American Journal of Emergency Medicine (2008) 26, 212220

www.elsevier.com/locate/ajem

Review

ST-elevation myocardial infarction: the role of adjunctive antiplatelet therapyB

William E. Boden MD a,*, James Hoekstra MD b , Chadwick D. Miller MD b
a b

Buffalo General and Millard Fillmore Hospitals, Buffalo, NY, USA Department of Emergency Medicine, Wake Forest University Baptist Medical Center, Winston-Salem, NC 27157, USA

Received 23 March 2007; accepted 27 March 2007

Abstract Antiplatelet therapy to reduce the risks of recurrent myocardial infarction and restenosis after primary percutaneous coronary intervention is critically important to optimize the early treatment of ST-segment elevation myocardial infarction (STEMI). Traditionally, acetylsalicylic acid (ASA; aspirin) has been recommended for patients with suspected STEMI, but this agent targets only one of several pathways of platelet aggregation. Antiplatelet agents with different inhibitory mechanisms may act synergistically with ASA. Glycoprotein IIb/IIIa inhibitors are generally not used with fibrinolytic agents in acute STEMI management; indeed, glycoprotein IIb/IIIa inhibitors plus bolus fibrinolytics increase the risk of intracranial hemorrhage. Aggressive antiplatelet therapy with clopidogrel reduces mortality in STEMI patients and offers significant clinical benefits, without an associated increase in major bleeding events. Recent trials support the development of an early and aggressive approach to more complete platelet inhibition using clopidogrel, in combination with ASA, for patients with STEMI. 2008 Elsevier Inc. All rights reserved.

1. Introduction
ST-elevation myocardial infarction (STEMI), the most malignant expression of acute coronary syndrome (ACS), results from thrombus-mediated total occlusion of an infarct-related coronary artery. Acute STEMI is associated with a worse short-term prognosis (0-3 months) than less severe presentations of ACS (unstable angina [UA] and non-STEMI [NSTEMI]) [1] and thus presents a particular
Editorial assistance for the development of this was provided by Jackie Campbell, with the financial support of the BMS/sanofi-aventis Pharmaceuticals Partnership. Corresponding author. Tel.: +1 716 859 2978; fax: +1 716 859 3949. E-mail address: wboden@kaleidahealth.org (W.E. Boden). 0735-6757/$ see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ajem.2007.03.033

challenge to emergency medicine physicians in terms of diagnosis and prompt treatment. Ideally, patients with suspected STEMI are admitted to the emergency department (ED), where high-priority evaluation and protocolbased treatment commence without delay. The principal goal of the initial treatment of STEMI is to achieve rapid reperfusion of the occluded infarctrelated artery (IRA) and enhanced myocardial tissue perfusion, thereby limiting ischemic necrosis. Reperfusion may be achieved with fibrinolytic therapy or primary percutaneous coronary intervention (PCI). Recent clinical studies have shown that combination antiplatelet therapy offers additional clinical benefits. This review assesses the role of aggressive adjunctive antiplatelet therapy in early STEMI management.

STEMI: the role of adjunctive antiplatelet therapy

213 associated with STEMI and NSTEMI/UA are illustrated in Fig. 1. The difference in composition of thrombi associated with STEMI and UA/NSTEMI underscores the different treatment strategies that have evolved for these conditions and explains why fibrinolytic therapy is effective in STEMI (high clot burden) but not NSTEMI (lower clot burden) [6]. However, fibrinolytic therapy alone does not influence the platelet component of thrombi associated with STEMI. Antiplatelet therapies that inhibit the formation of plateletrich thrombi associated with NSTEMI and UA have advanced standards of care in these particular areas and, based on recent clinical trials, may also improve outcomes in STEMI patients.

2. Pathology and diagnosis of STEMI

The most common underlying cause of ACS manifestations is atherothrombosis, the unhealthy coupling of atherosclerosis with superimposed acute thrombosis. Atherothrombosis begins with atherosclerotic plaque formation, followed by plaque fissuring or rupture, and subsequent acute and subacute thrombotic occlusion. Several wellrecognized cardiovascular risk factors, including cigarette smoking, diabetes, dyslipidemia, and hypertension, contribute to smooth muscle cell activation and to macrophage activation within cells lining the vascular endothelium of arterial walls. The results are deposition of extracellular lipid and subsequent recruitment of inflammatory mediators. Macrophages scavenge the lipoprotein deposits and develop into lipid-laden foam cells, which contribute to atherosclerotic plaque growth. Smooth muscle cell proliferation also occurs at the site of plaques, and such proliferation contributes to fibrous cap formation over the lesion. With time, the fibrous cap may be degraded and weakened by matrix metalloproteinases. Rupture of a portion of the thin, vulnerable fibrous cap leads to release of tissue factors that trigger platelet adhesion and activation, and subsequent thrombus formation [2]. Total occlusion of an epicardial coronary artery by a thrombus is likely to manifest clinically as STEMI, which may result in myocardial necrosis and significant permanent tissue damage if antegrade coronary blood flow is not promptly reestablished. Currently, factors predisposing individuals to STEMI rather than UA or NSTEMI are unknown, although patients with STEMI tend to be younger, with a higher propensity of single-vessel coronary artery disease, and with generally less advanced heart disease than patients with UA or NSTEMI [3].

3. Current options in STEMI treatment

Assessment for STEMI in a patient presenting to the ED with chest pain generally involves an initial clinical assessment of the patient's history, compatible with acute myocardial infarction (AMI; usually chest discomfort for 30 minutes), a physical examination (often unrevealing), together with an abnormal electrocardiogram, which shows ST-segment elevation of 1 mm in 2 or more limb leads or of 2 mm in 2 or more precordial leads. Upon diagnosis, the key determinant of short- and long-term outcome is time to reperfusion. Delayed time to treatment is significantly associated with increased mortality. In the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico trial [7], the first large-scale mortality trial for fibrinolytic therapy, a 47% reduction in mortality was observed in

2.1. Thrombus composition in STEMI and NSTEMI

The extent of plaque rupture is likely to be the critical factor determining whether the clinical presentation is silent or results in UA, NSTEMI, or STEMI [4]. Generally, a large plaque rupture will generate a large thrombus of sufficient size to completely occlude the artery and cause STEMI, whereas smaller ruptures may lead to smaller thrombi, resulting in partial (or subtotal) occlusion and UA or NSTEMI. A large thrombus has 2 components: a red corpus composed of fibrin and red blood cells (fibrin-rich thrombus) and a white head composed largely of aggregated platelets (platelet-rich thrombus). In contrast, rupture of a small plaque results in a nonocclusive thrombus consisting predominantly of aggregated platelets with little fibrin content. However, as the composition of an individual thrombus is in constant flux, depending on the location and stage of thrombus development, distinction between the types of thrombi causing STEMI, NSTEMI, and UA is not absolute [5]. The structures of thrombi

Fig. 1 The structure and composition of thrombi associated with STEMI and UA/NSTEMI. Reproduced with permission from Otterstad and Brosstad, Scandinavian Cardiovascular Journal 2003;37:316-323, Taylor & Francis Ltd. http://www.informaworld. com.

214 patients treated within 1 hour, compared with a 17% reduction in patients treated within 6 hours of the infarct event. Furthermore, a door-to-balloon time of N2 hours significantly increased the odds of mortality by 41% to 62% in a study of 27 080 patients with STEMI [8]. Reperfusion may be achieved by pharmacologic or mechanical means, depending on the capability of the receiving hospital. The main pharmacologic targets for intervention in STEMI are illustrated in Fig. 2. The benefits of fibrinolytic therapy in reducing STEMI-associated mortality have been firmly established [9]; and optimal fibrinolytic therapy has evolved in recent years from a combination of streptokinase and acetylsalicylic acid (ASA; aspirin) to the use of bolus fibrinolytic agents combined with unfractionated or low molecular weight heparin, together with ASA [9]. Mechanical revascularization of the IRA is achieved by primary PCI, a procedure that has yielded impressive results. More patients experience full restoration of normal coronary blood flow (Thrombolysis in Myocardial Infarction [TIMI] grade 3 flow) where PCI rather than fibrinolysis is used provided that the procedure is carried out promptly (within 90-120 minutes). A meta-analysis of 10 randomized trials comparing angioplasty with fibrinolytic therapy determined that mortality at 30 days was lower in

W.E. Boden et al. patients undergoing PCI than in those receiving fibrinolytic agents (4.4% vs 6.5%) [10]. However, these trials are now outdated; and in light of more recent findings, a new analysis is required. The optimal target times for achieving effective reperfusion are b30 minutes (after arrival in the ED) for fibrinolysis and b90 minutes (door-to-balloon time) for primary PCI [9]. Currently, however, these goals are met in b25% of patients and in only 3% to 4% of STEMI patients who present initially to community hospitals and are then transferred for primary PCI [11].

4. Limitations of current STEMI treatments

Pharmacologic and mechanical approaches to rapid treatment in STEMI patients have limitations. For instance, in large-scale clinical trials in the past decade, the time from symptom onset to the administration of reperfusion agents has remained consistent (2.5-3 hours), despite several dedicated educational efforts to reduce the time to treatment [12,13]. In addition, fibrinolytic monotherapy has limited efficacyinadequate reperfusion or reocclusion of the IRA occurs in many patients. Reocclusion occurs when thrombus disruption leads to thrombin release, which triggers additional platelet activation and aggregation and therefore de novo fibrin formation. Approximately 45% to 50% of patients treated during AMI fail to achieve early and complete restoration of coronary blood flow [14]. Furthermore, there are safety issues associated with fibrinolytic therapy; intracranial hemorrhage occurs in approximately 1% of patients, with the risk being greater in older patients (aged N75 years) [12,13]. An additional limitation of fibrinolytic therapy is that it may not be offered to all STEMI patients because of actual or perceived contraindications, including late presentation and atypical symptoms. Although primary PCI is associated with superior efficacy, higher rates of TIMI grade 3 flow, and lower reocclusion rates than fibrinolysis, this procedure also has limitations. High rates of success with PCI have generally been achieved in high-volume tertiary centers with experienced clinicians and where cardiac catheterization is available at all times [15]. However, primary PCI is unavailable in most rural or smaller community hospitals; and even hospitals with PCI facilities are unlikely to have round-the-clock PCI availability [16]. Primary PCI may be more difficult to achieve in a timely manner than medical therapy, particularly in STEMI patients who present de novo to a community hospital and, regarding the inevitable time delay associated with interhospital transfer, may carry additional risk [17,18]. A meta-analysis of 10 randomized trials of primary angioplasty vs fibrinolytic therapy in AMI (n = 1333) revealed that only 32% of patients presented for reperfusion treatment within 2 hours of symptom onset [19]. As noted previously, delays in doorto-balloon time create a challenging total time delay

Fig. 2 Principal targets in a pharmacologic antiplatelet strategy for STEMI. Adapted with permission from Otterstad and Brosstad, Scandinavian Cardiovascular Journal 2003;37:316-323, Taylor & Francis Ltd. http://www.informaworld.com. Acetylsalicylic acid (aspirin) permanently acetylates and inhibits the enzyme COX-1 and switches off platelet thromboxane A2 production. Clopidogrel irreversibly inhibits platelet ADP receptors, which regulate adenylate cyclase via inhibitory G proteins. Glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban) block fibrinogen binding to ADP receptors and inhibit platelet aggregation in a dose-dependent manner. TxA2 indicates thromboxane A2.

STEMI: the role of adjunctive antiplatelet therapy (symptom onset to ED arrival and door-to-balloon time) that impedes timely reperfusion in many instances.

215 surface, which is the final common pathway for platelet aggregation. These agents have proven mortality benefits, derived from clinical experience in NSTEMI patients and after PCI [21,22]: patients at greatest risk are likely to gain the greatest benefit [23]. Data from the National Registry of Myocardial Infarction reveal that the early use of GP IIb/IIIa inhibitors reduces mortality in patients with ST-segment abnormality (depression) or who are candidates for early PCI [24]. The use of GP IIb/IIIa inhibitors in combination with fibrinolytic therapy has also been investigated in patients with STEMI (see next section).

5. Antiplatelet therapy in STEMI

The composition of the occluding thrombus in STEMI means that fibrinolytic monotherapy is unlikely to be wholly successful in dispersing the clot. The platelet component will remain unaffected by fibrinolysis and is actually antagonistic to fibrinolytic agents because platelets may release plasminogen activator inhibitors. Fibrinolysis is itself a prothrombotic process, as it exposes free thrombin from the thrombus interior, ultimately leading to further platelet aggregation. Similarly, there is a risk of reocclusion after primary PCI because the vessel wall remains potentially thrombogenic. Effective inhibition of platelet aggregation therefore has a critical place in the early treatment of STEMI.

5.3. GP IIb/IIIa inhibitors and fibrinolytic therapy

The combination of a GP IIb/IIIa inhibitor plus low-dose fibrinolytic therapy generally produces greater tissue perfusion than full-dose fibrinolytic monotherapy. This has been shown through slightly higher TIMI grade 3 flow rates, more complete resolution of ST-segment elevation [25], and lower rates of in-hospital reinfarction [26]. However, these advantages are offset by an increased risk of noncerebral bleeding [26]. The routine use of a GP IIb/IIIa inhibitor in combination with a fibrinolytic agent as reperfusion therapy is not recommended because of the increased risk of bleeding, and most institutions have not implemented this combination strategy in STEMI management. Nonetheless, GP IIb/IIIa inhibitors have an application as adjunctive therapy in PCI and can therefore be used in STEMI patients undergoing PCI. Currently, 3 GP IIb/IIIa inhibitors are available commercially (abciximab, eptifibatide, and tirofiban). 5.3.1. Abciximab Abciximab is a humanized mouse antibody fragment with high binding affinity for the GP IIb/IIIa receptor. Abciximab plus standard-dose heparin during primary PCI of the IRA improves immediate clinical outcome (ie, reduces the rates of death, reinfarction, and urgent revascularization) but increases the risk of hemorrhagic complications [27]. The incidence of death, reinfarction, or urgent revascularization was improved by abciximab vs placebo at 7 days (3.3% vs 9.9%; P = .003), 30 days (5.8% vs 11.2%; P = .03), and 6 months (11.6% vs 17.8%; P = .05). Major bleeding, primarily at the arterial access site, occurred more frequently in abciximab recipients (16.6% vs 9.5%; P = .02). However, no intracranial hemorrhage was observed in abciximab or placebo recipients [27]. Thus, the use of abciximab with reduced-dose heparin during primary PCI seems to improve angiographic and clinical outcomes. Abciximab vs placebo administration before stenting was associated with fewer occurrences of a composite primary end point of death, reinfarction, or urgent revascularization at 30 days (6.0% vs 14.6%) in 300 patients with AMI who underwent coronary angioplasty [28]. Minor bleeding episodes occurred more frequently in the abciximab than in

5.1. Acetylsalicylic acid (aspirin)

Acetylsalicylic acid is an established antiplatelet agent. It reduces the risk of ischemic events in all manifestations of ACS and should form an essential part of the early management of all patients with suspected STEMI, as recommended in the American College of Cardiology/ American Heart Association practice guidelines [9]. Acetylsalicylic acid should be administered promptly upon presentation, and at least within the first 24 hours, at a dosage of 150 to 325 mg/d; it should be continued indefinitely at a dosage of 75 to 162 mg/d in all patients able to tolerate it. However, in patients with important ASA allergies, an alternative antiplatelet agent should be used [9]. Acetylsalicylic acid irreversibly inhibits cyclooxygenase1 (COX-1) in platelets and thereby blocks the formation of thromboxane A2. Because platelets are unable to regenerate COX-1, the immediate antithrombotic effect of ASA persists for the life span of the platelet (8-10 days). However, as ASA targets only one receptor, it leaves alternative routes for platelet activation available. Combination antiplatelet therapies with the promise of synergistic activity are becoming available. Such therapies have already been used with success in patients with UA/NSTEMI, regardless of surgical intervention [20]. Newer antiplatelet agents have not been widely used in the emergency treatment of STEMI. However, the availability of such agents, with distinct and complementary mechanisms of action, offers the potential for greater benefit when used in combination with ASA.

5.2. Glycoprotein IIb/IIIa receptor blockers

Glycoprotein (GP) IIb/IIIa receptor antagonists inhibit fibrinogen binding to GP IIb/IIIa receptors on the platelet

216 the placebo group (12.1% vs 3.3%), mostly in association with groin hematomas [28]. In another trial, abciximab reduced the occurrence of a primary composite end point (death, reinfarction, disabling stroke, and ischemia-driven revascularization of the target vessel) in patients who underwent percutaneous transluminal coronary angiography alone or who also received a stent [29]. In percutaneous transluminal coronary angiography recipients, the primary end point occurred in 16.5% of patients treated with abciximab vs 20% of those without abciximab. In stent recipients, a primary end point event occurred in 10.2% of patients treated with abciximab vs 11.5% of those without abciximab. There were no significant differences in the frequencies of major or minor bleeding events [29]. Moreover, in a broad population of patients undergoing PCI, lowdose heparin together with improved arterial sheath and access site management reduced bleeding rates associated with abciximab, while maintaining efficacy [30]. 5.3.2. Eptifibatide Eptifibatide is a heptapeptide inhibitor of platelet GP IIb/ IIIa receptors that has demonstrated efficacy in the treatment of patients during coronary angioplasty, myocardial infarction, and angina. In one study, the incidence of a combined primary end point of death, myocardial infarction, and urgent revascularization was lower with eptifibatide than with placebo (low dose: 9.2%; high dose: 9.9%; placebo: 11.4%) [31]. However, the treatment-placebo differences were not significant; and the eptifibatide dosages used were suboptimal, as they inhibited platelet aggregation by only 40% to 60% (target: 80%) [31]. Eptifibatide vs placebo achieved better rates of reperfusion (TIMI grade 3 flow: 66% vs 39%; P = .05) in 132 patients with AMI, suggesting that its addition to revascularization strategies may be beneficial [32]. In patients undergoing a stenting procedure, eptifibatide vs placebo produced a lower incidence of a composite end point of death, myocardial infarction, urgent target-vessel revascularization, and thrombotic bailout GP IIb/IIIa inhibitor therapy within 48 hours of randomization (6.6% vs 10.5%; P = .0015) [33]. Major bleeding, although infrequent, occurred more often in eptifibatide than in placebo recipients (1.3% vs 0.4%; P = .027) [33]. Another trial, which evaluated the efficacy of early eptifibatide therapy in 343 STEMI patients undergoing primary PCI, showed that eptifibatide, initiated in the ED rather than cardiac catheterization laboratory, increased epicardial blood flow and improved TIMI myocardial perfusion grade [34]. Early eptifibatide initiation was not associated with an increased incidence of bleeding complications [34]. 5.3.3. Tirofiban Tirofiban is a nonpeptide inhibitor of platelet GP IIb/IIIa receptors. Tirofiban was assessed in the Randomized Efficacy Study of Tirofiban for Outcomes and REstenosis in patients undergoing coronary interventions within 72

W.E. Boden et al. hours of AMI presentation [35]. The primary composite end point was the occurrence of death from any cause, myocardial infarction, coronary bypass surgery due to PCI failure or recurrent ischemia, repeated target-vessel PCI, and insertion of a stent. Two days after PCI, the tirofiban group had a 38% relative reduction in the composite end point (P b .005). However, at 30 days, the reduction in adverse cardiac events achieved with tirofiban was no longer statistically significant. The incidence of bleeding was similar to that with placebo [35]. Tirofiban vs standard heparin therapy was also shown to reduce ischemic events in patients with UA. The incidence of a composite end point of death, myocardial infarction, or refractory ischemia was lower at 48 hours in the tirofiban than in the heparin group (3.8% vs 5.6%; P = .01) in the Platelet Receptor Inhibition in Ischemic Syndrome Management Study [36]. The incidence of major bleeding did not differ between the groups [36]. In a related study, tirofiban reduced the incidence of early cardiac events; however, the 30-day incidence of cardiac events was not significantly different from that of placebo [37]. Early tirofiban administration before planned angioplasty confers benefit in patients with AMI. For example, the TIrofiban Given in the Emergency Room before Primary Angioplasty trial was a pilot study (n = 100) demonstrating significant improvement in TIMI grade flow, TIMI frame counts, and TIMI grade myocardial perfusion in patients treated with tirofiban early in the ED rather than later in the catheterization laboratory [38]. There were no differences between the early- and late-administration groups regarding bleeding complications, although the small sample size meant that modest differences in low-frequency events would not have been detected in this study [38].

5.4. Thienopyridines
Clopidogrel and ticlopidine are thienopyridines that selectively inhibit the adenosine diphosphate (ADP) mediated binding of fibrinogen to GP IIb/IIIa receptors. Ticlopidine can cause rare, but serious, adverse effects and is not generally used in patients with ACS. Clopidogrel monotherapy was superior to ASA in preventing a composite end point of ischemic stroke, myocardial infarction, or vascular death in the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events trial [39] and, unlike ticlopidine, does not induce neutropenia more frequently than ASA. Clopidogrel is currently recommended for use in patients with ACS who cannot tolerate ASA [9,40]. Because the mechanisms of action of clopidogrel and ASA are different, there is a rationale for the use of these agents in combination.

6. NSTEMI and UA: clopidogrel and ASA

Dual antiplatelet therapy, consisting of clopidogrel and ASA, is effective in preventing a composite end point of

STEMI: the role of adjunctive antiplatelet therapy death, myocardial infarction, and stroke in patients who have ACS without ST-segment elevation [41] or in patients who have undergone PCI [20,42]. The Clopidogrel in Unstable angina to prevent Recurrent Events study randomized 12 562 patients with UA/NSTEMI to clopidogrel (a loading dose of 300 mg, followed by 75 mg/d) or placebo, plus ASA (75-325 mg/d), for 3 to 12 months [41]. Clopidogrel was associated with a 20% relative reduction in risk of the composite primary end point of cardiovascular death, nonfatal myocardial infarction, or stroke (95% confidence interval [CI] 0.72-0.90; P b .001). The incidence of lifethreatening bleeding was not significantly increased by clopidogrel vs placebo (2.1% vs 1.8%; P = .13), although significantly more patients experienced major bleeding in the clopidogrel than in the placebo group (3.7% vs 2.7%; P = .001) [41]. In a prospectively designed study of patients undergoing PCI in the Clopidogrel in Unstable angina to prevent Recurrent Events trial, clopidogrel was effective in preventing cardiovascular death, myocardial infarction, and urgent target-vessel revascularization [42]. The long-term (12-month) benefit of clopidogrel, with a background of ASA therapy, after PCI was established in the Clopidogrel for the Reduction of Events During Observation trial in 2116 patients who underwent elective PCI [20]. In this study, a 26.9% reduction (relative to placebo) in a composite end point of death, myocardial infarction, or stroke was achieved at 1 year with clopidogrel (a loading dose of 300 mg, followed by 75 mg/d) (95% CI 3.9-44.4; P = .02). The risk of major bleeding at 1 year was not significantly greater for clopidogrel vs placebo (8.8% vs 6.7%; P = .07) [20]. Clopidogrel monotherapy in patients with symptomatic atherosclerotic disease [39] and dual therapy with ASA in patients with UA/NSTEMI [41] or who have undergone PCI [20,42] prevented a composite end point of death and ischemic complications. Two major studies recently examined whether aggressive antiplatelet therapy with clopidogrel in combination with ASA would be beneficial in STEMI patients (see next section).

217

Fig. 3 Efficacy of clopidogrel at 30 days in the CLARITY-TIMI 28 study. Reproduced with permission from Sabatine et al, New England Journal of Medicine 2005;352:1179-1189. Copyright 2005, Massachusetts Medical Society. All rights reserved. The odds ratio for the end point of death from cardiovascular causes, recurrent myocardial infarction, or recurrent ischemia leading to the need for urgent revascularization was significantly lower in the clopidogrel than in the placebo group at 30 days (11.6% vs 14.1%; odds ratio 0.80; P = .03).

7. STEMI: clopidogrel and ASA

A study in 3491 patients presenting within 12 hours of STEMI onset compared the effects of adding oral clopidogrel (a loading dose of 300 mg, followed by 75 mg/d) or placebo to an ASA- and heparin-based fibrinolytic regimen [43]. The primary efficacy end point was a composite of an occluded IRA (defined by TIMI flow grade 0 or 1) on angiography or recurrent infarction/death from any cause before angiography. The primary composite end point occurred in 15.0% of clopidogrel recipients and 21.7% of placebo recipients (P b .001). This improvement was driven largely by a lower incidence of IRA occlusion with clopidogrel than placebo (11.7% vs 18.4%; P b .001). Clopidogrel also reduced the

rate of recurrent myocardial infarction (2.5% vs 3.6%; P = .08), although there was no significant difference in the rate of death from any cause (2.6% vs 2.2%; P = .49). At 30 days, clopidogrel had reduced the odds of the composite end point of cardiovascular mortality, recurrent myocardial infarction, and recurrent ischemia leading to the need for urgent revascularization from 14.1% to 11.6% (P = .03) (Fig. 3). Compared with placebo, clopidogrel was also associated with a lower 30-day incidence of recurrent myocardial infarction (4.1% vs 5.9%; P = .02), recurrent ischemia leading to revascularization (3.5% vs 4.5%; P = .11), and stroke (0.9% vs 1.7%; P = .052). The benefit of clopidogrel was consistent across subgroups and was irrespective of age, sex, fibrinolytic regimen, and infarct location. The rates of major bleeding and hemorrhage were similar in the clopidogrel and placebo groups; safety outcomes are presented in Table 1 [43]. The bleeding rate in the above-mentioned trial was low [43], possibly because of adherence to weight-based guidelines for heparin dosing. The investigators concluded that clopidogrel offered an effective, simple, and safe means of improving patency of the IRA and reduced the rate of ischemic complications [43]. The PCI-CLARITY trial, a prospectively planned subanalysis of the 1863 patients from the Clopidogrel as Adjunctive Reperfusion TherapyThrombolysis in Myocardial Infarction 28 (CLARITY-TIMI 28) trial who underwent PCI, demonstrated that clopidogrel pretreatment, in addition to background ASA therapy, was beneficial in this subgroup [44]. Clopidogrel vs placebo recipients had a significantly reduced risk of the primary composite end point of

218
Table 1 Safety outcomes a in the CLARITY-TIMI 28 study at 30 days b Clopidogrel (n = 1733) Placebo (n = 1719) P

W.E. Boden et al. Although a loading dose was not used in this trial, the survival curves began to diverge as early as day 1 [45]. Consistent with findings from the CLARITY-TIMI 28 trial [43], the benefit of clopidogrel in COMMIT/CCS-2 was apparent across patient subgroups (ie, the benefit was irrespective of age, sex, and fibrinolytic regimen) [45]. Furthermore, the benefit seemed to be greatest when clopidogrel was administered early (within 6 hours) after symptom onset. The combined incidences of overall transfused, fatal, and cerebral bleeding were similar in the 2 groups (0.58% vs 0.55%; P = .59). However, minor bleeding events were more common with clopidogrel than with placebo (3.6% vs 3.1%; P = .005) [45]. The clear efficacy advantage for dual antiplatelet therapy over ASA monotherapy demonstrated by the CLARITY-

No. of patients (%) Through the day after angiography Major bleeding Minor bleeding Major or minor bleeding Intracranial hemorrhage At 30 d Major bleeding Minor bleeding Major or minor bleeding

23 17 40 8

(1.3) (1.0) (2.3) (0.5)

19 9 28 12

(1.1) (0.5) (1.6) (0.7)

.64 .17 .18 .38 .80 .12 .24

33 (1.9) 27 (1.6) 59 (3.4)

30 (1.7) 16 (0.9) 46 (2.7)

a For patients who underwent angiography, the incidence of bleeding through the day after angiography and at 30 days was ascertained. For those who did not undergo angiography, the incidence of bleeding was ascertained through day 8 or at discharge, whichever occurred first. The primary bleeding end point was major bleeding according to TIMI criteria (including intracranial hemorrhage) through the day after angiography. b Table adapted with permission from Sabatine et al, New England Journal of Medicine 2005;352:1179-89. Copyright 2005, Massachusetts Medical Society. All rights reserved.

cardiovascular death, myocardial infarction, or stroke after PCI through 30 days after randomization (odds ratio 0.54; 95% CI 0.35-0.85; P = .008). Clopidogrel pretreatment was also associated with a significant reduction in the combined incidence of recurrent myocardial infarction or stroke before PCI (odds ratio 0.62; 95% CI 0.40-0.90; P = .03). Furthermore, clopidogrel did not significantly increase the incidence of TIMI major or minor bleeding after PCI [44]. However, as these findings come from a subanalysis, they should be interpreted with caution until they are confirmed by a randomized controlled trial. The CLARITY-TIMI 28 trial [43] was not powered to show a survival benefit in STEMI patients; but the survival issue was addressed in a separate study, the ClOpidogrel and Metoprolol in Myocardial Infarction Trial/Second Chinese Cardiac Study (COMMIT/CCS-2)The Clopidogrel Arm [45]. This randomized, placebo-controlled trial, conducted in 46 000 patients in China, investigated the effects of dual antiplatelet therapy on mortality rates in STEMI. Patients presenting within 24 hours of STEMI onset were randomized to 4 weeks' administration of clopidogrel (75 mg/d) or placebo; all patients received ASA 162 mg/d for the duration of the study. Concomitant fibrinolytic therapy was administered to 50% and anticoagulants to 74% of patients. Clopidogrel vs placebo produced a 9% reduction in the primary composite end point of death, reinfarction, and stroke (95% CI 3-14; P = .002) (Fig. 4). At hospital discharge or day 28 (whichever came first), clopidogreltreated patients had a significantly lower rate of all-cause mortality than placebo recipients (7.5% vs 8.1%; P = .03).

Fig. 4 Efficacy of clopidogrel in the COMMIT/CCS2The Clopidogrel Arm. Reproduced with permission from the COMMIT Collaborative Group, The Lancet 2005;336:1607-1621. The timeto-event (death, reinfarction, or stroke before first discharge from hospital) analysis was based on a first relevant event during the treatment period. The mean treatment duration in survivors was 14.9 days. Events after discharge were not included. A risk reduction of 9% (P = .002) was achieved for the primary composite end point of death, reinfarction, and stroke in 22 958 patients in the clopidogrel arm.

STEMI: the role of adjunctive antiplatelet therapy TIMI 28 [43] and COMMIT/CCS-2 [45] clopidogrel trials was achieved in STEMI patients treated with an early medical management strategy. In the CLARITY-TIMI 28 trial [43], patients did not undergo coronary angiography for a median of 3.5 days; and in COMMIT/CCS-2 [45], patients undergoing surgical revascularization were excluded from the study. Furthermore, only 50% of patients in COMMIT/ CCS-2 received fibrinolytic therapy [45]. Previously, clopidogrel was shown to reduce the risk of recurrent atherothrombosis in patients with UA/NSTEMI, irrespective of whether these patients were medically managed or underwent surgical revascularization (PCI or coronary artery bypass grafting) [20,42]. The CLARITY-TIMI 28 [43] and COMMIT/CCS-2 [45] trials have clearly provided important data to advance the treatment standards for STEMI patients who are medically managed.

219 useful to further define the precise role of clopidogrel in STEMI management. Meanwhile, evidence from the aforementioned trials suggests that there is considerable scope for increasing the overall clinical benefit of clopidogrel-containing regimens by expanding the early use of clopidogrel in the emergency setting of acute STEMI.

References
[1] Roe MT, Parsons LS, Pollack Jr CV, et al, National Registry of Myocardial Infarction Investigators. Quality of care by classification of myocardial infarction: treatment patterns for ST-segment elevation vs nonST-segment elevation myocardial infarction. Arch Intern Med 2005;165:1630-6. [2] Libby P, Ridker P, Maseri A. Inflammation and atherosclerosis. Circulation 2002;105:1135-43. [3] Fox KA, Goodman SG, Klein W, et al. Management of acute coronary syndromes. Variations in practice and outcome; findings from the Global Registry of Acute Coronary Events (GRACE). Eur Heart J 2002;23:1177-89. [4] Otterstad JE, Brosstad F. Results from clinical trials on ST-elevation myocardial infarction in a historic perspective with some pathophysiological aspects. Scand Cardiovasc J 2003;37:316-23. [5] Schafer AI. Antiplatelet therapy. Am J Med 1996;101:199-209. [6] The TIMI IIIB Investigators. Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and nonQ-wave myocardial infarction. Results of the TIMI IIIB Trial. Thrombolysis in Myocardial Ischemia. Circulation 1994;89:1545-56. [7] Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986;1:397-402. [8] Cannon CP, Gibson CM, Lambrew CT, et al. Relationship of symptom-onset-to-balloon time and door-to-balloon time with mortality in patients undergoing angioplasty for acute myocardial infarction. JAMA 2000;283:2941-7. [9] Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). J Am Coll Cardiol 2004;44:E1-E211. [10] Weaver WD, Simes RJ, Betriu A, et al. Comparison of primary coronary angioplasty and intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review. JAMA 1997;278:2093-8. [11] Cannon CP, Bahit MC, Haugland JM, et al. Underutilization of evidence-based medications in acute ST-elevation myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 9 registry. Crit Pathw Cardiol 2003;1:44-52. [12] Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) Investigators. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Lancet 1999;354:716-22. [13] A comparison of reteplase with alteplase for acute myocardial infarction. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators. N Engl J Med 1997;337:1118-23. [14] Topol EJ. Towards a new frontier in myocardial reperfusion therapy. Emerging platelet pre-eminence. Circulation 1998;97:211-8. [15] Young JJ, Kereiakes DJ. Pharmacologic reperfusion strategies for the treatment of ST-segment elevation myocardial infarction. Rev Cardiovasc Med 2003;4:216-27. [16] Ghali WA, Donaldson CR, Knudtson ML, et al. Rising to the challenge: transforming the treatment of ST-segment elevation myocardial infarction. CMAJ 2003;169:35-7.

8. Underutilization of medications in STEMI

For patients with suspected STEMI, the emergency physician's primary concern is prompt diagnosis and initiation of reperfusion therapy. Although definitive guidelines are available for STEMI management with lifesaving medications [9], such recommendations often have limited effects on practice patterns [46,47]. Underutilization of reperfusion therapy for acute STEMI in the ED is particularly pronounced [11] and has led to the development of several guideline-oriented tools to facilitate adherence to quality indicators [48,49]. Such quality improvement programs have shown that guideline adherence regarding the use of appropriate medications is critically important to reducing both short- and long-term mortality in patients with STEMI.

9. Summary
The emergency physician has a vital role to play in the successful treatment of acute STEMI. Rapid reperfusion is critical to limit irreversible myocardial damage and can be achieved in several ways, depending on the specific needs of each patient and the expertise and capabilities of the physician and hospital. Fibrinolysis is the most widely used therapeutic approach to STEMI management worldwide, but its efficacy is limited by the nature and composition of thrombi associated with STEMI. Primary PCI is extremely effective and has emerged as the preferred acute management approach for STEMI in the United States. However, the availability of primary PCI is limited because of insufficient suitably equipped centers. The CLARITYTIMI 28 [43] and COMMIT/CCS2 [45] studies have demonstrated convincingly that the antiplatelet agent clopidogrel offers significant clinical benefit as adjunctive therapy and reduces mortality in STEMI patients who are medically managed. Relevant cost-benefit analyses might be

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