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Review
Buffalo General and Millard Fillmore Hospitals, Buffalo, NY, USA Department of Emergency Medicine, Wake Forest University Baptist Medical Center, Winston-Salem, NC 27157, USA
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.
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.
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].
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).
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.
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).
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
19 9 28 12
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
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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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