable, ranging from totally asymptomatic cases up to mild, severe or life-threatening manifestations related to the disease named COVID-19. Severe lung and systemic inflammation may develop in COVID-19 patients, with potential to induce respiratory failure, multi-organ dysfunction and finally, death. Although still largely unknown, the mechanisms underlying the most severe clinical manifestations involve hyperinflammation (the so-called cytokine storm) and a prothrombotic status, with relevant platelet activation, microvascular thrombosis and embolization. Therefore, a strong pathophysiological rationale for a potential therapeutic role for ASA in COVID-19 has been advocated because of its anti-inflammatory, antiplatelet aggregation and anticoagulant effects, as well as its modulation of the immune system and possible inhibition of viral replication and/or entry [138,139,140].

Since ASA is largely prescribed worldwide for the primary prevention of cardiovascular diseases, several studies retrospectively analyzed the effects of antiplatelet action of low-dose (81–100 mg/day) ASA in COVID-19. Based on this literature, a total of five systematic reviews with meta-analysis were published [140,141,142,143,144]. The most recent was conducted by Martha et al. and included six studies comprising 13,993 patients [141]. Overall, the meta-analysis agreed in finding that the use of low-dose ASA was significantly associated with a reduced risk of mortality compared with patients not undergoing this therapy. Only Martha’s study distinguished between individuals taking ASA routinely and those receiving low-dose ASA during hospitalization and reported that in both cases, ASA was significantly and independently associated with reduced mortality (pre-infection ASA: RR 0.46, 95% CI 0.35–0.61, p < 0.001; in-hospital ASA: RR 0.39, 95% CI 0.16–0.96, p < 0.001) [141]. However, the meta-analysis also agreed that a low certainty of evidence for the mortality-reducing effect of low-dose ASA can be assumed, mainly because of the retrospective design of the most included studies, with a possibility of relevant biases. For example, the meta-analysis included studies involving from 5 to more than 40,000 patients: only one study performed a separate meta-analysis after excluding such outliers, not confirming the effect of ASA on mortality [144].

Subsequently, two prospective clinical trials were published between October and November 2021. The first included symptomatic clinically stable outpatients with COVID-19 who were treated with ASA 81 mg/day compared to a placebo; unfortunately, this study was interrupted early, having documented an event rate lower than expected [145]. The second was a large multicentric RCT realized by the RECOVERY Collaborative Group, exploring the effect of 150 mg ASA (daily until discharge) compared to usual care in hospitalized COVID-19 patients, finding that ASA did not reduce neither the risk of invasive mechanical ventilation, nor 28-day mortality (RR 0.96, 95% CI 0.89–1.04; p = 0.35); conversely, in the ASA group, a statistically significant increase in major bleeding events was documented (1.6% vs. 1.0%; p = 0.003) [146].

In conclusion, regarding the potential effects of ASA in patients with COVID-19, the available literature reports conflicting results with low-level evidence, and the only available RCT has not confirmed the positive role of ASA. It should be noted that all the above studies explored essentially the antithrombotic effect of ASA, since at the low doses administered, the anti-inflammatory effects are limited [147]. Therefore, further RCTs are needed to prove a positive role of ASA in relevant outcomes in COVID-19 patients.