Aspirin at 120: Retiring, recombining, or repurposing?

Abstract

During the past 20 years, we have witnessed the following trends in aspirin usage: (i) a "dropping" trend, characterized by the early discontinuation of low-dose aspirin from dual antiplatelet therapy or triple antithrombotic therapy (oral anticoagulation plus dual antiplatelet therapy in patients with atrial fibrillation) following an acute coronary syndrome or after percutaneous coronary intervention; (ii) a "combinatorial" trend, featuring the addition of a lower dose of a P2Y₁₂ inhibitor or direct oral anticoagulant drug to low-dose aspirin for the long-term treatment of stable patients with atherosclerotic cardiovascular disease; and (iii) a "repurposing" trend, characterized by growing interest in the oncologic community to assess the chemopreventive effect of aspirin against certain types of cancers (particularly of the gastrointestinal tract), both as primary prevention and adjuvant therapy. The aim of this review is to present the mechanistic rationale underlying these trends, discuss the design and findings of trials testing novel treatments or new therapeutic applications of aspirin, and report on the ISTH Congress results on this topic.

Keywords: P2Y12 inhibitors; aspirin; cardiovascular disease; colorectal cancer; nonsteroidal anti‐inflammatory drugs; oral anticoagulants.

FIGURE 1

One hundred twenty years of aspirin‐inspired research and development. The figure schematically summarizes the three phases of aspirin development: (A) as an analgesic, antipyretic, and anti‐inflammatory agent; (B) as an antiplatelet drug; and (C) as a chemopreventive agent. Aspirin has inspired research throughout its 120‐year life, by providing a tool for mechanistic understanding and a template for new drug development. DAPT, dual antiplatelet therapy; GI, gastrointestinal; NSAID, nonsteroidal anti‐inflammatory drug; R&D, research and development

FIGURE 2

Number needed to treat (NNT) and number needed to harm (NNH) in trials adding one or two antithrombotic drugs to low‐dose aspirin. The figure depicts the NNT and NNH values for 12 months of therapy in patients with acute coronary syndromes treated with aspirin alone (SAPT), aspirin plus clopidogrel (DAPT‐C), aspirin plus prasugrel (DAPT‐P), aspirin plus ticagrelor (DAPT‐T), aspirin plus clopidogrel and low‐dose rivaroxaban (TAT‐R), aspirin plus clopidogrel and vorapaxar (TAT‐V); aspirin plus clopidogrel and full‐dose apixaban (TAT‐A)

FIGURE 3

The platelet contribution to colorectal cancer development: early versus late phases. In the first stages of intestinal tumorigenesis, platelets may play a key role, since they are activated in response to mucosal injury, and release various soluble mediators, for example, thromboxane A₂ (TXA₂), prostaglandin E₂ (PGE₂), and various growth factors, that may contribute to the induction of several signaling pathways associated with a phenotypic switch of the stromal cells. In this scenario, the activation of stromal cells, in turn, can lead to abnormal expression of cyclooxygenase (COX)‐2 in epithelial cells. These molecular events lead to enhanced biosynthesis of the pro‐tumorigenic prostanoid, PGE₂, which is generated mainly by COX‐1 in the normal mucosa and by COX‐1/COX‐2 and COX‐2 in the adenoma and adenocarcinoma, respectively. In addition, in the late phase of tumorigenesis, tumor cells may enter into the circulation and interact with platelets. The adhesion of platelets to tumor cells leads to platelet activation and their release of mediators that induce phenotypic changes in tumor cells thereby facilitating their extravasation and colonization of distal organs. The anticancer effect of low‐dose aspirin may also be explained by the fact that the drug, in addition to platelet COX‐1, is able to acetylate and inhibit COX‐1 in intestinal epithelial cells, thus preventing both the early and late phases of intestinal tumorigenesis. Reproduced from Patrignani and Patrono, ⁸ with permission