Aspirin is rapidly absorbed in the stomach and upper intestine. Peak plasma levels occur 30 to 40 minutes after oral intake, and maximal inhibition of platelet function is achieved by 1 hour.² In contrast, it can take up to 3 to 4 hours to reach peak plasma levels after the oral administration of enteric-coated aspirin. The oral bioavailability of regular aspirin tablets is approximately 50% over a wide range of doses,⁶ because of deacetylation of the drug during passage through the liver (first-pass effect). However, substantial variability has been reported in the oral bioavailability of enteric-coated aspirin formulations.⁷ Poor absorption from the higher pH environment of the small intestine and lower bioavailability of some enteric-coated aspirin preparations may result in inadequate platelet inhibition, particularly in heavier subjects.⁷

The plasma concentration of aspirin decays with a half-life of 15 to 20 minutes.² Despite the rapid clearance of the intact drug moiety from the circulation, aspirin induces a long-lasting functional defect in human platelets. This appears to be primarily, if not exclusively, due to permanent inactivation by aspirin of a key enzyme in platelet arachidonate metabolism (FIGURE 111.2). This enzyme, prostaglandin (PG) H-synthase 1, is responsible for the formation of PGH₂, the precursor of TXA₂. In human platelets, TXA₂ provides a mechanism for amplifying the activation signal by being synthesized and released in response to various platelet agonists (e.g., collagen, adenosine diphosphate [ADP], platelet-activating factor, thrombin) and, in turn, inducing irreversible aggregation.¹

Aspirin selectively acetylates the hydroxyl group of a single serine residue at position 529 (Ser⁵²⁹) within the polypeptide chain of platelet PGH-synthase 1. This enzyme exhibits two distinct catalytic activities: a bis-oxygenase (cyclooxygenase [COX]) involved in formation of PGG₂ and a hydroperoxidase (HOX) allowing a net two-electron reduction in the 15-hydroperoxyl group of PGG₂, thus yielding PGH₂ (FIGURE 111.2). An inducible form of PGH-synthase has been identified and termed PGH-synthase 2 or COX-2.⁸ While newly formed platelets can express both COX-1 and COX-2,⁹ mature platelets primarily display COX-1 activity. As a consequence of O-acetylation of Ser⁵²⁹ by aspirin, the COX activity of the enzyme is lost permanently, whereas the HOX activity is not affected. The highly hydrophobic environment of the COX-1 channel stabilizes the aspirinmodified serine side chain against hydrolysis. As a result of this permanent modification of the enzyme, COX activity can only resume through new protein synthesis (occurring within a few hours in nucleated cells) or cell turnover (occurring at a daily rate of 10% to 12% in the case of human platelets).² Aspirin is equally potent in acetylating COX-1 and COX-2, when tested in vitro.¹⁰ However, its unique mechanism of action and unusual pharmacokinetic features⁶ (short half-life and presystemic encounter with the platelet target in the portal blood prior to first-pass liver metabolism) allow selective, cumulative inhibition of platelet COX-1 at low doses while substantially sparing endothelial COX-2.² Whereas the effect of aspirin on COX-1-dependent TXA₂ production is saturable at daily doses as low as 30 mg,¹¹ its inhibitory effect on COX-2-derived PGI₂ production is dose dependent up to daily doses of 650 to 1,300 mg.¹²

The strikingly nonlinear relationship between inactivation of platelet COX-1 and inhibition of TXA₂-dependent platelet function by low-dose aspirin (i.e., relatively limited inhibition of platelet function between 0% and 95% inhibition of COX-1; exponential increase in platelet inhibition between 97% and 100% COX-1 inactivation)¹³, ¹⁴ has important clinical implications: (a) a substantial loss of platelet inhibition is associated

with less than maximal inactivation of COX-1; (b) recovery of platelet function is disproportionately rapid upon drug withdrawal; and (c) the requirement for virtually complete and persistent inhibition of platelet COX-1 cannot be met by most traditional NSAIDs, allowing their COX-2-dependent cardiotoxicity to be unmasked.¹⁵

A very large database of randomized clinical trials (RCTs) now offers the most compelling evidence that prevention of myocardial infarction and ischemic stroke by aspirin is largely due to permanent inactivation of platelet COX-1.², ⁵ These studies, which tested the efficacy and safety of the drug when given at daily doses ranging from as low as 30 mg to as high as 1,500 mg, have established two important facts. First, the antithrombotic effect of aspirin is saturable at doses in the range of 50 to 100 mg, as would be expected from human studies of platelet COX-1 inactivation.¹¹ Second, despite a half-life of approximately 20 minutes in the human circulation, the antithrombotic effect of aspirin is observed with a dosing interval of 24 to 48 hours, reflecting the permanent nature of platelet COX-1 inactivation and the duration of TXA₂ suppression following oral dosing in human.¹¹ Other mechanisms of action that have been suggested to contribute to the antithrombotic effect of aspirin, such as a direct anti-inflammatory effect of the drug, are incompatible with these unique properties, because they require higher doses and shorter dosing interval.²

Aspirin’s unique feature in inhibiting platelet COX-1—its ability to inactivate the enzyme permanently through a short-lived active moiety—is ideally suited to its role as an antiplatelet drug, because it limits the extent and duration of extraplatelet effects of the drug, including the inhibition of PGI₂.¹² Moreover, the cumulative nature of platelet COX-1 acetylation by repeated low doses of aspirin¹¹ explains the clinical efficacy of doses as low as 30 to 50 mg daily,² the predictable high-grade inhibition of platelet TXA₂ biosynthesis,¹⁴ and the persistence of the drug’s effect.² These features, in turn, may limit the consequences of less-than-ideal compliance in a real world setting.

Permanent inactivation of platelet COX-1 by aspirin may lead to the prevention of atherothrombosis as well as to excess bleeding. At least two distinct COX-1-dependent mechanisms contribute to the increased risk of upper gastrointestinal (GI) bleeding associated with aspirin exposure: inhibition of TXA₂-mediated platelet function and impairment of PGE₂-mediated cytoprotection in the GI mucosa.² Whereas the former effect is dose independent for daily doses >30 mg, the latter effect is clearly dose dependent.² Inhibition of platelet function is largely responsible for the twofold increase in the risk of upper GI bleeding associated with daily doses of aspirin in the range of 75 to 100 mg, inasmuch as a similar relative risk (RR) is associated with other antiplatelet agents (e.g., clopidogrel) that do not act on COX and therefore do not affect PGE₂-mediated cytoprotection.¹⁶ Inhibition of COX-1-dependent cytoprotection of the GI mucosa amplifies the risk of bleeding/perforation by causing new mucosal lesions or aggravating existing ones and is associated with a RR of four to six at the higher, analgesic, or anti-inflammatory doses of aspirin.²

The hypothesis that both the reduction in atherothrombotic complications and the increase in bleeding events are primarily due to inhibition of platelet TXA₂ biosynthesis is supported by the recent finding that a highly selective TXA₂ receptor (TP) antagonist, terutroban, and low-dose (100 mg daily) aspirin were associated with virtually identical rates of recurrent vascular events and major bleeds in an RCT of over 19,000 patients with a recent stroke.¹⁷ The possibility that aspirin may exert “pleiotropic” effects at low doses is not incompatible with a single mechanism of action, that is, inactivation of platelet COX-1, explaining antithrombotic, anti-inflammatory, and antiproliferative effects of the drug. In fact, there may be “pleiotropic” consequences of platelet inhibition by low-dose aspirin, resulting from reduced release of platelet-active prostanoids, inflammatory cytokines, and growth factors.¹ The recent reports¹⁸, ¹⁹ of long-term reduction in the risk of colorectal (and other) cancer and death associated with low-dose aspirin in RCTs using as low as 75 mg daily are consistent with this hypothesis.²⁰

Assessing the benefit/risk profile of aspirin requires an estimation of the absolute risk of the individual patient for atherothrombotic and hemorrhagic complications. In individuals at low risk for vascular occlusion (e.g., <1% per year), a very small absolute benefit may be offset by exposure of very large numbers of healthy subjects to undue serious bleeding complications (see Balance of Benefits and Risks). As the risk of experiencing a major vascular event increases, so does the absolute benefit of antiplatelet prophylaxis with aspirin (FIGURE 111.3), and, above a certain threshold, benefit clearly outweighs risk of bleeding (Table 111.1).², ⁵

The efficacy and safety of aspirin has been evaluated in numerous placebo-controlled RCTs of patients at variable risk of atherothrombotic complications, from asymptomatic low-risk individuals to patients presenting with an acute myocardial infarction or an acute ischemic stroke², ⁵; trials have extended from as short as a few weeks’ duration to as long as 10 years. In the Second International Study of Infarct Survival,²¹ a single tablet of aspirin (162.5 mg) started within 24 hours of the onset of symptoms of a suspected myocardial infarction and continued daily for 5 weeks produced highly significant reductions in the risk of vascular mortality (by 23%), nonfatal reinfarction (by 49%), and nonfatal stroke (by 46%). There was no increase in hemorrhagic stroke or GI bleeding in the aspirin-treated patients and only a small increase in minor bleeding.²¹ Treatment of 1,000 patients with suspected acute myocardial infarction with aspirin for 5 weeks will result in approximately 40 patients in whom a vascular event is prevented,²² with a proportional odds reduction of 30%. Two separate trials with a similar protocol, the International Stroke Trial²³ and the Chinese Acute Stroke Trial,²⁴ tested the efficacy and safety of early aspirin use in acute ischemic stroke. Approximately 40,000 patients were randomized within 48 hours of the onset of symptoms to 2 to 4 weeks of daily aspirin therapy (300 and 160 mg, respectively) or placebo. An overview of the results of both trials suggests an absolute benefit of nine fewer deaths or nonfatal strokes per 1,000 patients in the 1st month of aspirin therapy.²² The proportional odds reduction in fatal or nonfatal vascular events was only 10% in this setting. Although the background risk of hemorrhagic stroke was threefold higher in the Chinese Acute Stroke Trial than in the International Stroke Trial, the absolute increase in this risk associated with early use of aspirin was similar in the two studies (excess 2 per 1,000 patients).²³, ²⁴

Long-term aspirin therapy confers conclusive net benefit on the risk of subsequent myocardial infarction, stroke, or vascular death among subjects at high risk of vascular complications. These include patients with chronic stable angina,²⁵ patients with prior myocardial infarction,²² patients with unstable angina,²⁶, ²⁷, ²⁸, ²⁹ and patients with transient ischemic attack (TIA) or minor stroke³⁰, ³¹, ³², ³³, ³⁴, ³⁵ as well as other high-risk categories.²² The proportional effects of long-term aspirin therapy on vascular events in these different clinical settings showed substantial heterogeneity, ranging from no statistically significant benefits in patients with peripheral vascular disease³⁶ to approximately 50% risk reduction in patients with unstable angina.²² In terms of absolute benefit, these protective effects of aspirin translate into avoidance of a major vascular event in 50 per 1,000 patients with unstable angina treated for 6 months and in 36 per 1,000 patients with prior myocardial infarction, stroke, or TIA treated for approximately 30 months.²²

For patients with different manifestations of ischemic heart or brain disease, a consensus exists in defining a rather narrow range of recommended daily doses (i.e., 75 to 160 mg) for the prevention of atherothrombotic complications.³⁷, ³⁸ This is supported by separate trial data in patients randomized to treatment with low-dose aspirin or placebo as well as by an overview of all antiplatelet trials showing no obvious dose dependence, from indirect comparisons, for the protective effects of aspirin.²² There is no convincing evidence that the dose requirement for the antithrombotic effect of aspirin varies in different clinical settings.²

Among most high-risk patient groups, the expected number avoiding a serious vascular event by using aspirin substantially exceeds the number experiencing a major bleed (Table 111.1). However, it is unclear whether aspirin might benefit people who, although asymptomatic, are at low to intermediate risk of serious vascular events. The question of whether aspirin is effective and safe for the primary prevention of vascular events has been addressed in a meta-analysis of six randomized trials.³⁹ It is interesting to compare the effects of low-dose aspirin in primary prevention with the well-known benefits in secondary prevention.³⁹ In the six primary prevention trials among 95,000 low-risk individuals, with a mean follow-up of 6.9 years, aspirin allocation yielded a 12% RR reduction in serious vascular events,
from an annual rate of 0.57% to 0.51% (FIGURE 111.4). This effect was mainly due to a reduction in nonfatal myocardial infarction, from 0.23% to 0.18% per year. The net effect on stroke was not significant (from 0.21% to 0.20% per year), reflecting a small reduction in presumed ischemic stroke and counterbalancing effects on hemorrhagic stroke and other stroke.³⁹ There was no significant reduction in vascular mortality (from 0.19% to 0.19% per year). Aspirin allocation increased GI (or other extracranial) bleeds by about half, from 0.07% to 0.1% per year.³⁹