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Fig. 2. Schematic depiction of the GP Ilb/IIIa receptor (also known as aIIbb3 in the integrin nomenclature). Platelet agonists induce "inside-out" signaling, leading to the modulation of the ligand-binding affinity of the receptor. On the other hand, ligand-binding to GP IIb/IIIa induces "outside-in" signaling through GP IIb/IIIa, leading to the activation of intracellular signaling pathways. Courtesy of Jose A. Lopez, M.D.

Fig. 2. Schematic depiction of the GP Ilb/IIIa receptor (also known as aIIbb3 in the integrin nomenclature). Platelet agonists induce "inside-out" signaling, leading to the modulation of the ligand-binding affinity of the receptor. On the other hand, ligand-binding to GP IIb/IIIa induces "outside-in" signaling through GP IIb/IIIa, leading to the activation of intracellular signaling pathways. Courtesy of Jose A. Lopez, M.D.

Fig. 3. Under resting conditions, GP Ilb/IIIa has a low affinity for its ligands. After platelet activation, GP IIb/IIIa becomes receptive to ligand-binding. As a result of outside-in signaling induced by ligand binding, ligand-induced binding sites (LIBS) (neo-epitopes) are expressed on the receptor. In addition, receptor-induced binding sites (RIBS) on the ligand may also be expressed as a result of the interaction between the ligand and its receptor. Courtesy of Jose A. Lopez, M.D.

Fig. 3. Under resting conditions, GP Ilb/IIIa has a low affinity for its ligands. After platelet activation, GP IIb/IIIa becomes receptive to ligand-binding. As a result of outside-in signaling induced by ligand binding, ligand-induced binding sites (LIBS) (neo-epitopes) are expressed on the receptor. In addition, receptor-induced binding sites (RIBS) on the ligand may also be expressed as a result of the interaction between the ligand and its receptor. Courtesy of Jose A. Lopez, M.D.

Although aspirin is a potent inhibitor of platelet aggregation induced by arachidonic acid, it is a relatively weak antiplatelet agent when platelets are stimulated by a number of other agonists including ADP and thrombin. Aspirin does not prevent a-granule release in response to platelet agonists and does not inhibit epinephrine-induced platelet aggregation (34). Although aspirin blocked cyclic flow variations in a canine model of coronary stenosis and endothelial injury, this inhibition was overcome by the addition of epinephrine (35). In spite of these observations, there is abundant evidence of the clear clinical efficacy of aspirin as an antiplatelet agent.

Aspirin is readily absorbed in the stomach and small intestine, with a systemic bioavailability approaching 50% for single doses in the range of 20-1300 mg (36). Although salicylate levels in the portal vein increase within 5 min after aspirin ingestion, the time required to exert a clinically meaningful antiplatelet effect is not clear. In healthy volunteers, inhibition of arachidonic acid-induced platelet aggregation and TXA2 production were demonstrated within 15 min after the ingestion of 81 mg of aspirin (37). However, inhibition of thrombin-induced TXA2 generation in clotting blood probably does not occur until approx 24 h after the ingestion of 75 mg of aspirin (36).

Fig. 4. Activation of a resting platelet by a variety of agonists and the change in GP IIb/IIIa upon activation, leading to platelet aggregation. The mechanism of action of aspirin, thienopyridines, and GP IIb/IIIa antagonists is indicated. Courtesy of Jose A. Lopez, M.D.

Clinical Uses

The consistent and beneficial effects of aspirin have been documented in hundreds of thousands of patients suffering various manifestations of cardiovascular disease. In a meta-analysis of more than 75,000 patients with preexisting cardiovascular disease enrolled in several secondary prevention trials, aspirin reduced the combined end point of vascular death, myocardial infarction, and stroke by 27% in a highly significant way (38). More recently, in the Primary Prevention Project, low-dose aspirin (100 mg) reduced the risk of cardiovascular death by 44% among patients with at least one cardiovascular risk factor but with no known vascular disease, thus extending the indication of aspirin into a setting of primary prevention (39). Furthermore, in the Second International Study of Infarct Survival (ISIS-2) study, aspirin (162.5 mg) was as effective as streptokinase in reducing 5-wk vascular mortality in patients with suspected acute myocardial infarction (40). In consequence, because the ISIS-2

The benefits of aspirin in unstable angina pectoris have been clearly established by four major well-controlled clinical trials (Table 2). In the Veterans Administration Cooperative study (41), 1266 men were randomized to 324 mg of aspirin or placebo. At 3 mo, the combined risk of death or nonfatal myocardial infarction was reduced by 51% (10.1 vs 5%). This benefit was maintained at 12 mo with a 43% risk reduction of the combined end point, even though the study drugs were stopped 3 mo after enrollment. In the Canadian Multicenter Trial, 555 patients with unstable angina pectoris were randomized to receive aspirin, sulfinpyrazone, both, or placebo (42). At 2 yr, the risk reduction for the combined end point of cardiac death and nonfatal myocardial infarction, by intention-to-treat analysis, was 30%. An efficacy analysis for cardiac death alone showed a reduction of 70%. The Montreal Heart Institute study included 479 patients with unstable angina pectoris randomized to receive aspirin, heparin, both, or neither (43). Patients treated with aspirin had a risk reduction of 71% for in-hospital myocardial infarction. In the RISC study (44), 796 patients with unstable angina or non-Q wave myocardial infarction were randomized to aspirin, an intermittent bolus of heparin, both, or placebo. Risk reduction in the aspirin group was 57% at 5 d, 69% at 30 d, and 61% at 3 mo.

These observations have led to the firm recommendation that aspirin be administered to all patients as part of a primary and secondary prevention strategy for cardiovascular disease, to all patients undergoing PCI, and to all patients presenting with either a non-ST-elevation ACS or an acute myocardial infarction, unless they have a contraindication to its use.

Aspirin Dose

The dose of aspirin required to achieve optimal clinical response remains controversial. The dose-response effect of aspirin on platelet aggregation and TXA2 production is log-linear, but reaches a plateau at approx 80 mg (45). Lower doses can inhibit platelet aggregation without blocking the vascular production of vasodilating and anti-aggrega-tory prostaglandins, and also limit the frequency of gastrointestinal side effects (46,47). Therefore, theoretical reasons exist to favor low doses of aspirin vs higher doses. The meta-analysis performed by the Antiplatelet Trialists' Collaboration did not find lower aspirin doses (<350 mg) to be superior to higher doses in the prevention of cardiovascular events (38). A Dutch study involving 3131 patients with transient ischemic attacks compared the effects of aspirin 30 mg/d with 283 mg daily on the incidence of vascular death, stroke, or myocardial infarction. After a mean follow-up of 2.6 yr, there was no

Table 2

Major Trials of Aspirin, Heparin and Ticlopidine in Syndromes of Non-ST-Segment Elevation MI

Table 2

Major Trials of Aspirin, Heparin and Ticlopidine in Syndromes of Non-ST-Segment Elevation MI

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