Mechanism of Action

Acetylsalicylic acid, or aspirin, is the most widely used antiplatelet agent in the treatment of cardiovascular disease. Aspirin exerts its principal antiplatelet effect by acetylating a serine residue on the cyclooxygenase (COX) or prostaglandin H synthase enzyme and thus irreversibly inhibiting the action of this enzyme. After exposure to aspirin, the anucleate platelet is largely unable to synthesize COX during its 7- to 10-day lifespan. COX enzymes, which exist in at least two isoforms, are responsible for production of prostaglandins and thromboxane from arachidonic acid. Preferential inhibition of COX-1 results in decreased production of thromboxane A ₂ , a potent mediator of platelet aggregation. Other potential mechanisms of action include inhibition of intrinsic nitric oxide synthase and inhibition of transcription factors involved in inflammation ( Figure 7-1 ).

Platelet activation and the mechanism of thrombus formation. A, Endothelial injury exposes components of the extracellular environment such as collagen and von Willebrand factor (vWF). After binding to these components by means of glycoprotein receptors, platelets adhere to the subendothelium and become activated. Activation of the platelet causes a conformational change in the shape of the platelet, release of adenosine diphosphate (ADP) and thromboxane A ₂ (TxA ₂ ), and formation of thrombin on the platelet surface. The release of factors such as ADP and TxA ₂ causes activation of circulating platelets and amplifies the platelet response. These responses cause the platelet glycoprotein (GP) IIb/IIIa receptor to change shape and increase its affinity for adhesive proteins such as vWF and fibrinogen. Platelet aggregation ensues, and the additional interaction of the platelet aggregate with thrombin and fibrin results in thrombus formation. B, The agonists ADP, TxA ₂ , and thrombin bind to G protein–coupled receptors and trigger an intracellular signaling cascade. Several antiplatelet therapies are directed at inhibiting the interaction between these agonists and their respective receptors such as the ADP receptor antagonists, thromboxane inhibitors, and emerging protease activating receptor (PAR) antagonists. C1q/TNF, C1q complex/tumor necrosis factor; P2Y ₁ and P2Y ₁₂ , G protein–coupled purinergic receptors.

(From Meadows TA, Bhatt DL: Clinical aspects of platelet inhibitors and thrombus formation, Circ Research 100:1261-1275, 2007.)

Secondary Prevention

The salutary effect of aspirin for the secondary prevention of cardiovascular disease is well established. In the first small studies to examine this relationship in patients with a history of myocardial infarction, the results were suggestive of a mortality benefit but were statistically inconclusive. More convincing evidence arose from the Antiplatelet Trialists’ Collaboration (ATC), a meta-analysis of 31 randomized trials of antiplatelet therapy primarily with aspirin in patients who had sustained prior myocardial infarction, stroke, transient ischemic attack (TIA), or unstable angina. Of 29,000 patients, those treated with antiplatelet therapy demonstrated a 25% reduction in the odds of suffering a recurrent vascular event. In a second study, the ATC demonstrated an 18% reduction in the odds of vascular death among patients at high risk, as defined by history of myocardial infarction, stroke, TIA, or unstable angina.

Although intuited from smaller randomized studies, the benefit of aspirin in the setting of an acute myocardial infarction was persuasively demonstrated in the Second International Study of Infarct Survival (ISIS-2). In this trial of 17,187 patients with a suspected acute myocardial infarction, a 162.5-mg daily dose of aspirin administered for 1 month significantly reduced early vascular mortality in comparison with placebo (9.4% versus 11.8%, respectively). The protection afforded by aspirin extended to patients with unstable angina in a study of 1266 male veterans. In this randomized, placebo-controlled trial, a daily 324-mg buffered aspirin administered for 12 weeks resulted in a 51% reduction in myocardial infarction or death. Similar results emerged from the study by the Research Group on Instability in Coronary Artery Disease (RISC), which demonstrated a 57% to 69% reduction in the rate of the combined endpoint of myocardial infarction or death among 796 men with unstable angina or non–Q-wave myocardial infarction who were treated with low-dose aspirin.

The benefits of early aspirin therapy after an ischemic stroke were elucidated in two contemporaneous large, randomized trials of patients with acute stroke: the Chinese Acute Stroke Trial (CAST) and the Ischemic Stroke Trial (IST). In more than 20,000 patients enrolled in CAST, 160 mg of aspirin given within 48 hours of an ischemic stroke prevented 6.8 deaths or recurrent nonfatal strokes per 1000 patients treated. In a 2 × 2 factorial open-label design, IST investigators examined the effects of subcutaneous heparin, 300 mg of aspirin, or both administered within 48 hours of an ischemic stroke. Aspirin was associated with 11 fewer deaths or recurrent stroke per 1000 patients treated. The results of these trials, analyzed together, revealed that this benefit was offset slightly by an excess of 2 cases of intracranial hemorrhage per 1000 patients treated.

Treatment with aspirin has also been an essential adjunct in patients undergoing coronary revascularization. Among patients undergoing coronary artery bypass grafting (CABG), aspirin administration both before and soon after surgery has been demonstrated to improve both early and 1-year patency of the saphenous vein graft. Aspirin administered after coronary angioplasty has been associated with a decreased risk of the composite endpoint of death, restenosis, or myocardial infarction in comparison with placebo (30% versus 41%, respectively). As might be expected, the addition of aspirin to thrombolytic therapy also reduces rates of recurrent ischemia and infarct-related reocclusion of arteries.

The ATC provided irrefutable evidence in favor of aspirin for secondary prevention with a more recent meta-analysis of 195 trials that included more than 135,000 patients. This meta-analysis revealed similar risk reduction with antiplatelet therapy among patients at high risk, and this reduction also extended to patients with stable angina, atrial fibrillation, and peripheral artery disease.

Primary Prevention

To date, six large, randomized trials have been undertaken to study aspirin for the primary prevention of cardiovascular disease ( Table 7-1 ). The British Doctors’ Trial was conducted to evaluate the effect of a daily 500-mg dose of aspirin in healthy male physicians. Of the 5139 subjects studied, a majority of participants were older than 60 years and were either current or ex-smokers. After 6 years of follow-up, there were no statistically significant differences in the rates of fatal or nonfatal myocardial infarction, stroke, or all-cause mortality between patients assigned to receive aspirin therapy and those assigned to receive no aspirin. There was, however, an approximate 50% reduction in TIA among physicians treated with aspirin. This trial was not blinded and did not have a placebo control group. Over the course of the study, 44.3% of physicians assigned to receive aspirin therapy discontinued the drug.

The Physicians’ Health Study, a larger trial designed to assess the efficacy of aspirin in reducing cardiovascular events, enrolled 22,071 male physicians in the United States. In a double-blind, placebo-controlled design, healthy physicians were randomly assigned to receive 325 mg of aspirin every other day or beta-carotene in a 2 × 2 factorial design. The study, which was terminated early, demonstrated a significant (44%) risk reduction in the rate of total myocardial infarction. Similarly, there was an 18% risk reduction in the composite outcome of nonfatal myocardial infarction, nonfatal stroke and cardiovascular death. Despite this robust finding, aspirin therapy did not confer a cardiovascular mortality benefit in this study.

The effect of aspirin and warfarin in reducing cardiovascular events in 5085 men was evaluated in the Thrombosis Prevention Trial, a randomized, double-blind, placebo-controlled trial. In a 2 × 2 factorial design, men who did not have established cardiovascular disease but were deemed to be at high risk for vascular disease were randomly assigned to receive treatment with aspirin, 75 mg daily, and warfarin with a target international normalized ratio (INR) of 1.5. Aspirin therapy, either alone or in combination with warfarin, conferred a 20% reduction in the primary endpoint of cardiovascular death and fatal and nonfatal myocardial infarction. This reduction was driven primarily by a 32% reduction in the risk of nonfatal myocardial infarction. In a result concordant with those of the large studies preceding the Thrombosis Prevention Trial, no mortality benefit with aspirin therapy was demonstrated.

In the Hypertension Optimal Treatment study, the effect of low-dose aspirin was investigated in an international cohort of 18,790 men and women, aged 50 to 80, with hypertension. A separate arm of the study was concerned with the effect of antihypertensive therapy directed at diastolic blood pressure and cardiovascular outcomes. In this randomized, placebo-controlled, double-blind study, a daily dose of 75 mg of aspirin was associated with a 15% relative risk reduction in major cardiovascular events, defined as both fatal and nonfatal stroke, fatal and nonfatal myocardial infarction, or cardiovascular death.

Another trial designed to examine the efficacy of aspirin among men and women at risk for cardiovascular disease was the Primary Prevention Project. In an open-label 2 × 2 factorial design, 4495 patients were randomly assigned to receive a 100-mg daily dose of aspirin, as well as vitamin E. Patients were eligible for inclusion in the trial if they had a history of hypertension, hypercholesterolemia, diabetes, family history of premature coronary artery disease, were obese, or were older than 65. A majority of patients included in the study had at least two or more of these risk factors. The mean age of participants was more than 60 years, and 57.7% were women. The trial was terminated prematurely in part because data from the Hypertension Optimal Treatment and Thrombosis Prevention Trial provided evidence in favor of aspirin for primary prevention. After a mean follow-up period of 3.6 years, investigators demonstrated a 44% relative risk reduction in cardiovascular death among patients assigned to treatment with aspirin. Similarly, they demonstrated a 22% relative risk reduction in the primary endpoint of cardiovascular death, nonfatal myocardial infarction, or stroke.

The Women’s Health Study was designed to address the role of aspirin in the primary prevention of cardiovascular disease in women. A total of 39,876 female health professionals were randomly assigned to receive 100 mg of aspirin every other day. After a mean follow-up period of 10 years, this treatment was found to confer 17% and 22% reductions in the risk of stroke and TIAs, respectively, but no significant reduction in the risk of myocardial infarction or cardiovascular death. In the subgroup of women aged 65 and older, however, aspirin was associated with a significant (26%) reduction in the risk of the primary endpoint of cardiovascular death, nonfatal myocardial infarction, or stroke.

A large meta-analysis of the six aforementioned primary prevention trials concluded that aspirin reduces composite cardiovascular events by 12% and 14% in women and men, respectively. Overall, aspirin was not associated with a lower risk of cardiovascular death.

In an update, the ATC performed another meta-analysis of the six major primary prevention trials, which was strengthened by the availability of individual participant data. In primary prevention studies, aspirin was associated with a 12% reduction in the risk ratio of a major adverse cardiovascular event in comparison with no aspirin (0.51% versus 0.57% per year, respectively). The magnitude of this effect was similar in both men and women and was independent of age. Moreover, the small absolute benefit was counterbalanced by an increase in major extracranial hemorrhage in comparison to no aspirin (0.10% versus 0.07% per year, respectively). For secondary prevention, aspirin conferred an absolute reduction of 1.5% per year in the rate of occurrence of a serious vascular event.

Although previous primary prevention trials of aspirin included analyses of data from subgroups of patients with diabetes, these provided insufficient information with regard to efficacy in this important patient population. In the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial, 2539 men and women with well-controlled type 2 diabetes, with a mean age of 65 and without known cardiovascular disease, were randomly assigned to receive 81 or 100 mg daily of aspirin versus no aspirin. The overall event rate was low in this population, and a significant reduction in major cardiovascular events was not observed in the subjects taking aspirin. However, a reduction in the secondary composite endpoint of fatal stroke or myocardial infarction was observed. In a prespecified subgroup analysis of diabetic patients older than 65, a benefit was derived from low-dose aspirin in comparison with the control condition in the primary endpoint (6.3% versus 9.2% respectively).

In the Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial, which was contemporaneous with the JPAD trial, the efficacy of low-dose (100 mg) daily aspirin and antioxidant therapy in preventing cardiovascular events was evaluated in 1276 patients with diabetes and asymptomatic peripheral artery disease. The investigators did not observe a statistically significant benefit of aspirin over placebo in this randomized, controlled, double-blind study. In another trial, Aspirin for Asymptomatic Atherosclerosis, 3350 healthy men and women with asymptomatic peripheral artery disease (as defined by an ankle-brachial index <0.95) were randomly assigned to receive aspirin, 100 mg daily, or placebo. After a mean follow-up period of 8.2 years, no difference in major cardiovascular events or all-cause mortality was observed between participants randomly assigned to receive aspirin or placebo.

Several ongoing trials have been designed to address remaining questions regarding the efficacy of aspirin in primary prevention. The plan of A Study of Cardiovascular Events in Diabetes (ASCEND) is to assess the effectiveness of low-dose daily aspirin in 10,000 patients with diabetes. Similarly, the Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D) is designed to assess the efficacy of open-label daily aspirin, either alone or in combination with simvastatin, in reducing cardiovascular events in approximately 5000 patients with diabetes. Because researchers in most primary prevention studies have examined the benefit of aspirin in populations at relatively low risk, the ongoing Aspirin to Reduce Risk of Vascular Events (ARRIVE) trial will address the role of aspirin in an international cohort of approximately 12,000 patients deemed to be at moderate risk (20% to 30%) of developing a cardiovascular event over 10 years. The role of aspirin in the primary prevention of cardiovascular disease in elderly patients is being studied in the Aspirin in Reducing Events in the Elderly (ASPREE) trial. The aim of the Japanese Primary Prevention Project with Aspirin is to evaluate cardiovascular outcomes in 10,000 Japanese patients older than 60 with at least one additional traditional cardiovascular risk factor who are treated with 100 mg of aspirin daily.

Dosing

Daily aspirin doses of only 30 mg have been demonstrated to completely inhibit synthesis of platelet thromboxane. Despite this observation, the optimal dose of aspirin for an individual patient is not known. Some investigators have speculated that higher dosages of aspirin may paradoxically attenuate the antithrombotic effect of thromboxane inhibition by causing inhibition of the vasodilator prostacyclin. However, a wide variety of aspirin dosages (ranging from 50 to 1500 mg) have been demonstrated to be efficacious for prevention of cardiovascular events, and a formal comparison of several different doses has never been performed in the context of a randomized, controlled, prospective trial in coronary artery disease.

Results of one ATC meta-analysis suggested similar reduction in vascular events across a wide range of aspirin dosages. In a post hoc analysis of the Clopidogrel in Unstable Angina to prevent Recurrent Events (CURE) study, increasing dosages of aspirin (<100 mg, 101 to 199 mg, and >200 mg daily) administered with either placebo or clopidogrel were not associated with greater clinical benefit. Moreover, higher rates of major bleeding were observed with escalating dosages of aspirin compared with placebo (1.9%, 2.8%, and 3.7%, respectively). A meta-analysis of 31 randomized trials that included more than 192,000 patients reached a similar conclusion; the risk of major bleeding events was lowest in patients who took the lowest aspirin dosage. This finding was confirmed in an observational study of participants in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization (CHARISMA) trial. In this large prospective study of patients at high risk of cardiovascular events, patients were randomly assigned to receive clopidogrel or placebo in addition to background aspirin therapy (at daily doses of 162 mg or lower). A post hoc analysis demonstrated no significant reduction in the composite outcome of myocardial infarction, death, or stroke with increasing doses of aspirin. In fact, there was a suggestion of harm to patients treated with higher doses of aspirin in addition to clopidogrel, with increased rates of cardiovascular events and a greater incidence of bleeding, although this was not statistically significant.

Results of the Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions (CURRENT-OASIS 7) trial have enhanced the understanding of both aspirin and clopidogrel dosing in acute coronary syndromes (ACS). In a double-blind 2 × 2 factorial design, approximately 25,000 patients with ACS treated with an early invasive strategy were randomly assigned to receive conventional clopidogrel dosages (300-mg loading dose, followed by 75 mg daily) versus high-dose clopidogrel (600-mg loading dose, followed by 150 mg daily for 6 days and subsequent maintenance dosing of 75 mg daily). Subjects in each of these groups were further randomly assigned, in an open-label manner, to receive high-dose aspirin (300 to 325 mg) or low-dose aspirin (75 to 100 mg) after an initial 300-mg dose of aspirin. High-dose clopidogrel was associated with a significant reduction in the composite of death, myocardial infarction, or stroke at 30 days in patients undergoing percutaneous coronary intervention (PCI). No difference in efficacy or hemorrhagic risk was observed between patients who received low-dose aspirin and those who received high-dose aspirin. A prespecified substudy will also be conducted to examine the effects of aspirin dosing on urinary metabolites of thromboxane and prostacyclin among patients who experience adverse cardiac events and those who do not.

Formulations

Aspirin exists in a “regular” form, as well as in buffered and enteric-coated preparations. Aspirin is rapidly absorbed in the stomach and small intestine after ingestion; inhibition of portal platelet COX enzyme occurs before complete systemic absorption. Levels of aspirin in the systemic circulation peak within 40 minutes after ingestion of regular aspirin and 3 to 4 hours after ingestion of an enteric-coated preparation. A pharmacodynamic study in 12 healthy volunteers demonstrated that near-maximal platelet thromboxane inhibition, occurring over a mean of 13.6 minutes, is achieved most efficiently when a 325-mg aspirin tablet is chewed. Swallowing a whole buffered tablet doubles the time necessary to achieve maximal platelet inhibition. Although enteric-coated preparations may have theoretical benefit in reducing gastric irritation and bleeding, the risk of gastrointestinal bleeding observed with aspirin is also increased because of its systemic effect. Enteric-coated aspirin does not seem to confer protection against gastrointestinal bleeding in comparison with buffered or regular preparations of the same dose.

Hemorrhagic Complications

The most feared complications of antiplatelet therapy are sequelae from hemorrhage. The majority of bleeding complications arise from the gastrointestinal tract; the estimated relative risk was 2.1 in one meta-analysis of 22 randomized primary or secondary prevention studies in which 75- to 325-mg dosages of aspirin were compared with placebo. The relative risk of intracranial hemorrhage was 1.7; no differences between major bleeding and dosages of aspirin were observed. This translated to an annual absolute increase in major bleeding of 0.12%. In a prospective, observational study of 991 patients with coronary artery disease who were treated with 75- to 300-mg of aspirin, the incidence of upper gastrointestinal hemorrhage was 1.5% over 2 years of follow-up. It has been estimated that aspirin contributes to an excess of 5 cases of gastrointestinal hemorrhage per 1000 patients treated. Gastric toxicity, as measured by inhibition of gastric prostaglandin synthesis, is thought to be dose dependent, and a 50% reduction in gastric prostaglandin is observed at dosages as low as 30 mg/day. Therefore, all dosages currently prescribed in clinical practice can be expected to heighten the risk of gastrointestinal hemorrhage.

The extent to which this risk can be attenuated by proton pump inhibition has been examined in both asymptomatic patients and those with prior gastroduodenal ulcers. In a prospective, double-blind study of more than 900 asymptomatic patients requiring low-dose aspirin therapy, use of a proton pump inhibitor (PPI) for 26 weeks was associated with a lower rate of endoscopic ulcers than was placebo (1.6% versus 5.4%, respectively). In another study of 123 patients with recently healed gastroduodenal ulcers and treated Helicobacter pylori infection, the combination of 100 mg of aspirin and 30 mg of lansoprazole was associated with fewer recurrent ulcer complications was the combination of aspirin and placebo over 1 year (1.6% versus 14.8%, respectively). In a similar randomized, placebo-controlled trial of 320 patients with a recent bleeding ulcer, investigators studied the combination of clopidogrel 75 mg daily plus esomeprazole placebo twice daily versus 80 mg aspirin plus esomeprazole 20 mg twice daily. Clopidogrel was associated with a higher rate of recurrent bleeding over 1 year than was the combination of aspirin and PPI (0.7% versus 8.6%, respectively). During 12 weeks of follow-up, the histamine H2 receptor antagonist famotidine was demonstrated to decrease the risk of endoscopic esophagitis and peptic ulcers in comparison with placebo in patients who received 75 to 325 mg of daily aspirin therapy.

By consensus, the American College of Cardiology Foundation (ACCF), American College of Gastroenterology (ACG), and American Heart Association (AHA) recommend reducing chronic aspirin dosages to 81 mg daily with the addition of a daily dose of a PPI in patients with a history of gastrointestinal hemorrhage or ulcer or in patients at risk of these complications, such as those who take maintenance steroid medication, elderly patients, or patients with a history of dyspepsia.

In addition, testing and treatment of H. pylori is advocated initiation of chronic antiplatelet therapy in patients with a history of peptic ulcer disease. Replacing aspirin with clopidogrel is not recommended as a strategy for reducing the risk of recurrent gastrointestinal complications.

Drug Interactions

Other nonsteroidal anti-inflammatory drugs (NSAIDs) can interact in deleterious ways with aspirin. The addition of NSAIDs to aspirin potentiates the risk of gastrointestinal events. However, concomitant NSAID use may also mitigate the protective effect of aspirin. MacDonald and Wei reported on trends in mortality among more than 7000 patients with cardiovascular disease discharged from the hospital with prescriptions for aspirin or for the combination of aspirin and ibuprofen. The latter combination was associated with an excess risk of both all-cause mortality and cardiovascular death (hazard ratios, 1.9 and 1.7, respectively). The potential mechanism of this interaction was evaluated in healthy volunteers who were administered ibuprofen, followed by 81 mg of aspirin. Ibuprofen administered before aspirin or several times daily blocked normal aspirin-induced platelet inhibition. However, the administration of aspirin 2 hours before a single dose of ibuprofen resulted in expected irreversible COX-1 inhibition. Naproxen has also been demonstrated to antagonize the COX-1 inhibition of aspirin in vitro, presumably by functioning as a competitive inhibitor of the COX enzyme. Amplifying concerns about NSAIDs as a class, a large Finnish case-control study demonstrated a significant increase in the risk of first myocardial infarction with use of either conventional or selective COX-2 inhibitor NSAIDs.

Aspirin Resistance

Despite appropriate doses of aspirin, many patients develop recurrent ischemic events. This clinical dilemma has often been attributed to aspirin resistance, a broad term that encompasses the wide variety of factors thought to contribute to this phenomenon ( Figure 7-2 ). At the simplest level, patients’ nonadherence to aspirin therapy, underprescription by physicians, drug interaction with ibuprofen or naproxen, and malabsorption may all play a role. It is also known that platelet activation can occur via thromboxane-independent pathways. One such mechanism may involve COX independent production of the arachidonic acid derivative 8-iso–prostaglandin factor F _2α PGF _2α , a potent vasoconstrictor and platelet aggregrant, released in response to oxidative stress. Because aspirin is a relatively weak inhibitor of COX-2, it has also been postulated that platelet COX-2, normally expressed in response to inflammatory stimuli, may result in sufficient synthesis of thromboxane A ₂ to contribute to aspirin resistance. Other genetic factors may also contribute to observed differences in platelet responsiveness. The platelet polymorphism PI ^A2 has been associated with aspirin resistance. Aspirin resistance has been observed in patients with acute myocardial infarction and elicited by exercise in patients with stable coronary artery disease. One systematic review of 15 studies revealed a wide range in estimates of the prevalence of laboratory aspirin resistance (5% to 65%). The lack of a uniform definition of aspirin resistance and its measurement has limited the understanding of this entity. The “gold standard” test of platelet function, light transmission aggregometry, is the most precise; however, it is time consuming and cannot be performed at the patient’s bedside.

Possible mechanisms of aspirin resistance. COX, cyclooxygenase; GP, glycoprotein; mRNA, messenger ribonucleic acid; PGF _2α , prostaglandin factor 2α; vWF, von Willebrand factor.

(From Bhatt DL: Aspirin resistance: more than just a laboratory curiosity, J Am Coll Cardiol 43:1127-1129, 2004.)

The implications of inadequate aspirin-induced platelet inhibition were assessed in a nested case-control study of participants in the Heart Outcomes Prevention Evaluation (HOPE). Eikelboom and colleagues found an independent association between increasing urinary thromboxane levels, a marker of aspirin resistance, and major cardiovascular events. In another prospective study of 326 patients with stable cardiovascular disease, aspirin resistance, as measured by a one-time optical platelet aggregation test, was present in 5.2% of patients and associated with a significant increase in the rate of the combined endpoint of myocardial infarction, stroke, or death in comparison with patients not deemed resistant (24% versus 10%, respectively). In data congruent with these findings, Chen and colleagues demonstrated an almost threefold increase in the risk of periprocedural myocardial infarction in patients undergoing nonurgent PCI who were deemed aspirin resistant according to a commercial point-of-care assay. More recently, a prespecified analysis of the CHARISMA trial confirmed the findings of the HOPE substudy and revealed an increased risk of stroke, myocardial infarction, or death in patients whose urinary 11-dehydro-thromboxane B ₂ levels were in the highest quartile. Moreover, clopidogrel (in subjects who received it) did not appear to attenuate this relationship. Interestingly, female sex, increasing age, peripheral artery disease, tobacco use, and use of angiotensin-converting enzyme inhibitors or oral hypoglycemic agents were independently associated with incomplete thromboxane inhibition.

Guidelines

The U.S. Preventive Services Task Force (USPSTF) recommends the use of aspirin in men aged 45 to 79 and women aged 55 to 79 for the primary prevention of a cardiovascular event if the perceived benefit of aspirin outweighs the potential harm caused by an increased risk of gastrointestinal hemorrhage ( Figure 7-3 ). For patients at moderate risk for cardiovascular events, the American College of Chest Physicians (ACCP) recommends 75 to 100 mg of aspirin daily. The American Diabetes Association advocates the use of 75 to 162 mg of aspirin daily in patients with diabetes who are older than 40 or for those who have other traditional risk factors for cardiovascular disease. For patients with peripheral artery disease, the American College of Cardiology (ACC)/AHA recommends 75 to 325 mg of aspirin daily for the prevention of stroke, myocardial infarction, or cardiovascular death.

U.S. Preventive Services Task Force (USPSTF) recommendations for aspirin use in primary prevention. CHD, coronary heart disease; CVD, cardiovascular disease; GI, gastrointestinal; HDL, high-density lipoprotein; MI, myocardial infarction; NSAID, nonsteroidal anti-inflammatory drug.

(From U.S. Preventive Services Task Force: Aspirin for the prevention of cardiovascular disease: clinical summary of U.S. Preventive Services Task Force Recommendation, AHRQ Publication No. 09-05129-EF-3, Rockville, MD, March 2009, Agency for Healthcare Research and Quality. Available at: http://www.ahrq.gov/clinic/uspstf09/aspirincvd/aspcvdsum.htm .)

After an ST-elevation myocardial infarction (STEMI), the ACCP recommends initiation of aspirin at a dose of 160 to 325 mg, with subsequent reduction to 75 to 100 mg, to be continued indefinitely. The ACCP also recommends indefinite low-dose aspirin (75 to 100 mg daily) after PCI, CABG, carotid endarterectomy, and peripheral revascularization. A focused update of the 2004 STEMI guidelines recommends aspirin initiation at a dose of 162 to 325 mg for 1, 3, and 6 months after bare-metal, sirolimus, and paclitaxel drug-eluting stents, respectively, with reduction to 75 to 162 mg daily thereafter (ACC/AHA Class 1, level of evidence B). The AHA/American Stroke Association (ASA) recommends administration of 325 mg of aspirin within 24 to 48 hours of an acute ischemic stroke, except for patients receiving thrombolytic therapy, for whom aspirin should be deferred 24 hours.

Mechanism of Action

The thienopyridines, of which ticlopidine and clopidogrel are the prototypes, irreversibly inhibit platelets by binding to P2Y ₁₂ , the G protein–coupled receptor that is normally activated by ADP released from injured endothelium and red blood cells. Through interaction with the P2Y ₁₂ and P2Y ₁ platelet receptors, ADP triggers a cascade of events that result in platelet aggregation and in further release of ADP from the activated platelet, thus potentiating the initial response.

Ticlopidine

Ticlopidine, first studied in humans in 1975, inhibits ADP-induced platelet aggregation in a dose-dependent manner, with an onset of action of 24 to 48 hours. Like clopidogrel, ticlopidine is a prodrug and must be metabolized by the cytochrome P-450 system to an active metabolite. Although many early trials provided evidence to support the use of ticlopidine in patients with established cardiovascular disease, adverse hematologic side effects and rather slow onset of action in comparison with clopidogrel have curtailed its widespread subsequent use. Among patients taking ticlopidine, serious neutropenia has been reported in fewer than 1% to as high as 3.4%, and thrombotic thrombocytopenic purpura has been reported in 0.02%.

Two such early trials were the Canadian American Ticlopidine Study (CATS) and the Ticlopidine Aspirin Stroke Study (TASS). In the CATS trial, more than 1000 patients with recent thromboembolic stroke were randomly assigned to receive treatment with ticlopidine or placebo; a nearly 25% relative risk reduction was demonstrated in the rate of the combined endpoint of vascular death, myocardial infarction, or death. In TASS, ticlopidine was compared with high-dose aspirin in more than 3000 patients who had sustained a recent neurologic event; a 21% relative risk reduction was demonstrated in the rate of recurrent fatal and nonfatal stroke in favor of ticlopidine. Incongruent with this result were the findings of the African-American Antiplatelet Stroke Prevention Study (AAASPS), which did not show a reduction in the composite endpoint of stroke, myocardial infarction, or vascular death in African American patients treated with ticlopidine after an ischemic stroke.

The Swedish Ticlopidine Multicentre Study demonstrated a 29% reduction in all-cause mortality among 687 patients with established peripheral artery disease treated with ticlopidine, in comparison with placebo. This mortality benefit was explained entirely by a reduction in fatal myocardial infarction. The early use of ticlopidine was further supported by a study that demonstrated a nearly 47% relative risk reduction in vascular death among 653 patients with unstable angina treated with ticlopidine in an open-label trial. The additional antiplatelet benefit of ticlopidine was later demonstrated to extend to PCIs, previously complicated by stent thrombosis in the era of single antiplatelet therapy and oral anticoagulation. Soon after, the results of the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS) suggested superiority of the combination of aspirin and clopidogrel over that of aspirin and ticlopidine in patients undergoing placement of coronary stents. Although this study was not statistically powered to compare the efficacy of these two antiplatelet regimens, the combination of aspirin and clopidogrel was associated with significantly fewer noncardiac adverse effects than was the combination of ticlopidine and aspirin (4.6% versus 9.1%, respectively). More conclusive evidence arose from a meta-analysis of both registry and randomized trial data in which clopidogrel and ticlopidine were compared: The rate of major adverse cardiac events was reduced 50% with combination clopidogrel and aspirin in comparison with ticlopidine and aspirin.

Clopidogrel

Secondary Prevention

Clopidogrel has been tested in the secondary prevention of cardiovascular disease in several trials ( Table 7-2 ). The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study was the first large, randomized, placebo-controlled trial to test the efficacy of clopidogrel in preventing cardiovascular events. This international, multicenter study included 19,185 patients, predominately male, with a mean age of 63 who had sustained a recent myocardial infarction, stroke, or symptomatic peripheral artery disease. The subjects were monitored for a mean of almost 2 years. Clopidogrel (75 mg daily) conferred an 8.7% relative risk reduction in the rate of the composite endpoint of myocardial infarction, stroke, or vascular death in comparison with a daily 325-mg dose of aspirin. In subgroup analyses of patients with diabetes and prior CABG in the CAPRIE trial, clopidogrel was also more efficacious than aspirin in reducing the rate of the combined endpoint of vascular death, myocardial infarction, or stroke.

TABLE 7–2

Major Randomized Trials of Clopidogrel Therapy

Trial	No. of Patients	Population	Follow-Up	Treatment	Primary Endpoint	Relative Risk Reduction	P
Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE)	19,185	Patients with established vascular disease	Mean: 1.9 years	Clopidogrel versus aspirin	Stroke, vascular death, or MI	8.7%	0.043
Clopidogrel in Unstable Angina to prevent Recurrent Events (CURE)	12,562	Patients with ACS	3-12 months	Clopidogrel + aspirin versus aspirin alone	CV death, nonfatal MI, or stroke	20%	<0.001
PCI-CURE	2658	Patients with NSTEMI and undergoing PCI	30 days	Clopidogrel + aspirin versus aspirin alone	CV death, MI, urgent TLR	30%	0.03
Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT)	45,852	Patients with acute MI	Mean: 15 days	Clopidogrel + aspirin versus aspirin alone	Death, stroke, or reinfarction	9%	0.002
Clopidogrel as Adjunctive Reperfusion Therapy– Thombolysis In Myocardial Infarction (CLARITY-TIMI 28)	3491	Patients with STEMI and receiving fibrinolytics	Angiography after median of 84 hours	Clopidogrel + aspirin versus aspirin alone	Death, MI, or infarct-related occlusion of artery	31%	<0.001
Clopidogrel for the Reduction of Events During Observation (CREDO)	2116	Patients undergoing elective PCI or with high likelihood of needing PCI	1 year	Clopidogrel + aspirin versus aspirin alone	Death, stroke, or MI	26.9%	0.02
PCI-CLARITY	1863	Patients with STEMI and receiving fibrinolytics and PCI	30 days after PCI	Clopidogrel + aspirin versus aspirin alone	Death, recurrent MI, or stroke	42%	0.008
Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization (CHARISMA)	15,603	Patients with known CV disease or multiple risk factors for CV disease	Median: 28 months	Clopidogrel + aspirin versus aspirin alone	CV death, stroke, or MI	7%	0.22
Management of Atherothrombosis with Clopidogrel in High-Risk Patients (MATCH)	7599	Patients with recent TIA or stroke and risk factor for stroke	18 months	Clopidogrel + aspirin versus clopidogrel alone	Ischemic stroke, vascular death, MI, or rehospitalization for ischemia	6.4%	0.244
Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE)–W	6706	Patients with AF and risk factors for stroke	Median: 1.28 years	Clopidogrel + aspirin versus warfarin	Stroke, MI, vascular death, or non-CNS systemic embolus	−44%	<0.001
ACTIVE-A	7554	Patients with AF and risk factors for stroke but ineligible for VKA	Median: 3.6 years	Clopidogrel + aspirin versus aspirin alone	Stroke, MI, vascular death, or non-CNS systemic embolus	11%	0.01

 

ACS, acute coronary syndrome; AF, atrial fibrillation; CNS, central nervous system; CV, cardiovascular; MI, myocardial infarction, NSTEMI, non–ST-elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction; TIA, transient ischemic attack; TLR, target lesion revascularization; VKA, vitamin K antagonists.

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