Antithrombotic and Thrombolytic Therapy, 8th Ed : ACCP Guidelines: ANTITHROMBOTIC AND THROMBOLYTIC THERAPY, 8TH ED: ACCP GUIDELINES |

Antiplatelet Drugs*: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) FREE TO VIEW

Carlo Patrono, MD; Colin Baigent, MD; Jack Hirsh, MD, FCCP; Gerald Roth, MD
Author and Funding Information

*From the Catholic University School of Medicine (Dr. Patrono), Rome, Italy; Clinical Trial Service Unit (Dr. Baigent), University of Oxford, Oxford, UK; Hamilton Civic Hospitals (Dr. Hirsh), Henderson Research Centre, Hamilton, ON, Canada; and Seattle VA Medical Center (Dr. Roth), Seattle, WA.

Correspondence to: Carlo Patrono, MD, Catholic University School of Medicine, Largo F. Vito 1, 00168 Rome, Italy; e-mail: carlo.patrono@rm.unicatt.it

Chest. 2008;133(6_suppl):199S-233S. doi:10.1378/chest.08-0672
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This article about currently available antiplatelet drugs is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). It describes the mechanism of action, pharmacokinetics, and pharmacodynamics of aspirin, reversible cyclooxygenase inhibitors, thienopyridines, and integrin αIIbβ3 receptor antagonists. The relationships among dose, efficacy, and safety are thoroughly discussed, with a mechanistic overview of randomized clinical trials. The article does not provide specific management recommendations; however, it does highlight important practical aspects related to antiplatelet therapy, including the optimal dose of aspirin, the variable balance of benefits and hazards in different clinical settings, and the issue of interindividual variability in response to antiplatelet drugs.

Figures in this Article

Platelets are vital components of normal hemostasis and key participants in atherothrombosis by virtue of their capacity to adhere to injured blood vessels and to accumulate at sites of injury.1 Although platelet adhesion and activation can be viewed as a physiologic repair response to the sudden fissuring or rupture of an atherosclerotic plaque, uncontrolled progression of such a process through a series of self-sustaining amplification loops can lead to intraluminal thrombus formation, vascular occlusion, and transient ischemia or infarction. Currently available antiplatelet drugs interfere with some steps in the activation process, including adhesion, release, and/or aggregation,1and have a measurable impact on the risk of arterial thrombosis that cannot be dissociated from an increased risk of bleeding.2

In discussing antiplatelet drugs, it is important to appreciate that approximately 1011 platelets are produced each day under physiologic circumstances, a level of production that can increase up to 10-fold at times of increased need.3 Platelets are anucleate blood cells that form by fragmentation of megakaryocyte cytoplasm and have a maximum circulating life span of about 10 days in humans.3Platelets provide a circulating source of chemokines, cytokines, and growth factors, which are preformed and packaged in storage granules. Moreover, activated platelets can synthesize prostanoids (primarily, thromboxane [TX] A2) from arachidonic acid released from membrane phospholipids through rapid coordinated activation of phospholipase(s), cyclooxygenase (COX)-1 and TX synthase (Fig 1 ). Newly formed platelets also express the inducible isoforms of COX (COX-2) and prostaglandin (PG) E synthase, and this phenomenon is markedly amplified in association with accelerated platelet regeneration.4 Although activated platelets are not thought to synthesize proteins de novo, they can translate constitutive messenger RNAs into proteins, including interleukin-1β, over several hours.5 Thus, platelets may play previously unrecognized roles in inflammation and vascular injury, and antiplatelet strategies may be expected to affect platelet-derived protein signals for inflammatory and/or proliferative responses.1

Negative modulation of platelet adhesion and aggregation is exerted by a variety of physiologic mechanisms, including endothelium-derived prostacyclin (PGI2), nitric oxide, CD39/ecto-ADPase, and platelet endothelial cell adhesion molecule-1. Some drugs may interfere with these regulatory pathways, as exemplified by the dose-dependent inhibition of PGI2 production by aspirin and other COX inhibitors.2

Aspirin has been thoroughly evaluated as an antiplatelet drug6and was found to prevent vascular death by approximately 15% and nonfatal vascular events by about 30% in a metaanalysis of > 100 randomized trials in high-risk patients.7

2.1 Mechanism of Action of Aspirin

The best characterized mechanism of action of the drug is related to its capacity to inactivate permanently the COX activity of prostaglandin H-synthase-1 and -2 (also referred to as COX-1 and COX-2).812 These isozymes catalyze the first committed step in prostanoid biosynthesis (ie, the conversion of arachidonic acid to PGH2) [Fig 1]. PGH2 is the immediate precursor of PGD2, PGE2, PGF, PGI2, and TXA2. COX-1 and COX-2 are homodimers of a ∼ 72 kd monomeric unit. Each dimer has three independent folding units: an epidermal growth factor-like domain; a membrane-binding domain; and an enzymatic domain.,12 Within the enzymatic domain, there is the peroxidase catalytic site and a separate, but adjacent site for COX activity at the apex of a narrow, hydrophobic channel.

The molecular mechanism of permanent inactivation of COX activity by aspirin is related to blockade of the COX channel as a consequence of acetylation of a strategically located serine residue (Ser529 in the human COX-1, Ser516 in the human COX-2) that prevents access of the substrate to the catalytic site of the enzyme.13 The hydrophobic environment of the COX channel stabilizes the modified serine side-chain against hydrolysis.13Thus, inhibition of COX-1–dependent platelet function can be achieved with low doses of aspirin given once daily. In contrast, inhibition of COX-2–dependent pathophysiologic processes (eg, hyperalgesia and inflammation) requires larger doses of aspirin (probably because acetylation is determined by the oxidative state of the enzyme and is inhibited in cells with high peroxide tone)14 and a much shorter dosing interval (because nucleated cells rapidly resynthesize the enzyme). Thus, there is an approximately 100-fold variation in daily doses of aspirin when used as an antiinflammatory rather than as an antiplatelet agent. Furthermore, the benefit/risk profile of the drug depends on the dose and indication because its GI toxicity is dose dependent (see below).

Human platelets and vascular endothelial cells process PGH2 to produce primarily TXA2 and PGI2, respectively.11 TXA2 induces platelet aggregation and vasoconstriction, whereas PGI2 inhibits platelet aggregation and induces vasodilation.,11 Whereas TXA2 is largely a COX-1–derived product (mostly from platelets) and thus highly sensitive to aspirin inhibition, vascular PGI2 can derive both from COX-1 and, to a greater extent even under physiologic conditions, from COX-2.,16 COX-1–dependent PGI2 production occurs transiently in response to agonist stimulation (eg, bradykinin),15 and is sensitive to aspirin inhibition. COX-2–mediated PGI2 production occurs long term in response to laminar shear stress,17and is largely insensitive to aspirin inhibition at conventional antiplatelet doses. This may explain the substantial residual COX-2–dependent PGI2 biosynthesis in vivo at daily doses of aspirin in the range of 30 to 100 mg,18 despite transient suppression of COX-1–dependent PGI2 release.,15 It is not established that more profound suppression of PGI2 formation by higher doses of aspirin is sufficient to initiate or predispose to thrombosis. However, two lines of evidence suggest that PGI2 is thromboprotective. The first is the observation that mice lacking the PGI2 receptor had increased susceptibility to experimental thrombosis.,19The second is the observation of the cardiovascular toxicity associated with COX-2 inhibitors20that also supports the concept of PGI2 acting as an important mechanism of thromboresistance in the setting of inadequate inhibition of platelet TXA2 biosynthesis.21

2.2 Pharmacokinetics

Aspirin is rapidly absorbed in the stomach and upper intestine. Peak plasma levels occur 30 to 40 min after aspirin ingestion, and inhibition of platelet function is evident by 1 h. In contrast, it can take up to 3 to 4 h to reach peak plasma levels after administration of enteric-coated aspirin. If only enteric-coated tablets are available, and a rapid effect is required, the tablets should be chewed. The oral bioavailability of regular aspirin tablets is approximately 40 to 50% over a wide range of doses.22 A considerably lower bioavailability has been reported for enteric-coated tablets and sustained-release, microencapsulated preparations.22Lower bioavailability of some enteric-coated preparations and poor absorption from the higher pH environment of the small intestine may result in inadequate platelet inhibition, particularly in heavier subjects.23 Both a controlled-release formulation15 and a transdermal patch24 with negligible systemic bioavailability have been developed in an attempt to achieve selective inhibition of platelet TXA2 production without suppressing systemic PGI2 synthesis. The former was used successfully in the Thrombosis Prevention Trial (see below), but it remains unknown whether there is any advantage to the controlled-release formulation vis-à-vis plain aspirin.

The plasma concentration of aspirin decays with a half-life of 15 to 20 min. Despite the rapid clearance of aspirin from the circulation, the platelet-inhibitory effect lasts for the life span of the platelet25 because aspirin irreversibly inactivates platelet COX-1.89 Aspirin also acetylates the enzyme in megakaryocytes before new platelets are released into the circulation.10,2628 The mean life span of human platelets is approximately 8 to 10 days. Therefore, about 10 to 12% of circulating platelets are replaced every 24 h.2930 However, the recovery of TXA2 biosynthesis in vivo following prolonged aspirin administration is somewhat faster than predicted by the rate of platelet turnover,,18 possibly because of the nonlinear relationship between inhibition of platelet COX-1 activity and inhibition of TXA2 biosynthesis in vivo,31 (Fig 2 ).

2.3 Issues Concerning the Antithrombotic Effects of Aspirin

A number of issues related to the clinical efficacy of aspirin continue to be debated. These include the following: (1) the optimal dose of aspirin in order to maximize efficacy and minimize toxicity; (2) the suggestion that part of the antithrombotic effect of aspirin is unrelated to inhibition of platelet TXA2; and (3) the possibility that some patients may be aspirin “resistant.”

2.3.1 The Optimal Dose of Aspirin: Well-designed, placebo-controlled randomized trials have shown that aspirin is an effective antithrombotic agent when used long term in doses ranging from 50 to 100 mg/d, and there is a suggestion that it is effective in doses as low as 30 mg/d.67 Aspirin, 75 mg/d, was shown to be effective in reducing the risk of acute myocardial infarction (MI) or death in patients with unstable angina32and chronic stable angina,33as well as in reducing stroke or death in patients with transient cerebral ischemia34and the risk of postoperative stroke after carotid endarterectomy.35In the European Stroke Prevention Study (ESPS)-2, aspirin 25 mg bid was effective in reducing the risks of stroke and of the composite outcome stroke or death in patients with prior stroke or transient ischemic attack (TIA).36Moreover, in the European Collaboration on Low-Dose Aspirin in Polycythemia vera Trial,37 aspirin, 100 mg/d, was effective in preventing thrombotic complications in patients with polycythemia vera, despite a higher-than-normal platelet count. The lowest effective dose of aspirin for these various indications is shown in Table 1 .

The clinical effects of different doses of aspirin have been compared directly in a relatively small number of randomized trials.3843 In the United Kingdom TIA study,41no difference in efficacy was found between 300 and 1,200 mg/d of aspirin (see below). In a study of 3,131 patients after a TIA or minor ischemic stroke, aspirin in a dose of 30 mg/d was compared with a dose of 283 mg/d, and the hazard ratio for the group receiving the lower dose was 0.91 (95% confidence interval [CI], 0.76 to 1.09).42The Acetylsalicylic Acid and Carotid Endarterectomy Trial reported that the risk of stroke, MI, or death within 3 months of carotid endarterectomy is significantly lower for patients taking 81 or 325 mg/d aspirin than for those taking 650 or 1,300 mg (6.2% vs 8.4%; p = 0.03).43 Thus, there is no convincing evidence from randomized studies that have compared different doses of aspirin that higher doses are more effective in reducing the risk of serious vascular events. In fact, both this limited set of randomized comparisons and the indirect comparisons reported in the overview of the Antithrombotic Trialists’ (ATT) Collaboration (Table 2 ) are compatible with the reverse (ie, blunting of the antithrombotic effect at higher doses of aspirin, consistent with dose-dependent inhibition of PGI2). Such inhibition of PGI2 may be a potential mechanism by which COX-2 inhibitors produce an excess risk of MI (see below).

The antithrombotic effects of a range of doses of aspirin also have been compared with an untreated control group in a number of thrombotic vascular disorders. The doses have varied between 50 and 1,500 mg/d. Aspirin has been shown to be effective in the following conditions: unstable angina in which the incidence of acute MI or death was significantly reduced in four separate studies using daily doses of 75 mg,32 325 mg,44650 mg,45and 1,300 mg46; stable angina in which a dose of 75 mg/d reduced the incidence of acute MI or sudden death33; aortocoronary bypass surgery in which the incidence of early occlusion was similarly reduced with daily doses of 100 mg,47325 mg,48975 mg,49 and 1,200 mg49; thromboprophylaxis of patients with prosthetic heart valves who also received warfarin in whom the incidence of systemic embolism was reduced with daily doses of 100 mg,50500 mg,51and 1,500 mg5253; thromboprophylaxis of patients with arterial venous shunts undergoing long-term hemodialysis in whom a dose of 160 mg/d was shown to be effective54; acute MI in which a dose of 162.5 mg/d reduced early (35-day) mortality as well as nonfatal reinfarction and stroke55; transient cerebral ischemia in which doses between 50 and 1,200 mg/d were effective34,36,41,5658; acute ischemic stroke in which doses of 160 to 300 mg/d were effective in reducing early mortality and stroke recurrence5960; and polycythemia vera in which 100 mg,37 but not 900 mg,61 was effective in reducing fatal and nonfatal vascular events.

Thus, aspirin is an effective antithrombotic agent in doses between 50 and 1,500 mg/d. It is also possible from the results of the Dutch TIA study that 30 mg/d is effective.42 There is no evidence that low doses (50 to 100 mg/d) are less effective than high doses (650 to 1,500 mg/d) and, in fact, the opposite may be true. These clinical findings are consistent with saturability of platelet COX-1 inactivation at doses as low as 30 mg/d.62

There is evidence, however, that doses of approximately 300 mg/d produce fewer GI side effects than doses of approximately 1,200 mg/d.41There is also some evidence that a dose of 30 mg/d produces fewer side effects than 300 mg/d.42 The Clopidogrel in Unstable Angina To Prevent Recurrent Events (CURE) investigators have retrospectively investigated the relationship between the aspirin dose (the CURE protocol recommended 75 to 325 mg/d) and risk of major bleeding.63 This study was a randomized comparison of clopidogrel with placebo on a “background” of aspirin therapy. Patients with acute coronary syndromes receiving aspirin, ≤ 100 mg/d, had the lowest rate of major or life-threatening bleeding complications both in the placebo (1.9%) and in the clopidogrel (3%) arms of the trial. Bleeding risks increased with increasing aspirin dose with or without clopidogrel.63

In summary, the saturability of the antiplatelet effect of aspirin at low doses, the lack of dose-response relationship in clinical studies evaluating its antithrombotic effects, and the dose dependence of its side effects all support the use of as low a dose of aspirin as has been found to be effective in the treatment of various thromboembolic disorders (Table 1). Use of the lowest effective dose of aspirin (50 to 100 mg/d for long-term treatment) is currently the most appropriate strategy to maximize its efficacy and minimize its toxicity.6

2.3.2 Effects of Aspirin Not Related to TXA2: Aspirin has been reported to have effects on hemostasis that are unrelated to its ability to inactivate platelet COX-1. These include dose-dependent inhibition of platelet function,6468 enhancement of fibrinolysis,6971 and suppression of plasma coagulation.7275

In contrast to the saturable and well-characterized (nanomolar aspirin concentration, rapid time course, physiologic conditions, single serine modification) inhibition of COX-1 by aspirin,13,62,76 the putative mechanisms underpinning the non-PG effects of aspirin on hemostasis are dose dependent and less clearly defined. For example, inhibition of shear-induced platelet aggregation depends on the level of aspirin provided, and enhanced fibrinolysis due to N-acetylation of lysyl residues of fibrinogen is seen in vivo with high doses of aspirin (650 mg bid),69 and proceeds more rapidly in vitro under nonphysiologic alkaline conditions.,77 Aspirin suppresses plasma coagulation through several mechanisms. The first, initially described in 1943 by Link et al and confirmed by others,7273 is caused by an antivitamin K effect of aspirin. It requires very high doses of aspirin and does not contribute to the antithrombotic effect of aspirin when the drug is used in doses up to 1,500 mg/d. The second is platelet dependent and is characterized by inhibition of thrombin generation in a whole blood system.7475 A single dose of 500 mg depresses the rate of thrombin generation, whereas repeated daily dosing with 300 mg of aspirin reduces the total amount of thrombin formed.78 An interaction with platelet phospholipids, which is blunted in hypercholesterolemia, has been proposed to explain the effects of aspirin on thrombin generation.78 It is possible (but unproven) that this effect occurs as a consequence of impaired platelet coagulant activity secondary to inhibition of TX-dependent platelet aggregation. It is unknown whether lower doses of aspirin are able to produce this effect. This sort of in vitro effect has been shown for other platelet inhibitors, such as glycoprotein (GP)-IIb/IIIa antagonists (see below). Furthermore, high-dose aspirin can cause abnormal coagulation in vitro by direct acetylation of one or more clotting factors. This can be demonstrated in platelet-poor plasma and, thus, is not related to platelet inhibition or vitamin K antagonism.

Additional studies in both animal models and human subjects have reported antithrombotic effects of aspirin that may occur, at least in part, through mechanisms unrelated to inactivation of platelet COX-1. In animal models, Buchanan et al66 and Hanson et al64 reported that optimal antithrombotic activity of aspirin required doses in excess of those required to inhibit TXA2. In clinical studies, the results of a subgroup analysis of the North American Symptomatic Carotid Endarterectomy Trial study,79suggested that aspirin in doses of ≥ 650 mg/d might be more effective than ≤ 325 mg/d for the prevention of perioperative stroke in patients having carotid artery surgery.80 This retrospective observation was refuted by a second prospective study, the Acetylsalicylic Acid and Carotid Endarterectomy Trial,43 which tested the hypothesis that the wide area of collagen exposed by endarterectomy is a sufficiently strong stimulus to platelet aggregation to require a larger dose of aspirin. Approximately 3,000 patients scheduled for carotid endarterectomy were randomly assigned 81, 325, 650, or 1,300 mg/d aspirin, started before surgery and continued for 3 months. The combined rate of stroke, MI, or death at 3 months was significantly (p = 0.03) lower in the low-dose groups (6.2%) than in the high-dose groups (8.4%) [primary analysis]. There were no significant differences between the 81-mg and 325-mg groups or between the 650-mg and 1,300-mg groups in any of the secondary analyses of the data.43

A subgroup analysis of the Physicians’ Health Study,81based on post hoc measurements of baseline plasma C-reactive protein performed in 543 apparently healthy men who subsequently had MI, stroke, or venous thrombosis, and in 543 study participants who did not report vascular complications, has found that the reduction in the risk of a first MI associated with the use of aspirin (325 mg on alternate days) appears to be directly related to the level of C-reactive protein, raising the possibility of antiinflammatory as well as antiplatelet effects of the drug in cardiovascular prophylaxis.82 This hypothesis is unlikely to be correct because, as noted above, the antiinflammatory effects of aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) are largely related to their capacity to inhibit COX-2 activity induced in response to inflammatory cytokines,12 as these clinical effects can be fully reproduced by highly selective COX-2 inhibitors (coxibs) in patients with rheumatoid arthritis.83As shown in Table 3 , the dose and time dependence of the effects of aspirin on nucleated inflammatory cells expressing COX-2 vs anucleated platelets expressing COX-1 are markedly different, thus making a clinically relevant antiinflammatory effect of the drug at 325 mg every other day pharmacologically implausible. Finally, aspirin has been reported to modify the way in which neutrophils and platelets84 or erythrocytes and platelets8586 interact, to protect endothelial cells from oxidative stress,87and to improve endothelial dysfunction in atherosclerotic patients.88 However, neither the molecular mechanism(s) nor the dose dependence of these effects have been clearly established. Although improved endothelial dysfunction could reflect an antiinflammatory effect of aspirin of relevance to atherogenesis, it should be emphasized that the hypothesis has never been tested by an appropriately sized controlled prospective study.

All of the evidence detailed above suggesting dose-dependent effects for aspirin is indirect and inconsistent with the failure to show a dose effect in randomized clinical trials and in the ATT overview analysis.7 This failure to show a dose effect is the critical point of the discussion because it correlates with the saturability of the aspirin effect on platelet COX-1. For example, in studies with purified enzyme and with isolated platelets, nanomolar concentrations of aspirin will completely block PG synthesis within 20 min after exposure.89 Higher concentrations and longer exposures will not alter the inhibitory effect of aspirin on PG synthesis because of this saturable quality. Exactly the same feature (maximal effect at low doses, absence of dose effect) is seen in clinical trials with aspirin as an antithrombotic agent. When one raises the dose of aspirin in this situation, no further or additional effect can be appreciated because the critical event has already taken place, namely, maximal inhibition of platelet TX synthesis. Thus, the consistency of dose requirements and saturability of the effects of aspirin in acetylating the platelet enzyme,8 inhibiting TXA2 production,,25,62 and preventing atherothrombotic complications67 constitutes the best evidence that aspirin prevents thrombosis through inhibition of TXA2 production. It is likely, therefore, that any of the potential effects of aspirin on other determinants of arterial thrombosis are much less important than the inhibition of platelet COX-1 activity.

2.3.3 Aspirin “Resistance”: The term aspirin resistance has been used to describe a number of different phenomena, including the inability of aspirin to (1) protect individuals from thrombotic complications, (2) cause a prolongation of the bleeding time, (3) reduce TXA2 production, or (4) produce a typical effect on one or more in vitro tests of platelet function.90 From a therapeutic standpoint, it is important to establish whether aspirin resistance can be overcome by increasing the dose of aspirin, but unfortunately very few data bear directly on this issue. The fact that some patients may experience recurrent vascular events despite long-term aspirin therapy should be properly labeled as treatment failure rather than aspirin resistance. Treatment failure is a common phenomenon occurring with all drugs (eg, lipid-lowering or antihypertensive drugs). Given the multifactorial nature of atherothrombosis and the possibility that platelet-mediated thrombosis may not be responsible for all vascular events, it is not surprising that only a fraction (usually one fourth to one third) of all vascular complications can be prevented by any single preventive strategy.

It has been reported that a variable proportion (up to one fourth) of patients with cerebrovascular disease only achieve partial inhibition of platelet aggregation at initial testing, and some (up to one third) seem to develop resistance to aspirin over time, even with increasing doses.9193 The results of these long-term studies carried out by Helgason et al are at variance with those of a short-term study of Weksler et al,94showing that aspirin, 40 mg/d, inhibited platelet aggregation and TXA2 formation as effectively as higher doses of aspirin in patients who had recent cerebral ischemia. Variable platelet responses to aspirin have also been described in patients with peripheral arterial disease95 and with ischemic heart disease.9698 In the Buchanan and Brister study,96 aspirin nonresponders were identified on the basis of bleeding time measurements. Approximately 40% of patients undergoing elective coronary artery bypass grafting showed no prolongation of bleeding time in response to aspirin. This finding was associated with increased platelet adhesion and 12-HETE synthesis.96 In contrast, repeated measurements of platelet aggregation performed over 24 months of placebo-controlled treatment by Berglund and Wallentin99 demonstrated that 100 patients with unstable coronary artery disease randomized to receive aspirin, 75 mg/d, in the Research Group on Instability in Coronary Artery Disease in Southeast Sweden study32 had consistently reduced platelet aggregation without attenuation during long-term treatment. Based on measurements of platelet aggregation in response to arachidonate and adenosine diphosphate (ADP), 5% and 24% of patients with stable cardiovascular disease who were receiving aspirin (325 mg/d for ≥ 7 days) were defined as resistant and semiresponders, respectively.97Using a variety of techniques, including conventional aggregometry, shear stress-induced activation, and the expression of platelet surface receptors, Sane et al98 recently reported that 57% of a group of 88 patients with documented heart failure who had been treated with aspirin, 325 mg/d, for ≥ 1 month showed aspirin nonresponsiveness. Overall, the majority of these studies were characterized by the following major limitations: (1) biochemical or witnessed verification of patient’s adherence to the prescribed therapy were absent; (2) there was a single measurement of any given test; (3) intrasubject and intersubject variability and stability of the assay over time were usually not reported; (4) the criteria to define the normal vs the aspirin-resistant range and the assay conditions differed among studies; (5) doses of aspirin were heterogeneous, ranging from 75 to 1,300 mg; and (6) none of these studies were properly controlled.

Lack of biochemical assessment of compliance is a major issue for the majority of studies assessing platelet function in response to aspirin, and this aspect is crucial in studies investigating aspirin unresponsiveness. Interestingly, a recent study100 in 190 patients with a history of MI compared arachidonate-induced platelet aggregation in patients while receiving their usual aspirin therapy, after 7 days of withdrawal, and 24 h after a single witnessed intake of aspirin of 325 mg. Although 9% of the patients who declared having taken their usual therapy failed to show inhibition of platelet aggregation, this percentage dropped to < 1% (1 patient of 190) after a witnessed dose.100Furthermore, this single patient admitted NSAID intake 12 h before testing. Similar results were reported in the study by Lev et al,101where after a witnessed dose of 325 mg of aspirin, the mean of arachidonic acid-induced light transmission aggregometry became < 20% (the established limit to define resistance) in formerly resistant patients. Other studies have reported up to 40% noncompliance with long-term aspirin use.102 It is therefore clear that questionnaires cannot be a reliable parameter to assess the compliance to any given treatment, including aspirin, and that studies not relying on salicylate measurements or serum TXB2 have a major, intrinsic bias, seriously hampering the interpretation of results. Furthermore, the few studies directly comparing different functional assays failed to find any significant agreement between tests, generating the disappointing conclusion that aspirin nonresponsiveness may be highly test specific.

Several relatively small studies (n = 39 to 180) of stroke patients103105 have suggested that aspirin resistance may contribute to treatment failure (ie, recurrent ischemic events while on antiplatelet therapy) and that doses higher than 500 mg may be more effective than lower doses in limiting this phenomenon. The uncontrolled nature and small sample size of these studies make it difficult to interpret the results. As noted above, a much larger database failed to substantiate a dose-dependent effect of aspirin in stroke prevention,,7 an effect that one would theoretically expect if aspirin resistance could be overcome at least in part by increasing the daily dose of the drug.

Gum et al106 reported that 5% of 326 stable cardiovascular patients were aspirin resistant based on the results of platelet aggregation induced by ADP and arachidonic acid. The aspirin-resistant group had an increased risk of death, MI, or cerebrovascular accident during almost 2 years of follow-up. There were, however, relatively few events in this study, and the rationale for the particular definition of aspirin resistance is uncertain.

Among a wide range of patients with vascular disease in whom the annual rate of serious vascular events ranges from 40 to 80 per 1,000, aspirin typically prevents at least 10 to 20 fatal and nonfatal vascular events for every 1,000 patients treated for 1 year.6 Thus, 30 to 60 vascular events are expected to occur for every 1,000 patients treated with low-dose aspirin for 1 year not because of resistance, but because of the multifactorial nature of atherothrombosis. Thus, we do not agree with the definition given by Wang et al,107whereby “in its broadest sense, resistance refers to the continued occurrence of ischemic events despite adequate antiplatelet therapy and compliance.” Indeed, as suggested by Hennekens et al,108 “given the multiple pathways by which platelets may be activated, it is perhaps more surprising that a clinical benefit is detectable in randomized trials of cardiovascular disease than that treatment failures complicate aspirin therapy.”

At least three potential mechanisms may underlie the occurrence of aspirin-resistant TXA2 biosynthesis. The transient expression of COX-2 in newly formed platelets in clinical settings of enhanced platelet turnover4 is a potentially important mechanism that deserves further investigation. Extraplatelet sources of TXA2 (eg, monocyte/macrophage COX-2) may contribute to aspirin-insensitive TXA2 biosynthesis in acute coronary syndromes.,109Furthermore, Catella-Lawson et al110 reported that concomitant administration of a traditional NSAID (eg, ibuprofen) may interfere with the irreversible inactivation of platelet COX-1 by aspirin. This is due to competition for a common docking site within the COX channel (arginine-120), which aspirin binds to with weak affinity before irreversible acetylation of Serine-529.,13 This pharmacodynamic interaction also has been described between naproxen and aspirin111 but does not occur with rofecoxib,110 celecoxib,112 or diclofenac,110 drugs endowed with variable COX-2 selectivity.83 Thus, concomitant treatment with readily available over-the-counter NSAIDs may limit the cardioprotective effects of aspirin and contribute to aspirin resistance. Based on current analysis of available data,113115 the US Food and Drug Administration (FDA) has issued a statement informing patients and health-care professionals that ibuprofen can interfere with the antiplatelet effect of low-dose aspirin (81 mg/d), potentially rendering aspirin less effective when used for cardioprotection and stroke prevention (http://www.fda.gov/cder/drug/infopage/ ibuprofen/default.htm).

The clinical relevance of aspirin-resistant TXA2 biosynthesis has been explored by Eikelboom et al,116 who performed a nested case-control study of baseline urinary TX metabolite excretion in relation to the occurrence of major vascular events in aspirin-treated high-risk patients enrolled in the Heart Outcomes Prevention Evaluation trial. After adjustment for baseline differences, the odds for the composite outcome of MI, stroke, or cardiovascular death increased with each increasing quartile of 11-dehydro-TXB2 excretion, with patients in the upper quartile having a 1.8-times higher risk than those in the lower quartile. One limitation in this study, however, was the inability to differentiate between variable compliance in taking aspirin as prescribed (or avoiding NSAIDs) and variable occurrence of aspirin-resistant sources of TXA2 biosynthesis.

Thus, in summary, both the mechanism(s) and clinical relevance of aspirin resistance, as defined by platelet aggregation measurements, remain to be established.117Until its true nature and prevalence vis-à-vis other antiplatelet drugs are better defined, no test of platelet function is recommended to assess the antiplatelet effect of aspirin in the individual patient.119 On the other hand, additional studies on the mechanisms and clinical relevance of aspirin-resistant TXA2 biosynthesis are clearly warranted.

2.4 The Antithrombotic Effect of Aspirin

2.4.1 Prevention of Atherothrombosis in Different Clinical Settings: The efficacy and safety of aspirin are documented from analysis of approximately 70 randomized clinical trials that included > 115,000 patients at variable risk of thrombotic complications of atherosclerosis. A detailed analysis of individual trials is beyond the scope of this article. It is more appropriately dealt within specific clinical sections of this volume.

Aspirin has been tested in patients demonstrating the whole spectrum of atherosclerosis, from apparently healthy low-risk individuals to patients presenting with an acute MI or an acute ischemic stroke; similarly, trials have extended for as short as a few weeks’ duration or as long as 10 years.67 Although aspirin has been shown consistently to be effective in preventing fatal and/or nonfatal vascular events in these trials, both the size of the proportional effects and the absolute benefits of antiplatelet therapy are somewhat heterogeneous in different clinical settings.

In the Second International Study of Infarct Survival,55 a single tablet of aspirin (162.5 mg) started within 24 h of the onset of symptoms of a suspected MI 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.55 Treatment of 1,000 patients with suspected acute MI with aspirin for 5 weeks will result in approximately 40 patients in whom a vascular event is prevented,7 with a proportional odds reduction of 30% (see the “Acute ST-Segment Elevation Myocardial Infarction” chapter).

Two separate trials with a similar protocol, the International Stroke Trial59and the Chinese Acute Stroke Trial,60 tested the efficacy and safety of early aspirin use in acute ischemic stroke. Approximately 40,000 patients were randomized within 48 h of the onset of symptoms to 2 to 4 weeks of daily aspirin therapy (300 mg and 160 mg, respectively) or placebo. An overview of the results of both trials suggests an absolute benefit of 9 fewer deaths or nonfatal strokes per 1,000 patients in the first month of aspirin therapy.7 The proportional odds reduction in fatal or nonfatal vascular events is 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).5960 The broad clinical implications of these findings are discussed in the “Antithrombotic and Thrombolytic Therapy for Ischemic Stroke” chapter. In terms of their research implications, these results are consistent with biochemical evidence of episodic platelet activation during the first 48 h after the onset of symptoms of an acute ischemic stroke and with suppression of in vivo TXA2 biosynthesis in patients receiving low-dose aspirin in this setting.,120

Long-term aspirin therapy confers conclusive net benefit on risk of subsequent MI, stroke, or vascular death among subjects with high risk of vascular complications. These include patients with chronic stable angina,33 patients with prior MI,7 patients with unstable angina,32,4446 and patients with TIA or minor stroke34,36,41,5658 as well as other high-risk categories.7 The proportional effects of long-term aspirin therapy on vascular events in these different clinical settings are rather homogeneous, ranging between 20% and 25% odds reduction based on an overview of all randomized trials.7 However, individual trial data show substantial heterogeneity, ranging from no statistically significant benefits in patients with peripheral vascular disease to approximately 50% risk reduction in patients with unstable angina.7 Although other factors may play a role, we interpret these findings as reflecting the variable importance of TXA2 as a mechanism amplifying the hemostatic response to plaque destabilization in different clinical settings. 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 MI, stroke, or TIA treated for approximately 30 months.,7

For patients with different manifestations of ischemic heart or brain disease, a widespread consensus exists in defining a rather narrow range of recommended daily doses (ie, 75 to 160 mg) for the prevention of MI, stroke, or vascular death. 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 aspirin7(Table 3). There is no convincing evidence that the dose requirement for the antithrombotic effect of aspirin varies in different clinical settings.

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. However, it is unclear whether aspirin might benefit people who, although apparently healthy, are at intermediate risk of serious vascular events. The question of whether aspirin is effective for the primary prevention of vascular events has been addressed in a metaanalysis of randomized trials.332

Six primary prevention trials81,121125 including 92,873 participants were studied (Table 4 ). Mean follow-up was approximately 6 years. There was a 15% reduction in the odds of cardiovascular events (OR, 0.85; 95% CI, 0.79 to 0.92; p < 0.001) and highly significant reductions of 23% in total coronary heart disease (CHD) [OR, 0.77; 95% CI, 0.70 to 0.86; p < 0.001] and 24% in nonfatal MI (OR, 0.76; 95% CI, 0.67 to 0.85; p < 0.001).

There was no overall effect on stroke (OR, 0.95; 95% CI, 0.84 to 1.06; p = 0.3), but data were not available separately for hemorrhagic and nonhemorrhagic stroke,126128 so the effects on these two stroke subtypes could not be examined in detail. Aspirin had no significant effect on the aggregate of all vascular causes of death (OR, 0.89; 95% CI, 0.72 to 1.10; p = 0.3), or on overall mortality (OR, 0.94; 95% CI, 0.87 to 1.00; p = 0.07). In summary, therefore, in primary prevention, aspirin chiefly prevents nonfatal MI, and appears to have little effect on fatal vascular events.

2.5 Balance of Benefit and Harm

Previous metaanalyses of the effects of antiplatelet therapy among people at high risk of occlusive vascular disease7 have shown that the benefits of aspirin far exceed the bleeding risks among such patients. By contrast, the majority of participants (92%) in the primary prevention trials were at low absolute risk of coronary disease; on average, the annual risk of a vascular event in the primary prevention trials was only about one tenth of that occurring in the high-risk trials. Hence, although the proportional benefits of aspirin appeared broadly similar in primary and secondary prevention, the absolute benefits and risks of aspirin in the primary prevention trials were very small. Each year, fewer than 1 person in every 1,000 could expect to avoid an occlusive vascular event by taking aspirin, whereas a comparably small number could expect to experience a major extracranial bleed. The relative size of these opposing effects is too imprecisely known in low-risk people to predict the net public health consequences of widespread aspirin use in healthy people. The ATT Collaboration is currently analyzing individual participant data from the six primary prevention trials, and these new analyses will help to clarify the benefits and risks of aspirin in particular groups of individuals. Until the benefits of aspirin can be defined more precisely, however, the possibility of a benefit does not seem to justify the probability of a hazard. This emphasizes the need for trials of aspirin for primary prevention among specific groups at increased risk of vascular disease, such as people > 70 years of age and people with diabetes but no vascular disease.

2.5.1 Atrial Fibrillation: Moderate-dose warfarin alone (international normalized ratio [INR], 2.0 to 3.0) is very effective in reducing the risk of stroke in patients with nonvalvular atrial fibrillation.129131 The effectiveness of aspirin in doses between 75 and 325 mg has been compared with warfarin and placebo in three randomized trials of patients with nonvalvular atrial fibrillation.130,132133 In one study,130 aspirin was significantly more effective than placebo, whereas in the other two132133 there was a nonsignificant trend in favor of aspirin. Pooled analysis of the three studies shows a relative risk reduction in favor of aspirin over placebo of about 25% (range, 14 to 44%). Aspirin was significantly less effective than warfarin in two studies on an intention-to-treat analysis,132133 and in the third study on an efficacy analysis.130 On pooled analysis, warfarin was significantly more effective than aspirin, with a 47% relative risk reduction (range, 28 to 61%; p < 0.01).134Moreover, adjusted-dose warfarin therapy (INR, 2.0 to 3.0) was more effective than fixed low-dose warfarin therapy (INR, 1.2 to 1.5) and aspirin, 325 mg/d, in high-risk patients with atrial fibrillation.135Thus, aspirin appears to be effective in preventing stroke in patients with atrial fibrillation but is substantially less effective than warfarin.136137

2.5.2 Deep Vein Thrombosis: The Pulmonary Embolism Prevention Trial138 has established that aspirin is effective in preventing venous thromboembolism after surgery for hip fracture. This was a double-blind multicenter study of 13,356 patients undergoing surgery for hip fracture and of an additional 4,088 patients undergoing elective hip or knee arthroplasty. Patients were assigned 160 mg of aspirin or placebo qd for 5 weeks, with the first dose starting before surgery. Other forms of prophylaxis were allowed, and either heparin or low-molecular-weight heparin was used in about 40% of the patients. Among the 13,356 patients with hip fracture, aspirin produced a 36% reduction in symptomatic deep vein thrombosis or pulmonary embolism (PE) [absolute risk reduction 0.9%; p = 0.0003]. A similar relative risk reduction in patients who were assigned aspirin was observed in patients who also received heparin.

This important study,138therefore, clearly shows that aspirin reduces the incidence of fatal PE and symptomatic nonfatal deep vein thrombosis or PE in patients with hip fracture. The results of the Pulmonary Embolism Prevention trial are consistent with the meta-analysis performed by the Antiplatelet Trialists’ Collaboration,139and supersede the findings in most of the previous trials.140142 However, in three randomized studies in major orthopedic surgery comparing aspirin with either warfarin143or a low-molecular-weight heparin,144145 the incidence of venous thrombosis was significantly higher in the aspirin group in all three.

2.5.3 Placental Insufficiency: The pathogenesis of preeclampsia and fetal growth retardation is related to reduced placental blood flow, which is believed to be caused by constriction and/or thrombosis of small placental arteries.146The initial reports that low-dose aspirin therapy reduces the risk of severe low birth weight among newborns,147 and the risk of cesarean section in mothers with pregnancy-induced hypertension,146 led to the widespread use of prophylactic aspirin to prevent preeclampsia. Subsequently, several larger trials reported no beneficial effects of aspirin.148154

A systematic review155 of data from 39 trials in > 30,000 women showed that antiplatelet therapy (mostly aspirin, 60 mg/d) is associated with a 15% decrease in the risk of preeclampsia. This effect was consistent, regardless of risk status (moderate or high), dose of aspirin, or gestation at trial entry. There was some evidence that there may be greater benefits for women given > 75 mg of aspirin, although the numbers of women in the subgroup were small and so a potential for random error. There was also an 8% reduction in the risk of preterm birth and a 14% reduction in the risk of fetal or neonatal death for women allocated antiplatelet therapy.155 Remaining questions are whether particular subgroups of high-risk women might have greater benefit and whether earlier treatment (ie, before 12 weeks) or aspirin doses of > 75 mg would have additional benefits without an increase in adverse effects.,155 The potential involvement of extra platelet sources of vasoactive eicosanoids expressing COX-2 in response to a local growth-promoting milieu might contribute, at least in part, to the limited efficacy of low-dose aspirin therapy in this setting.

2.6 Adverse Effects of Aspirin

Aspirin does not cause a generalized bleeding abnormality unless it is given to patients with an underlying hemostatic defect, such as hemophilia, uremia, or that induced by anticoagulant therapy. Aspirin-induced impairment of primary hemostasis cannot be separated from its antithrombotic effect and is similar at all doses ≥ 75 mg/d.6

The balance between preventing vascular occlusion and causing excess bleeding with aspirin depends critically on the absolute thrombotic vs hemorrhagic risk of the patient. Thus, in individuals at low risk for vascular occlusion (eg, ≤ 1%/yr), a very small absolute benefit is offset by exposure of a large number of healthy subjects to undue bleeding complications. In contrast, in patients at high risk of cardiovascular or cerebrovascular complications (eg, > 3%/yr), the substantial absolute benefit of aspirin prophylaxis clearly outweighs the harm (Table 5 ). For example, the absolute excess of major bleeds (ie, those requiring transfusion) in acute MI is approximately 1/100th the absolute number of major vascular events avoided by aspirin therapy.7

The overall risk of major extracranial and intracranial hemorrhage associated with antiplatelet drugs is difficult to assess in individual trials because their incidence is low (ie, < 1%/yr), making detection of even a 50 to 60% relative increase in risk unrealistic in most trials of a few thousand patients.

Aspirin-induced GI toxicity, as detected in randomized clinical trials, appears to be dose related in the range of 30 to 1,300 mg/d.156 This, along with studies of the relationship of efficacy to dose, is based largely on indirect comparisons of different trials and on a limited number of randomized, direct comparisons of different aspirin doses, as reviewed above. Such a dose-response relationship is thought to reflect at least two COX-1-dependent components, dose-dependent inhibition of COX-1 in the GI mucosa and dose-independent (within the range of examined doses) inhibition of COX-1 in platelets.6 Thus, it is not surprising that the antithrombotic effect of aspirin can be dissociated, at least in part, from its most common side effect. However, even when administered at low doses, aspirin can cause serious GI bleeding, as reported in studies using 30 to 50 mg/d.36,42 Because of the underlying prevalence of gastric mucosal erosions related to concurrent use of other NSAIDs and/or Helicobacter pylori infection in the general population, it should be expected that any antiplatelet dose of aspirin will cause more bleeding from preexisting lesions than a placebo. Consistent with this mechanistic interpretation, the relative risk of hospitalization due to upper-GI bleeding and/or perforation associated with low-dose aspirin therapy (mostly, 100 to 300 mg/d) is comparable to that of other antiplatelet agents and anticoagulants (ie, 2.3 [95% CI, 1.7 to 3.2], 2.0 [95% CI, 1.4 to 2.7], and 2.2 [95% CI, 1.4 to 3.4], respectively) in a large population-based observational study.,157

In the overview of the ATT Collaboration,7 information was available on 787 major extracranial hemorrhages in 60 trials recording at least one such hemorrhage. These were generally defined as hemorrhages that were fatal or required transfusion; among them, 159 (20%) caused death. Overall, the proportional increase in risk of a major extracranial bleed with antiplatelet therapy was about one half (odds ratio [OR], 1.6; 95% CI, 1.4 to 1.8), with no significant difference between the proportional increases observed in each of the five high-risk categories of patients. After allowing for noncompliance in the trials, they are compatible with the 2- to 2.5-fold excess observed in case-control studies.

A case-control study with hospital and community controls has examined the risks of hospitalization for bleeding peptic ulcer associated with three different regimens of aspirin prophylaxis.158ORs were raised for all doses of aspirin taken: 75 mg, OR 2.3 (95% CI, 1.2 to 4.4); 150 mg, OR 3.2 (95% CI, 1.7 to 6.5); and 300 mg, OR 3.9 (95% CI, 2.5 to 6.3). Additional epidemiologic studies have found a dose-response relationship between aspirin prescription and upper-GI complications, as reviewed by García Rodríguez et al.159 It has been calculated that approximately 900 of the 10,000 episodes of ulcer bleeding occurring in people > 60 years of age each year in England and Wales could be associated with, and ascribed to, prophylactic aspirin use.158 A general change to lower doses of aspirin (75 mg) would not eliminate risks but would reduce risk by about 40% compared with 300-mg doses and by 30% compared with 150-mg doses if the assumptions from indirect comparisons are correct.158 Given that the mortality rate among patients who are hospitalized for NSAID-induced upper-GI bleeding is about 5 to 10%,160161 such a strategy could save a significant number of lives.

The widely held belief that enteric-coated and buffered varieties of aspirin are less likely to occasion major upper-GI bleeding than plain tablets was tested in data from a multicenter case-control study.162 The relative risks of upper-GI bleeding for plain, enteric-coated, and buffered aspirin at average daily doses of ≤ 325 mg were 2.6, 2.7, and 3.1, respectively. At doses > 325 mg, the relative risks were 5.8 for plain and 7.0 for buffered aspirin; there were insufficient data to evaluate enteric-coated aspirin at this dose level.162Similar conclusions were reached by a case-control study using data from the UK General Practice Research Database.163 Thus, physicians who recommend aspirin in an enteric-coated or buffered form should not assume that these formulations are less likely to cause GI tract bleeding than plain aspirin.

Suppressing acid secretion is thought to reduce the risk of ulcers associated with regular use of NSAIDs. In patients who required continuous treatment with NSAIDs and who had ulcers or > 10 erosions in either the stomach or duodenum, omeprazole healed and prevented ulcers more effectively than did ranitidine.164In these patients, maintenance therapy with omeprazole was associated with a lower rate of relapse and was better tolerated than misoprostol.165In high-risk patients (history of previous ulcer bleeding) taking low-dose aspirin for 6 months, omeprazole and H pylori eradication were associated with similar rates of recurrent bleeding (0.9% vs 1.9%),166 although clinically important differences between the two preventive strategies could not be excluded owing to the small sample size (n = 250).

Two relatively small studies167168 have challenged current guidelines that recommend clopidogrel for patients who have major GI contraindications to aspirin, principally recent significant bleeding from a peptic ulcer or gastritis.169170 Both studies enrolled patients with ulcer bleeding after the use of low-dose aspirin. In the study of Chan et al,167 after healing of ulcers and eradication of H pylori, if present, 320 patients were randomly assigned to receive either clopidogrel, 75 mg/d, or aspirin, 80 mg/d, plus 20 mg bid of esomeprazole for 12 months. The cumulative incidence of recurrent bleeding was 8.6% (95% CI, 4.1 to 13.1%) among patients who received clopidogrel and 0.7% (95% CI, 0 to 2.0%) among those who received aspirin plus esomeprazole (p = 0.001).,167In the study of Lai et al,168 170 patients with prior ulcer bleeding were randomly assigned to treatment with clopidogrel, 75 mg/d, or aspirin, 100 mg/d, and esomeprazole, 20 mg/d, for 1 year. The cumulative incidence of recurrent ulcer complications was 13.6% and 0%, respectively (95% CI for the difference, 6.3 to 20.9%; p = 0.0019).168 The consistent findings of two independent studies suggest that the combination of esomeprazole and low-dose aspirin is superior to clopidogrel in preventing recurrent ulcer bleeding in patients with a history of aspirin-related ulcer bleeding.

Substantially less information is available about the risk of intracranial hemorrhage associated with aspirin use. In the Nurses’ Health Study171 cohort of approximately 79,000 women 34 to 59 years of age, infrequent use of aspirin (1 to 6 tablets per week) was associated with reduced risk of ischemic stroke, whereas high frequency of use (≥ 15 aspirin tablets per week) was associated with increased risk of subarachnoid hemorrhage, particularly among older or hypertensive women. In the overview of the ATT Collaboration,7 the overall absolute excess of intracranial hemorrhage due to aspirin therapy was < 1 per 1,000 patients per year in high-risk trials, with somewhat higher risks in patients with cerebrovascular disease.

Low-dose aspirin therapy has not been reported to affect renal function or BP control,172consistent with its lack of effect on renal prostaglandins173 that derive primarily from constitutively expressed COX-2 in the human kidney.83 Moreover, aspirin, 75 mg/d, did not affect BP or the need for antihypertensive therapy in intensively treated hypertensive patients.122 The suggestion that the use of aspirin and other antiplatelet agents is associated with reduced benefit from enalapril in patients with left ventricular systolic dysfunction174is not supported by the results of a large metaanalysis of MI trials.175Similarly, no negative interaction occurs between angiotensin-converting enzyme (ACE) inhibition and the cardiovascular benefits of low-dose aspirin in intensively treated hypertensive patients.176The ACE Inhibitors Collaborative Group177 has performed a systematic overview of data for 22,060 patients from six long-term randomized trials of ACE inhibitors to assess whether aspirin altered the effects of ACE inhibitor therapy on major clinical outcomes. Even though results from these analyses cannot rule out the possibility of some sort of interaction, they show unequivocally that even if aspirin is given, the addition of ACE inhibitor therapy produced substantial additional benefit in all major vascular outcomes. Therefore, in the absence of clear contraindications, concomitant use of aspirin and ACE inhibitors should be considered in all patients at high risk of major vascular events.177

Thus, in summary, inhibition of TXA2-dependent platelet function by aspirin is effective for the prevention of thrombosis, but is also associated with excess bleeding. Assessing the net effect requires an estimation of the absolute thrombotic vs hemorrhagic risk of the individual patient. In individuals at very low risk for vascular occlusion, a very small absolute benefit may be offset by exposure of very large numbers of healthy subjects to undue bleeding complications. As the risk of experiencing a major vascular event increases, so does the absolute benefit of antiplatelet prophylaxis with aspirin, as shown in Figure 3 , for a number of clinical settings in which the efficacy of the drug has been tested in randomized clinical trials. Based on the results of such trials, the antithrombotic effect of aspirin does not appear to be dose related over a wide range of daily doses (30 to 1,300 mg), an observation consistent with saturability of platelet COX inhibition at very low doses. In contrast, GI toxicity of the drug does appear to be dose related, consistent with dose- and dosing interval-dependent inhibition of COX activity in the nucleated lining cells of the GI mucosa. Thus, aspirin once daily should be considered in all clinical conditions in which antiplatelet prophylaxis has a favorable benefit/risk profile. Because of GI toxicity and its potential impact on compliance, physicians are encouraged to use the lowest dose of aspirin shown effective in each clinical setting (Table 1).

2.7 Reversible COX Inhibitors

In the absence of definitive randomized studies, traditional NSAIDs have long been thought to pose no cardiovascular hazard or to be somewhat cardioprotective. Because of their reversible mechanism of action in inhibiting platelet COX-1 and of their short half-lives, most traditional NSAIDs inhibit TXA2-dependent platelet activation only transiently and incompletely in the vast majority of users.178A notable exception is provided by naproxen, which when administered regularly at 500 mg bid, has been shown to inhibit TXA2 biosynthesis in vivo to the same extent as low-dose aspirin,179 consistent with its relative COX-1 selectivity and longer half-life than other commonly used NSAIDs.

The only reversible COX inhibitors that have been tested in randomized clinical trials for their antithrombotic efficacy are sulfinpyrazone, indobufen, flurbiprofen, and triflusal. Sulfinpyrazone is a uricosuric agent structurally related to the antiinflammatory agent phenylbutazone. When used at the highest approved dosage of 200 mg qid, the drug inhibits platelet COX activity by approximately 60%, after conversion from an inactive sulfoxide to an active sulfide metabolite.180 The conflicting or negative results obtained in randomized clinical trials of sulfinpyrazone in patients with MI or unstable angina7 (reviewed in the “Valvular and Structural Heart Disease” chapter) are not surprising in light of the drug being a weak COX inhibitor with no other established antiplatelet mechanism of action.

In contrast, indobufen is a very potent inhibitor of platelet COX-1 activity and has comparable biochemical, functional, and clinical effects to those of a standard dose of aspirin. Thus, at therapeutic plasma levels achieved after oral dosing of 200 mg bid, indobufen inhibits serum TXB2 by > 95% throughout the dosing interval181and reduces urinary TX metabolite excretion to an extent quite comparable to aspirin.182The finding that indobufen is as effective as aspirin in preventing coronary graft occlusion in two randomized trials183184 is mechanistically consistent with the concept of platelet COX-1 inhibition largely accounting for the antithrombotic effect of aspirin, as discussed above. Indobufen also has been investigated in a small placebo-controlled study of patients with heart disease at increased embolic risk185and compared with warfarin186and ticlopidine187 in patients with nonrheumatic atrial fibrillation and patients with recent reversible cerebral ischemia, respectively. However, none of these studies in > 4,000 patients clearly established an advantage of indobufen vs standard treatments, although the 95% CIs for these comparisons are wide. Indobufen has been reported to suppress in vivo TXA2 biosynthesis more effectively than low-dose aspirin in patients with unstable angina, an effect possibly related to inhibition of monocyte COX-2 by therapeutic plasma levels of indobufen.,14 The clinical relevance of these findings remains to be established.

Flurbiprofen has been evaluated in a single placebo- controlled, randomized trial of 461 patients with acute MI.188 The 6-month reinfarction rate was significantly lower in the flurbiprofen group (3%) than in the placebo group (10.5%), with an extremely low mortality rate (1.1%) in both groups. The small sample size of the study limits interpretation of these findings.

Triflusal, a salicylic acid derivative, reversibly inhibits platelet COX activity after conversion to a long-lived metabolite, 2-hydroxy-4-trifluoromethyl-benzoic acid.189Although the half-life of the parent compound is only about 30 min, that of the deacetylated metabolite approximates 2 days. Although triflusal is claimed to have negligible effects on vascular PGI2 production, this is likely to reflect the experimental conditions used for the assessment of PGI2 production ex vivo. The limited sample size of head-to-head comparisons of triflusal vs aspirin in patients randomized within 24 h of acute MI190 and in patients with cerebrovascular disease191 precludes unequivocal interpretation of the similar rates of major vascular events in the two treatment groups. None of these reversible COX inhibitors are approved as an antiplatelet drug in the United States, and it is unclear under which circumstances they are prescribed instead of aspirin in other countries.

2.8 Coxibs and Cardiovascular Disease

Coxibs were developed in an attempt to prevent the adverse GI effects of nonselective NSAIDs (by avoiding inhibition of COX-1) while maintaining equivalent antiinflammatory efficacy (by inhibiting COX-2).83 Several large randomized trials192194 have demonstrated that coxibs are associated with lower risk of serious GI events than nonselective NSAIDs, but the Vioxx GI Outcomes Research Study193 among approximately 8,000 patients with rheumatoid arthritis showed that those allocated to rofecoxib, 50 mg/d, experienced a higher risk of vascular events than those allocated to naproxen 500 mg bid. This excess was almost entirely accounted for by a difference in the incidence of MI (20 in 2,699 person-years of follow-up among rofecoxib-allocated patients, vs 4 in 2,699 person-years among naproxen-allocated patients). There were no significant differences in stroke (11 rofecoxib vs 9 naproxen) or vascular deaths (7 rofecoxib vs 7 naproxen).193 Three placebo-controlled trials have now revealed a twofold- to threefold-increased risk of vascular events in approximately 6,000 patients treated short term (10 days) with valdecoxib195or long term (up to 3 years) with celecoxib196or rofecoxib197both with and without concomitant aspirin treatment. These recent findings are consistent with a mechanism-based cardiovascular hazard for the class198 and have led to the withdrawal of rofecoxib and valdecoxib from the market.

A metaanalysis of tabular data from 138 randomized trials of five different coxibs in approximately 145,000 patients has revealed that in placebo comparisons, allocation to a coxib was associated with a 42% increased incidence of vascular events with no statistically significant heterogeneity among the different coxibs.20 This excess risk of vascular events was derived primarily from a twofold-increased risk of MI. Overall, there was no significant difference in the incidence of vascular events between a coxib and any traditional NSAID, but there was evidence of a significant difference between naproxen and the other traditional NSAIDs.20 Given the nonlinear relationship between inhibition of platelet COX-1 activity and inhibition of platelet activation in vivo(Fig 2),,31 it is perhaps not surprising that the cardiovascular safety profile of coxibs and some nonnaproxen NSAIDs (primarily diclofenac and ibuprofen) appears similar because these drugs fail to inhibit platelet activation adequately irrespective of their COX-2 selectivity. The results of the Multinational Etoricoxib and Diclofenac Arthritis Long-Term study,199 comparing long-term treatment with etoricoxib and diclofenac in approximately 35,000 arthritis patients, are consistent with this conclusion. Whether the variable level and duration of COX-1 inhibition by different NSAIDs modulate the cardiovascular consequences of COX-2 inhibition presently is unknown, given the limited utilization of NSAIDs other than ibuprofen, diclofenac, and naproxen in coxib trials. Thus, coxibs and some traditional NSAIDs moderately increase the risk of vascular events, particularly MI, but there remains considerable uncertainty about the magnitude of this hazard for particular drug regimens and patients subgroups. A metaanalysis of individual participant data from randomized coxib trials is currently being conducted by the Coxib Trialists’ Collaboration in order to address some of the open questions related to the influence of dose, duration, and baseline characteristics, including the concomitant use of low-dose aspirin, on this cardiotoxicity.

Dipyridamole is a pyrimidopyrimidine derivative with vasodilator and antiplatelet properties. The mechanism of action of dipyridamole as an antiplatelet agent has been a subject of controversy.200 Both inhibition of cyclic nucleotide phosphodiesterase (the enzyme that degrades cyclic adenosine monophosphate [AMP] to 5(1)-AMP, resulting in the intraplatelet accumulation of cyclic AMP, a platelet inhibitor) and blockade of the uptake of adenosine (which acts at A2 receptors for adenosine to stimulate platelet adenylyl cyclase and thus increase cyclic AMP) have been suggested. Moreover, direct stimulation of PGI2 synthesis and protection against its degradation have been reported, although the dipyridamole concentrations required to produce these effects far exceed the low micromolar plasma levels achieved after oral administration of conventional doses (100 to 400 mg/d).,200Dipyridamole also differentially inhibits the expression of critical inflammatory genes in platelet-leukocyte aggregates.201

The absorption of dipyridamole from conventional formulations is quite variable and may result in low systemic bioavailability of the drug. A modified-release formulation of dipyridamole with improved bioavailability has been developed in association with low-dose aspirin.202 Dipyridamole is eliminated primarily by biliary excretion as a glucuronide conjugate and is subject to enterohepatic recirculation. A terminal half-life of 10 h has been reported. This is consistent with the twice-daily regimen used in recent clinical studies.

Although the clinical efficacy of dipyridamole, alone or in combination with aspirin, has been questioned on the basis of earlier randomized trials,2,203 the whole issue has been reopened by the reformulation of the drug to improve bioavailability and the results of the ESPS-2 and European Stroke Prevention Reversible Ischemia Trial (ESPRIT) studies.36,204 In ESPS-2, the new preparation of dipyridamole was evaluated in 6,602 patients with prior stroke or TIA.36 This study showed that the addition of modified-release dipyridamole 200 mg bid to aspirin 25 mg bid was associated with a 22% relative risk reduction of major vascular events compared with aspirin alone. Headache was the most common adverse effect of dipyridamole. Bleeding at any site was almost doubled in the two aspirin arms but was surprisingly indistinguishable from placebo in the dipyridamole-treated patients.36 In a post hoc analysis of cardiac events in patients with CHD or MI at entry, dipyridamole did not result in a higher number of fatal and nonfatal cardiac events.,204

More recently, the ESPRIT Study Group205 has performed a randomized trial in which they assigned 2,739 patients within 6 months of a TIA or minor stroke of presumed arterial origin to aspirin (30 to 325 mg/d) with or without dipyridamole (200 mg bid). The primary outcome (a composite of major vascular events or major bleeding complications) was significantly reduced by the combined treatment vs aspirin alone by 20%. Patients receiving aspirin and dipyridamole discontinued trial medication almost three times more often than those receiving aspirin alone, mainly because of headache.205 Addition of the ESPRIT data to the metaanalysis of previous trials resulted in an overall risk ratio of 0.82 (95% CI, 0.74 to 0.91) for the composite of vascular death, stroke, or MI. However, based on the most recent Cochrane review,203 the additional benefit of the combination over aspirin alone is not detectable in patients with other types of vascular disease. Whether this apparent discrepancy reflects a different prevalence of dipyridamole-sensitive mechanisms of disease or, perhaps more likely, the different types of formulation and daily dosage of the drug remains to be established. The fixed combination of modified-release dipyridamole and low-dose aspirin has been approved for stroke prevention by the FDA and other regulatory authorities.

Ticlopidine and clopidogrel are structurally related thienopyridines with platelet-inhibitory properties. Both drugs selectively inhibit ADP-induced platelet aggregation with no direct effects on arachidonic acid metabolism.206 Although ticlopidine and clopidogrel also can inhibit platelet aggregation induced by collagen and thrombin, these inhibitory effects are abolished by increasing the agonist concentration and, therefore, are likely to reflect blockade of ADP-mediated amplification of the platelet response to other agonists.

Neither ticlopidine nor clopidogrel affect ADP-induced platelet aggregation when added in vitro, up to 500 μmol/L, thus suggesting that in vivo hepatic transformation to an active metabolite(s) is necessary for their antiplatelet effects. In the liver, clopidogrel is metabolized into 2-oxo-clopidogrel through a cytochrome P450-dependent pathway. This intermediate metabolite is then hydrolyzed and generates the highly labile active metabolite,207which reacts as a thiol reagent with the ADP receptors on platelets when they pass through the liver.208 The active metabolite belongs to a family of eight stereoisomers, only one of which (bearing 7S, 3Z, and 4S or 4R configuration) retains biological activity.208

Experimental evidence suggests that clopidogrel and, probably, ticlopidine induce irreversible alterations of the platelet receptor P2Y12 mediating inhibition of stimulated adenylyl cyclase activity by ADP.209210 The active metabolite of clopidogrel couples through a disulfide bridge to the P2Y12 receptor, presumably to the cysteine residue in the first extracellular loop; this results in oligomers dissociating into dimeric receptors that are partitioned out of lipid rafts, thereby losing the ability to bind their endogenous ligand.211Interestingly, mutations in the P2Y12 gene are associated with a congenital bleeding disorder and abnormality in the platelet response to ADP, resembling that induced by thienopyridines.212 Permanent modification of a platelet ADP receptor by thienopyridines is consistent with time-dependent cumulative inhibition of ADP-induced platelet aggregation on repeated daily dosing with ticlopidine or clopidogrel and with slow recovery of platelet function after drug withdrawal.206

4.1 Ticlopidine