Low-dose aspirin for the prevention of atherosclerotic cardiovascular disease

Abstract

During the past 30 years, several developments have occurred in the antiplatelet field, including the role of aspirin in primary prevention of atherosclerotic cardiovascular disease. There have been several attempts to develop antiplatelet drugs more effective and safer than aspirin and a shift in emphasis from efficacy to safety, advocating aspirin-free antiplatelet regimens after percutaneous coronary intervention. Evidence supporting a chemopreventive effect of low-dose aspirin against colorectal (and other digestive tract) cancer has also strengthened. The aim of this article is to revisit the role of aspirin in the prevention of atherothrombosis across the cardiovascular risk continuum, in view of developments in the antiplatelet field. The review will offer a clinical perspective on aspirin's mechanism of action, pharmacokinetics, and pharmacodynamics. This will be followed by a detailed discussion of its clinical efficacy and safety.

Keywords: Antiplatelet therapy; Aspirin; Atherosclerotic cardiovascular disease; Atherothrombosis; Bleeding; Clopidogrel; Colorectal cancer; P2Y12 inhibitors; Ticagrelor.

Graphical Abstract

Acetylation of serine-529 (Ser-529) of platelet prostaglandin H synthase-1 by low micromolar concentrations of aspirin permanently blocks the cyclooxygenase (COX)-1 channel near the catalytic pocket. Inactivation of platelet COX-1 is cumulative upon repeated daily dosing, because of the irreversible nature of enzyme acetylation, ensuring virtually complete suppression of thromboxane (TX) A₂ biosynthesis at very low daily doses and limited interindividual variability. In randomized, placebo-controlled clinical trials, suppression of TXA₂-dependent platelet activation by low-dose aspirin reduces risk of coronary atherothrombosis and its recurrence, increases risk of gastrointestinal bleeding from pre-existing mucosal lesions, and decreases risk of sporadic colorectal (CR) adenoma recurrence. Arg-120, arginine-120; ID₅₀ = 50% inhibitory dose; MI, myocardial infarction; NNT, number needed to treat; RR, rate ratio; UGIC, upper gastrointestinal complication.

Figure 1

Mechanism of action of aspirin. Arachidonic acid, a 20-carbon fatty acid containing 4 double bonds, is liberated from the sn2 position of membrane phospholipids by several forms of phospholipase A₂, which are activated by diverse stimuli. Arachidonic acid is converted by cytosolic prostaglandin H synthases, which have both cyclooxygenase and hydroperoxidase activity, to the unstable intermediates PGG₂ and PGH₂, respectively. The synthases are colloquially termed cyclooxygenases and exist in two forms, COX-1 and COX-2. Low-dose aspirin selectively inhibits COX-1, whereas high-dose aspirin inhibits both COX-1 and COX-2. PGH₂ is converted by tissue-specific isomerases to multiple prostanoids. These bioactive lipids activate specific cell membrane receptors of the superfamily of G-protein–coupled receptors, such as the thromboxane A₂ receptor (TP), the PGD₂ receptors (DPs), the PGE₂ receptors (EPs), the PGF_2α receptors (FPs), and the prostacyclin (PGI₂) receptor (IP). COX, cyclooxygenase; HOX, hydroperoxidase. Reproduced from Patrono et al., with permission from the Massachusetts Medical Society

Figure 2

Agonists, receptors, and effector systems in platelet activation. The activation of platelets is induced by the interaction of several agonists with receptors expressed on the platelet membrane. Panels A, B, and C depict outside-in signalling mediated by thromboxane A₂, adenosine diphosphate, and thrombin, respectively. Thromboxane A₂ is synthesized by activated platelets from arachidonic acid through the cyclooxygenase pathway (A). Once formed, thromboxane A₂ can diffuse across the membrane and activate other platelets. In platelets, there are two splice variants of the TXA₂ receptor, TPα and TPβ, which differ in their cytoplasmic tail. TPα and TPβ couple to the proteins Gq and G12 or G13, all of which activate phospholipase C. Adenosine diphosphate is released from platelets and red cells. Platelets express at least two adenosine diphosphate receptors, P2Y₁ and P2Y₁₂, which couple to Gq and Gi, respectively (B). The activation of P2Y₁₂ inhibits adenylate cyclase, causing a decrease in the cyclic adenosine monophosphate level, and the activation of P2Y₁ causes an increase in the intracellular Ca²⁺ level. The P2Y₁₂ receptor is the major receptor able to amplify and sustain platelet activation in response to adenosine diphosphate. Thrombin is rapidly generated at sites of vascular injury from circulating prothrombin and, besides mediating fibrin generation, represents the most potent platelet activator (C). Platelet responses to thrombin are largely mediated through G-protein–linked protease-activated receptors, which are activated after thrombin-mediated cleavage of their N-terminal exodomain. Human platelets express PAR1 and PAR4. PAR1 couples to members of the G_12/13, G_q, and G_i protein families. Panel D depicts inside-out signalling. The effects of agonists mediated by the decrease in cAMP levels and increase in intracellular Ca²⁺ levels lead to platelet aggregation through the change in the ligand-binding properties of the glycoprotein IIb/IIIa (αIIbβ3), which acquires the ability to bind soluble adhesive proteins such as fibrinogen and von Willebrand factor. The release of adenosine diphosphate and thromboxane A₂ induces further platelet activation and aggregation. AA, arachidonic acid; ADP, adenosine diphosphate; cAMP, cyclic adenosine monophosphate; COX, cyclooxygenase; PAR, protease-activated receptors; PGH₂, prostaglandin H₂; PLA₂, phospholipase A₂; PLC, phospholipase C; TXAS, thromboxane synthase; TXA₂, thromboxane A₂. Reproduced from Davì and Patrono, with permission from the Massachusetts Medical Society

Figure 3

Aspirin antiplatelet pharmacodynamics in healthy subjects. (A) Tridimensional model of human PGG/H synthase-1. Acetylation of Ser-529 by aspirin permanently blocks the COX-1 channel near the catalytic pocket. (B) Inhibition of platelet thromboxane A₂ production by oral aspirin in healthy subjects. Thromboxane A₂ production during whole blood clotting was measured before and 24 h after a single aspirin ingestion. The results are expressed as per cent inhibition, each subject serving as his or her own control. Mean values ± 1 SD are plotted. Numbers in parentheses indicate the number of subjects for each dose of aspirin. Reproduced from Patrignani et al., J Clin Invest 1982, with permission from the American Society for Clinical Investigation. (C) Long-term effects of low-dose (0.45 mg/kg per day) aspirin on platelet thromboxane A₂ and renal PGI₂ synthesis. Serum thromboxane A₂ concentrations and urinary excretion of 6-keto-PGF_Iα were measured in three healthy subjects before, during, and after aspirin therapy. Mean values ± SEM are plotted. Reproduced from Patrignani et al., J Clin Invest 1982, with permission from the American Society for Clinical Investigation. (D) Dose dependence of the inhibition of platelet thromboxane B₂ production by aspirin. Serum thromboxane B₂ was measured before and after single (▴) or daily (●) dosing with aspirin in four healthy subjects. Individual data are expressed as per cent inhibition, with each subject serving as his or her own control. Daily dosing values represent measurements obtained at steady-state inhibition. ID₅₀ = 50% inhibitory dose. Reproduced from Patrono et al., with permission from Wolters Kluwer Health, Inc. SD, standard deviation; ID₅₀, 50% inhibitory dose; TXB₂, thromboxane B₂

Figure 4

Platelet biochemical and functional assays before and during aspirin intake in healthy subjects. Maximal aggregation (T_max) values of adenosine diphosphate (A), collagen-induced (B), and arachidonic acid–induced (C) aggregation; aspirin response units of VerifyNow Aspirin (D); and absolute values of serum thromboxane B₂ (E) and urinary 11-dehydro-thromboxane B₂ (F) at baseline and during aspirin intake. Values are mean ± standard deviation of baseline [week 0 (n = 48), week 1 (n = 47), week 2 (n = 42), week 3 (n = 34), week 4 (n = 28), week 5 (n = 23), week 6 (n = 17), week 7 (n = 11), and week 8 (n = 6)]. *P < .01 vs. baseline. ^#P < .001 vs. baseline. Reproduced from Santilli et al., with permission from Elsevier

Figure 5

Model of altered aspirin pharmacodynamics in essential thrombocythemia. Upper panel: under conditions of normal megakaryopoiesis (healthy subjects), low-dose aspirin acetylates cyclooxygenase isozymes in both circulating platelets and bone marrow megakaryocytes, and negligible amounts of unacetylated enzymes are resynthesized within the 24 h dosing interval. This pharmacodynamic pattern is associated with virtually complete suppression of platelet thromboxane A₂/B₂ production in clotted peripheral blood throughout the dosing interval. Under conditions of abnormal megakaryopoiesis such as in essential thrombocythemia, an accelerated rate of cyclooxygenase isozyme resynthesis occurs in bone marrow megakaryocytes and platelet precursors, accompanied by faster peripheral release of immature platelets with unacetylated enzyme(s) during the aspirin dosing interval and in particular between 12 and 24 h after dosing. This pharmacodynamic pattern is associated with incomplete suppression of platelet thromboxane A₂ production in peripheral blood and time-dependent recovery of thromboxane A₂–dependent platelet function during the 24 h dosing interval. Lower panel: when low-dose aspirin is administered more frequently (i.e. twice daily), the daily platelet thromboxane A₂ production in the peripheral blood of essential thrombocythemia patients is steadily inhibited. ET, essential thrombocythemia; TXB₂, thromboxane B₂

Figure 6

Absolute effects of antiplatelet therapy with aspirin on the risk of vascular events (non-fatal myocardial infarction, non-fatal stroke, or death from vascular causes) in five groups of high-risk patients. The figure is based on an analysis of data from the Antithrombotic Trialists’ Collaboration. Reproduced from Patrono et al., with permission from the Massachusetts Medical Society

Figure 7

Inducing new gastroduodenal lesions versus enhancing bleeding from pre-existing lesions. (A) Gastroduodenal erosions and ulcers induced by non-steroidal anti-inflammatory drugs. (B) Twelve-week cumulative incidences of gastroduodenal ulcers in osteoarthritis patients treated with low-dose aspirin, placebo, or ibuprofen. The figure was drawn with data from Laine et al., Gastroenterology 2004. (C) Gastrointestinal complications induced by non-steroidal anti-inflammatory drugs. (D) Estimated rates of upper gastrointestinal complications in men, according to age and the presence or absence of a history of such complications and regular treatment with low-dose aspirin. The vertical lines connecting each pair of black and red symbols depict the absolute excess of complications related to aspirin therapy. Reproduced from Patrono et al., with permission from the Massachusetts Medical Society

Figure 8

Stages of colorectal carcinogenesis and aspirin chemopreventive effects. The figure depicts the three clinical settings in which aspirin and other cyclooxygenase inhibitors have been or are being evaluated by randomized clinical trials. CR, colorectal; CRC, colorectal cancer; Lynch S., Lynch syndrome; RCT, randomized controlled trial. Reproduced from Patrono, with permission from the American Society for Pharmacology and Experimental Therapeutics

Figure 9

Role of platelet activation in vascular tissue repair and atherothrombosis. The intensity and duration of the haemostatic response to coronary plaque erosion or rupture is controlled by a local balance between stimuli to platelet activation and counter-regulatory thromboresistance mechanisms (e.g. endothelial prostacyclin synthesis) of the vessel wall and fibrinolysis. Increased thromboxane A₂–dependent platelet activation, in concert with impaired endothelial thromboresistance mechanisms (e.g. because of non-steroidal anti-inflammatory drug use), may favour uncontrolled progression towards vascular occlusion over physiological tissue repair and plaque healing