Antiplatelet Agents in Acute Coronary Syndromes

Plaque disruption, platelet activation, and intracoronary artery thrombus formation are the key events in the pathogenesis of acute coronary syndromes. Antiplatelet therapies significantly reduce the risk of ischemic complications both during the acute phase and in the long term in patients with acute coronary syndromes. Aspirin remains the cornerstone of antiplatelet therapy, but there is incremental benefit when clopidogrel or ticlopidine is added to aspirin. Dual antiplatelet therapy with the combination of clopidogrel and aspirin is becoming the new standard of care for the management of patients with non-ST-segment elevation acute coronary syndrome and undergoing percutaneous coronary intervention and is currently being further evaluated in ST-segment elevation acute coronary syndrome.

Activated platelets provide a phospholipid surface for the assembly of procoagulant clotting factors and, thereby, further promote thrombin generation. The resulting intracoronary thrombus may temporarily or permanently obstruct blood flow, causing myocardial ischemia and the clinical manifestations of unstable angina or acute myocardial infarction.
Aspirin is an effective antiplatelet agent, reducing the risk of death and major ischemic events by about 25% in a broad range of high-risk patients. [7][8][9] However, despite aspirin therapy more than 10% of patients with acute coronary syndromes experience myocardial infarction, stroke, or death during the next 2 to 3 years, 8,10,11 and there is evidence of persistent platelet activation and Platelets play a pivotal role in the pathogenesis of acute coronary syndromes. [1][2][3][4][5][6] Spontaneous atherosclerotic plaque rupture or mechanical plaque disruption during catheterization of an atheromatous coronary artery exposes subendothelial proteins to the circulating blood, which leads to platelet adhesion, activation, and aggregation. The process of platelet adhesion and activation is enhanced under conditions of high shear, which occurs when atherosclerotic plaque and superimposed intraluminal thrombus impair coronary blood flow. 6 Exposed tissue factor activates the coagulation system, which leads to thrombin generation. Thrombin converts fibrinogen to fibrin and also promotes platelet activation and recruits additional platelets to the site of vascular injury. Tirofiban thrombin generation in patients with acute coronary syndromes, which is independently predictive of future risk of atherothrombotic vascular events. 12,13 This suggests that more intensive antiplatelet therapy may be beneficial in these patients. Increasing recognition of the key role of platelets in arterial thrombus formation and the limitations of aspirin has led to intensive efforts to develop more effective antithrombotic strategies for the treatment of atherothrombosis. This article reviews the pharmacology and clinical applications of antiplatelet therapies currently used in the management of patients with acute coronary syndromes.

PHARMACOLOGY OF ANTIPLATELET DRUGS
The mechanism of action of antiplatelet drugs currently used for the treatment of patients with acute coronary syndromes is summarized in Table 1. Specific inhibitors of platelet adhesion are also being developed, but their role for treating patients with unstable angina or acute myocardial infarction has not yet been evaluated. 14

Aspirin
The antiplatelet effects of aspirin have been recognized for the past 50 years. 15 Aspirin exerts its primary antithrombotic effect by acetylating platelet prostaglandin H synthase (commonly known as cyclooxygenase), thereby irreversibly blocking the production of thromboxane A 2 by platelets. 15 Although aspirin has a half-life of only 15 to 20 minutes, its antithrombotic effects last for the life of the platelet (5 to 10 days) because platelets are anucleate and lack the biosynthetic machinery necessary to regenerate cyclooxygenase-1.
Aspirin selectively inhibits platelet thromboxane generation while maintaining endothelial cell synthesis of prostacyclin. This is due, in part, to a first-pass effect of low-dose aspirin. 16 Exposure of platelets in the portal circulation to aspirin results in complete acetylation and inhibition of platelet cyclooxygenase-1. Vascular endothelial cells in the posthepatic (systemic) circulation are exposed to much lower concentrations of aspirin because the portal blood is diluted by blood from other circulations. Therefore, endothelial cell cyclooxygenase is only partially inhibited and there is limited inhibition of endothelial cell prostacyclin synthesis by aspirin. 16 However, even at high doses, aspirin is still a relatively selective inhibitor of platelet thromboxane production because aspirin has a short half-life and cyclooxygenase can be rapidly regenerated by endothelial cells. 17 Aspirin may have other antithrombotic effects that are unrelated to its ability to inactivate platelet cyclooxygenase-1. 7 These include nonspecific dose-dependent inhibitory effects on shear-induced platelet activation, 18 platelet aggregation, 19,20 and blood coagulation [21][22][23][24] as well as inhibitory effects on platelet-erythrocyte interactions, 25,26 the endothelium, 27,28 and inflammation. 29,30 However, the clinical importance of these mechanisms for the prevention of atherothrombosis is yet to be demonstrated.
Aspirin is rapidly absorbed from the gastrointestinal tract after oral administration, with peak levels achieved within 30 to 40 minutes after ingestion. 7 Enteric coating delays absorption and reduces the systemic bioavailability of aspirin, but because platelet cyclooxygenase is acetylated in the presystemic circulation, the antiplatelet effect of aspirin is independent of systemic bioavailability. 31 A single 100-mg dose of aspirin blocks the production of thromboxane A 2 in the majority of individuals. 32 Doses of aspirin in excess of 150 mg/day are clinically no more effective than 75 to 150 mg/day for prevention of atherothrombosis ( Fig. 1). 8 However, higher doses are associated with an increased risk of gastrointestinal bleeding. 7,8 Thienopyridines: Clopidogrel and Ticlopidine Clopidogrel and ticlopidine are structurally related thienopyridines that irreversibly inhibit platelet aggregation by adenosine diphosphate (ADP). 33 ADP activates two membrane-bound G protein-coupled receptors: P2Y1, which activates phospholipase A2 and triggers shape change and intracellular calcium mobilization, and P2Y12, which reduces adenylate cyclase activity. 34 Block-ade of either of these receptors inhibits ADP-induced platelet aggregation, but thienopyridines do not directly inhibit ADP-induced shape change or calcium flux; this suggests that clopidogrel and ticlopidine selectively block the P2Y12 receptor.
Thienopyridines also inhibit platelet aggregation induced by thrombin, collagen, and thromboxane analogues. However, these inhibitory effects can be overcome by increasing agonist concentrations and are believed to be due to indirect blockade by thienopyridines of ADP-mediated amplification of the response to other platelet agonists. 7 Thienopyridines are well absorbed after oral administration but require metabolism in the liver to acquire activity. 35, 36 The bioavailability of clopidogrel is unaffected by food, whereas the bioavailability of ticlopidine is enhanced by food and decreased by antacids. Ticlopidine causes rash, diarrhea, nausea, or vomiting in more than 10% of patients and potentially fatal neutropenia in 1 to 2%. 37 Clopidogrel has a more favorable safety profile and is at least as effective as ticlopidine. 38 However, compared with aspirin, clopidogrel is still associated with a significantly increased risk of rash (6.0% versus 4.6%; p < 0.001) and diarrhea (4.5% versus 3.4%; p < 0.001). 39,40 Clopidogrel at 75 mg/day produces a dose-and time-dependent inhibition of platelet aggregation, reaching a maximum inhibition of ADP-induced platelet aggregation after 3 to 5 days. 41 More rapid platelet inhibition (within hours) can be achieved by administering a 300-or 600-mg oral loading dose. 7,42 Glycoprotein IIb/IIIa Inhibitors: Abciximab, Eptifibatide, and Tirofiban Activation of the glycoprotein IIb/IIIa receptor on platelets causes it to undergo a conformational change that allows fibrinogen binding and cross-linking of adjacent platelets as the final common pathway for platelet aggregation. Glycoprotein IIb/IIIa inhibitors bind to the receptor and block interaction with fibrinogen and other ligands such as von Willebrand factor. Intravenous glycoprotein IIb/IIIa inhibitors, including abciximab (the Fab fragment of the chimeric human-murine monoclonal antibody 7E3), 43,44 eptifibatide (a synthetic cyclic heptapeptide), 45 and tirofiban (a nonpeptide derivative of tyrosine), 46,47 are widely used in the management of acute coronary syndromes. 48,49 Oral glycoprotein IIb/IIIa inhibitor preparations have also been evaluated in phase 3 clinical trials for this indication 50 but are associated with adverse outcomes for reasons that have not been fully elucidated. 51, 52 The pharmacology and clinical role of intravenous glycoprotein IIb/IIIa inhibitors for the management of patients with acute coronary syndromes are discussed by Drs. Maree and Fitzgerald elsewhere in this issue. 53

Other Antiplatelet Agents
Other antiplatelet agents that have been evaluated for the management of patients with atherothrombosis include inhibitors of cyclooxygenase (sulfinpyrazone, indobufen), platelet arachidonic acid metabolism (triflusal), phosphodiesterase (dipyridamole, cilostazol, trapidil), thromboxane synthetase (piracetam), and thromboxane receptor (vapiprost) as well as combined thromboxane synthetase/receptor inhibitors (ridogrel, picotamide). However, none of these agents have been shown to be superior to aspirin or have found application in the management of patients with acute coronary syndromes.

Aspirin
Initial randomized trials conducted in the 1970s and early 1980s did not consistently demonstrate a benefit of aspirin compared with placebo in patients with acute myocardial infarction. [54][55][56][57] However, these were relatively small studies and the negative trials may have been un- derpowered to demonstrate a benefit. The Second International Study of Infarct Survival (ISIS-2) pilot study of 619 patients with myocardial infarction treated with streptokinase showed a reduction in mortality in patients randomly assigned to aspirin compared with placebo. 57 Subsequently, the ISIS-2 trial randomly assigned 17,187 patients presenting within 24 hours of onset of suspected acute myocardial infarction to intravenous streptokinase, aspirin 162.5 mg/day for 30 days, both, or neither. 58 At the end of 5 weeks, aspirin reduced the risk of death by 23% and nonfatal myocardial infarction or stroke by 49% and 46%, respectively, with no increase in major or intracranial bleeding. The survival benefits of aspirin in patients with acute myocardial infarction were also seen in patients receiving concomitant heparin therapy and were additive to the benefits of streptokinase (Fig. 2). A long-term follow-up of patients randomly assigned in the ISIS-2 trial demonstrated that the benefits of aspirin remained evident even at 10 years (Fig. 3). 59 Meanwhile, at least six randomized trials have compared aspirin with placebo or untreated control for the long-term management of patients with myocardial infarction, [60][61][62][63][64][65] five of which demonstrated a trend toward decreased mortality with aspirin.
The efficacy of aspirin as an adjunct to thrombolytic therapy and for the long-term management of patients with myocardial infarction treated has been summarized by the Antithrombotic Trialists' Collaboration. 8 Among more than 19,000 patients randomly assigned in 15 trials, antiplatelet therapy (primarily aspirin) compared with placebo or untreated control and continued for a mean of 1 month after the acute event was associated with a 30% reduction in the odds of recurrent myocardial infarction, stroke, or cardiovascular death (p < 0.0001). This is equivalent to preventing 38 (SE 5) events for every 1000 patients treated. Among more than 20,000 patients with a past history of myocardial infarction randomly assigned in 12 trials, antiplatelet therapy (again primarily aspirin) compared with placebo or untreated control and continued for a mean of 27 months was associated with a 25% reduction in the odds of recurrent myocardial infarction, stroke, or cardiovascular death (p < 0.0001). 8 This is equivalent to preventing 36 (SE 5) events for every 1000 patients treated. Aspirin has also been directly compared with oral anticoagulation for the long-term treatment of patients with acute myocardial infarction. [65][66][67][68][69] A difference in myocardial infarction or death between aspirin and warfarin was not demonstrated in the early trials, [65][66][67] and the results of a subsequent meta-analysis of trials comparing warfarin with aspirin were inconclusive. 70 However, two recent trials demonstrated that high-intensity warfarin (target international normalized ratio 2.8 to 4.2 [43] or 3.0 to 4.0 [44]) was superior to aspirin for preventing myocardial infarction, stroke, or death in patients with previous myocardial infarction. 68,69 Nevertheless, high-intensity warfarin is not routinely employed in place of aspirin in the majority of patients with previous myocardial infarction because it is inconvenient to use and associated with a modest increase in major bleeding.

Clopidogrel and Ticlopidine
No studies have compared clopidogrel or ticlopidine with placebo or untreated control as an adjunct to thrombolytic therapy for the acute treatment of patients with ST-segment elevation acute coronary syndrome. However, the combination of clopidogrel plus aspirin compared with aspirin alone is currently being evaluated in the 30,000-patient Clopidogrel Metoprolol Myocardial Infarction Trial (COMMIT) and the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY ) study.
The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial compared clopidogrel 75 mg/day with aspirin 325 mg/day for the longterm prevention of atherothrombotic vascular events. 39 Among 19,185 patients with a history of symptomatic atherothrombosis, including 8446 with prior myocardial infarction, clopidogrel compared with aspirin reduced the risk of myocardial infarction, stroke, or cardiovascular death by 8.7% (95% confidence interval [CI] 0.3 to 16.5, p = 0.04) (Fig. 4). Clopidogrel compared with aspirin was associated with a significantly lower risk of gastrointestinal bleeding (2.0% versus 2.7%; p < 0.002). 39,40

Guidelines for Antiplatelet Therapy in ST-Segment Elevation Acute Coronary Syndrome
The American College of Cardiologists/American Heart Association (ACC/AHA) Guidelines for the Management of Patients with Acute Myocardial Infarction in 1999 71 recommend aspirin 160 to 325 mg/day given on day 1 of acute myocardial infarction and continued indefinitely in all patients. Clopidogrel or another oral antiplatelet agent (e.g., ticlopidine, dipyridamole) is recommended as an alternative to aspirin only when there is a contraindication or intolerance to aspirin.

Aspirin
Randomized trials have demonstrated the benefits of aspirin compared with placebo or untreated control for the management of patients with non-ST-segment elevation acute coronary syndromes. 72-78 Aspirin 75 to 1300 mg/day reduced the risk of myocardial infarction by approximately 50% at 2 years 73-76 and progression to severe angina requiring cardiac catheterization by about 30% at 1 year. 77 The Antithrombotic Trialists' Collaboration metaanalysis of antiplatelet therapy (primarily aspirin) in more than 5000 patients with unstable angina demonstrated a 46% reduction in the odds of myocardial infarction, stroke, or cardiovascular death with antiplatelet therapy versus placebo or untreated control (p < 0.0001). 8 As- Figure 4 Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study. Cumulative incidence of myocardial infarction, stroke, or death for patients at high risk of atherothrombosis treated with long-term clopidogrel compared with aspirin. (Reprinted with permission from CAPRIE Steering Committee. 39 ) pirin has also been directly compared with heparin during the acute phase in patients with unstable angina with inconsistent results. 75,77,79,80 However, the combination of aspirin plus heparin or low-molecular-weight heparin is superior to aspirin alone for preventing death or myocardial infarction in patients with non-ST-segment elevation acute coronary syndrome. 81

Clopidogrel and Ticlopidine
No studies have compared clopidogrel with placebo/ control in the absence of aspirin or compared clopidogrel directly with aspirin in patients with non-ST-segment elevation acute coronary syndrome. One open-label study of 652 patients with unstable angina demonstrated that ticlopidine compared with control reduced the risk of death or myocardial infarction by 46% at 6 months (P = 0.009). 82 The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study of 12,562 patients with non-ST elevation acute coronary syndrome demonstrated that the combination of clopidogrel (300 mg loading dose followed by 75 mg/day) and aspirin (75 to 325 mg/day) was superior to aspirin alone (75 to 325 mg/day) in preventing stroke, myocardial infarction, and vascular death (relative risk [RR] 0.80; 95% CI 0.72 to 0.90, p < 0.001) (Fig. 5). 10 There was also a reduction in other in-hospital events, including refractory ischemia, recurrent angina, radiologically confirmed heart failure, and need for coronary revascularization. Furthermore, the benefits of clopidogrel were seen irrespective of baseline risk, concomitant medical therapies, or revascularization strategy; emerged within the first 24 hours of commencing treatment; and continued to accrue throughout the duration of the study.
In the CURE trial, the combination of clopidogrel and aspirin was associated with an increased risk of major bleeding (RR 1.38; 95% CI 1.13 to 1.67, P = Figure 5 Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Cumulative hazard rates for the primary outcome of myocardial infarction, stroke, or cardiovascular death during the 12 months of the trial. (Reprinted with permission from Yusuf et al. 10 ) 0.001) but no excess of intracranial or fatal bleeding. The incidence of bleeding with clopidogrel was lower in patients receiving an aspirin dose of less than 100 mg/day than in those receiving higher doses. 83 There was no excess of major bleeding after coronary artery bypass graft surgery in patients who discontinued clopidogrel at least 5 days prior to surgery (4.4 versus 5.3%; P = 0.53). However, patients who did not discontinue clopidogrel at least 5 days prior to surgery had an increased risk of major bleeding during the first 7 days after surgery (9.6% versus 6.3%; P = 0.06). 10 Taken together, these data suggest that the risk of major bleeding can be minimized by using the lowest proven effective dose of aspirin and by discontinuing clopidogrel at least 5 days prior to planned coronary artery bypass graft surgery.

Guidelines for Antiplatelet Therapy in Non-ST-Segment Elevation Acute Coronary Syndrome
The updated ACC/AHA Guidelines for the Management of Patients with Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction in 2002 84 recommend aspirin as soon as possible after presentation and continued indefinitely. Because of concerns regarding the risk of bleeding in patients undergoing early intervention who may require coronary artery bypass graft surgery, these guidelines currently recommend that clopidogrel should be routinely added to aspirin only in patients undergoing an early noninterventional approach with treatment continued for up to 9 months. However, because clopidogrel reduces the risk of major ischemic events irrespective of whether an early interventional strategy is used, and given the reversible nature of the majority of bleeding episodes, a more reasonable approach may be to start the combination of clopidogrel and aspirin as early as possible in all patients presenting with non-ST-segment elevation acute coronary syndrome who do not have a contraindication. Clopidogrel should be withheld for at least 5 days in patients for whom elective coronary artery bypass surgery is planned.

PERCUTANEOUS CORONARY INTERVENTION
Percutaneous coronary intervention involves the use of one or more revascularization devices designed to remove (e.g., rotational atherectomy), ablate (e.g., excimer laser angioplasty), or scaffold (e.g., stents) atherosclerotic plaque. 85 This results in local vascular trauma, exposing highly thrombogenic subendothelium to the circulating blood and leading to local thrombus formation. Prior to the widespread use of antiplatelet therapies, intracoronary stenting was commonly complicated by acute (<24 hours) or subacute (1 to 14 days) thrombosis. 86 However, periprocedural use of antiplatelet drugs has substantially reduced the incidence of early ischemic complications.

Aspirin
Aspirin started prior to angioplasty reduced the risk of periprocedural ischemic complications in patients undergoing balloon angioplasty, 87 with the addition of dipyridamole yielding no additional benefit. 88 Although the optimal dose of aspirin in the setting of percutaneous coronary intervention has not been established, 80 to 325 mg/day is most commonly recommended. 89

Clopidogrel and Ticlopidine
Randomized trials have demonstrated that the combination of ticlopidine plus aspirin compared with anticoagulation alone 89,90 or anticoagulation plus aspirin 91,92 reduces the risk of early thrombotic complications and ischemic events in patients undergoing percutaneous coronary intervention with stent insertion. Combined thienopyridine and aspirin therapy was associated with a reduced risk of bleeding complications in three of the four studies 90,91,93 and the clinical benefits remained evident during long-term follow-up. 94 Trials of ticlopidine in percutaneous coronary intervention demonstrated a lag time of several days before the benefits of treatment became evident, consistent with the delayed peak antiplatelet effects of orally administered ticlopidine. The duration of pretreatment with ticlopidine prior to percutaneous coronary intervention was also correlated with a reduction in procedurerelated ischemic complications, with the lowest incidence of non-Q-wave myocardial infarction seen in patients treated with ticlopidine for more than 72 hours prior to stent insertion. 95 More recently, the combination of clopidogrel and aspirin was shown to be at least as effective as the combination of ticlopidine and aspirin for preventing thrombotic complications in patients undergoing percutaneous coronary intervention with stent insertion. 96,97 The Clopidogrel for the Reduction of Events During Observation (CREDO) trial was designed to determine the optimal duration of pretreatment with clopidogrel prior to percutaneous coronary intervention as well as the benefits of continuing clopidogrel therapy beyond 30 days after the procedure. 98 CREDO randomly assigned 2116 patients to receive clopidogrel 300 mg loading dose or placebo 3 to 24 hours prior to percutaneous coronary intervention. All patients received clopidogrel 75 mg/day through to day 28 but thereafter patients who had received a preprocedure loading dose continued to receive clopidogrel 75 mg/day for 1 year while patients who did not receive a loading dose of clopidogrel were continued on placebo. All patients were also treated with aspirin. Clopidogrel compared with placebo was associated with a 26.9% (95% CI 3.9 to 44.4%; P = 0.02) relative reduction in the primary composite outcome of myocardial infarction, stroke, and cardiovascular death (Fig. 6). There was no significant excess of bleeding and the benefits of clopidogrel were The CREDO study demonstrated a nonsignificant trend to a reduction in the 28-day outcome with the clopidogrel loading dose compared with placebo (risk reduction 18.5%; 95% CI -14.2 to 41.8%). These data are consistent with results from the Percutaneous Coronary Intervention substudy of the CURE trial of 2568 patients, 99 which demonstrated that a pretreatment with clopidogrel (median duration of pretreatment = 10 days) compared with placebo was associated with a 30% reduction in myocardial infarction, stroke, or cardiovascular death at 30 days (RR 0.70; 95% CI 0.50 to 0.97, P = 0.03).

Guidelines for Antiplatelet Therapy in Patients Undergoing Percutaneous Coronary Intervention
The ACC/AHA Guidelines for Percutaneous Coronary Intervention in 2001 89 recommend aspirin 80 to 325 mg at least 2 hours prior to the procedure given in combination with either ticlopidine or clopidogrel given for at least 72 hours prior to the procedure where possible. Aspirin should be continued long term, and the current recommendations indicate that clopidogrel or ticlopidine should be continued for at least 2 to 4 weeks. However, the more favorable safety profile of clopidogrel compared with ticlopidine coupled with the results of the PCI-CURE study and CREDO trial is likely to lead to changes in these recommendations, particularly in rela-tion to the use of clopidogrel in preference to ticlopidine and the duration of clopidogrel therapy, as there is now clear evidence of benefit from continuing thienopyridine treatment for at least 12 months in patients undergoing percutaneous coronary intervention.

CONCLUSION
An increasing number of antiplatelet therapies are of proven effectiveness for the acute and long-term management of patients with acute coronary syndromes. Aspirin remains the cornerstone of treatment in patients with acute coronary syndrome because it is inexpensive and highly effective. Aspirin should be started as soon as the diagnosis is suspected and continued indefinitely. There is currently no proven role for clopidogrel in patients with ST-segment elevation acute coronary syndrome except in patients who are unable to take aspirin because of allergy or major gastrointestinal intolerance. Further studies with the combination of clopidogrel and aspirin are ongoing in this group of patients. In patients with non-ST-segment elevation acute coronary syndrome and acute coronary syndrome undergoing percutaneous coronary intervention, the combination of clopidogrel and aspirin is the new standard of care. Clopidogrel should be started early, given initially as a loading dose and ideally at least 72 hours prior to planned percutaneous coronary intervention, and continued for at least 9 to 12 months. Glycoprotein IIb/IIIa inhibitors are a further class of antiplatelet agent that are of proven benefit in the management of patients with acute coronary syndrome and undergoing percutaneous coronary intervention.