The Medical Management of Acute Coronary Syndromes and Potential Roles for New Antithrombotic Agents

The Journal of Emergency Medicine, Vol. 34, No. 4, pp. 417– 428, 2008 Copyright © 2008 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/08 $–see front matter

doi:10.1016/j.jemermed.2007.08.058

Selected Topics: Cardiology Commentary

THE MEDICAL MANAGEMENT OF ACUTE CORONARY SYNDROMES AND POTENTIAL ROLES FOR NEW ANTITHROMBOTIC AGENTS Charles V. Pollack, Jr.,

MA, MD*

and A. David Goldberg,

CHB, MD†

*Department of Emergency Medicine, Pennsylvania Hospital, University of Pennsylvania Health System, Philadelphia, Pennsylvania and †Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan Reprint Address: Charles V. Pollack, Jr., MA, MD, Department of Emergency Medicine, Pennsylvania Hospital, 800 Spruce Street, Philadelphia, PA 19107

e Abstract—Antithrombic therapy is recommended to prevent ischemic complications in patients with high-risk non-ST-segment elevation acute coronary syndromes, including patients with unstable angina/non-ST-segment elevation myocardial infarction and patients with ST-segment elevation myocardial infarction undergoing fibrinolysis with fibrin-specific agents. Ischemic benefit from these agents must be balanced against an increased risk of bleeding, which may itself carry adverse long-term consequences. Recent trials suggest that the low-molecular-weight heparin enoxaparin may be superior to unfractionated heparin for preventing ischemic complications, although it also may be associated with an increase in bleeding risk. In two other contemporary trials, the Factor Xa inhibitor fondaparinux improved mortality and morbidity in patients with unstable angina/non-ST-segment elevation myocardial infarction and in patients with ST-segment elevation myocardial infarction undergoing fibrinolytic reperfusion, without increasing bleeding risk. These data underscore the promise of new antithrombotic agents to improve outcomes in acute coronary syndrome (ACS) patients being medically managed. © 2008 Elsevier Inc.

acute coronary syndrome (ACS) encompasses a spectrum of symptomatic coronary artery disease that ranges from unstable angina (UA), to non-ST-segment elevation myocardial infarction (NSTEMI), to ST-segment elevation myocardial infarction (STEMI) (1,2). Despite the advent of several effective therapies, prompt evaluation, more accurate tools for diagnosis, and sound clinical evidence to guide the selection of optimal treatment strategies for patients with ACS, the disease remains a challenge to emergency physicians, internists, and cardiologists. To disseminate new information and ensure its application in clinical practice, professional societies including the American College of Cardiology (ACC) and the American Heart Association (AHA) have developed clinical practice guidelines—most recently, the 2002 ACC/AHA UA/NSTEMI and 2004 ACC/AHA STEMI guidelines—that present an evidence-based approach to the care of patients with ACS (1,2). In addition, updated practice guidelines for the management of patients with ACS were presented at the 2006 European Society of Cardiology meeting, and the new ACC/AHA UA/ NSTEMI guidelines were released in August 2007. Current medical therapies for patients with ACS focus on the coagulation cascade and on platelet inhibition. The contemporary practice of using aggressive antithrombotic therapy, coupled with early cardiac catheterization and revascularization, has reduced ischemic events, but at the expense of a generally increased risk of

e Keywords—acute coronary syndromes; medical management; anticoagulants; antiplatelet agents; fibrinolysis

INTRODUCTION Coronary artery disease and its sequelae comprise the leading cause of death in the United States. The term

RECEIVED: 5 December 2006; FINAL ACCEPTED: 15 August 2007

SUBMISSION RECEIVED:

3 August 2007; 417

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bleeding complications (3). Anticoagulation and hemorrhage are delicately balanced, and the selection of appropriate anticoagulant therapy must weigh efficacy against safety considerations. Commonly used anticoagulants such as unfractionated heparin (UFH), lowmolecular-weight heparins (LMWH), and direct thrombin inhibitors (DTIs) have demonstrated an ischemic benefit in patients with ACS, although with an inherent increased risk of bleeding (4 –7). Concerns about safety, particularly bleeding, are of paramount importance in selecting antithrombotic therapy for patients with ACS. Bleeding leads to serious long-term consequences, as underscored recently by two independent pooled analyses that demonstrated a stepwise increase in both short- and long-term mortality as severity of bleeding increased; even mild bleeding was associated with a higher risk of death and myocardial infarction (MI) (3,8). Several risk factors for bleeding have been identified, including advanced age, concomitant treatment with other agents that affect hemostasis (e.g., non-steroidal anti-inflammatory drugs), renal insufficiency, and use of anticoagulants (3,8,9). Importantly, the risk of bleeding is likely to be higher among patients encountered in clinical practice who likely have more comorbidities than those enrolled in controlled clinical trials (8,9). Despite the availability of guidelines, several studies show that in actual practice, many effective therapies for ACS are underutilized, unavailable, or delayed in their delivery, leading to increased ischemic morbidity and mortality (10 –12). For example, percutaneous coronary interventions (PCI) are associated with improved outcomes with fewer bleeding complications, but only a minority of US hospitals have catheterization capabilities and even fewer have 24-h accessibility (13). Moreover, data from the Global Registry of Acute Coronary Events indicated that only about 20% of patients presenting with acute STEMI worldwide are afforded primary PCI, most likely due to the limited availability of catheterization facilities and other logistical constraints (14,15). In the case of patients with STEMI, fibrinolytic therapy is the most common form of reperfusion therapy globally and is readily available for patients without contraindications; however, data from the Global Registry of Acute Coronary Events indicated that an estimated 30 – 40% of patients with signs of acute STEMI did not receive reperfusion therapy at all (16). Furthermore, recent data suggest that timing, and not the treatment strategy—whether it is fibrinolysis or primary PCI—is the most critical aspect of emergency care. The Vienna STEMI registry recently reported comparable mortality outcomes for patients undergoing fibrinolysis or primary PCI, which were reduced if treatment was administered within the first 2 h of symptom onset, confirming the need for immediate therapy, whether pharmacologic or mechanical (15).

C. V. Pollack and A. D. Goldberg

The results from several clinical trials released after the publication of the AHA/ACC guidelines in 2002 (UA/NSTEMI) and 2004 (STEMI) are likely to impact how physicians manage their patients with ACS. For instance, important trial data recently have become available regarding the use of the glycoprotein (GP) IIb/IIIa inhibitor abciximab, the LMWH enoxaparin, and most recently the DTI bivalirudin— used separately or in conjunction—as adjunctive therapies in patients undergoing interventional procedures (17–19). In the ACUITY trial, bivalirudin significantly improved clinical outcomes in moderate- to high-risk ACS patients undergoing an early invasive treatment strategy, and was shown to be superior to combination therapy (GP IIb/IIIa inhibitors plus anticoagulants) (20). Although this and other information has recently emerged regarding the benefit of an early invasive approach, this article focuses only on the medical management of patients with ACS as discussed in the ACC/AHA UA/NSTEMI and STEMI guidelines, and explores recent clinical trial data in the context of current treatment pathways for these disorders.

INITIAL EVALUATION AND RISK STRATIFICATION A rapid and accurate initial evaluation of patients with suspected ACS is of paramount importance, especially for patients with STEMI, because the effectiveness of many therapies that reduce morbidity and mortality diminishes rapidly with delays in implementation (2). In those patients for whom a diagnosis of STEMI has been excluded based on results from the 12-lead electrocardiogram, the goals of subsequent evaluations are to determine the likelihood (high, intermediate, low) that a patient’s symptoms are caused by UA/NSTEMI and to stratify those patients into high-, intermediate-, and lowrisk groupings for ischemic complications (death and MI) (1,2,21,22). A structured strategy for initial evaluation and management must be in place to screen patients with suspected MI or UA, who should be considered high-priority triage cases (Figure 1). Patients considered to be at low or moderate risk can be managed conservatively, with pharmacologic therapy only; whereas early invasive therapy, including coronary angiography, PCI, or coronary-artery bypass grafting (CABG), should be considered for high-risk patients. It is important to note that most patients, regardless of risk, are ultimately treated medically— even those transferred to the catheterization laboratory receive pharmacologic treatment, most often before their transfer, and potentially after angiography if an interventional procedure is ruled out.

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Figure 1. Diagnostic and treatment algorithm in the ED for patients with UA/NSTEMI (22). *For patients receiving early cardiac catheterization after ED presentation, the authors of the 2002 ACC/AHA UA/NSTEMI guidelines recommended that that GP IIb/IIIa inhibitors be given in the cardiac catheterization laboratory prior to PCI (1). Adapted with permission from Gibler et al. (22). ED, Emergency Department; ECG, electrocardiogram; ACS, acute coronary syndrome; CAD, coronary artery disease; PCI, percutaneous coronary intervention; TnT, troponin T; Tnl, troponin I; ACEI, angiotensin-converting enzyme inhibitor; LMWH, low–molecular-weight heparin; UFH, unfractionated heparin; GP, glycoprotein; CABG, coronary-artery bypass grafting.

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CURRENT TREATMENT OF STEMI All STEMI patients presenting to the Emergency Department (ED) with chest pain should be considered highpriority triage cases and should undergo rapid evaluation for reperfusion therapy based on institution-specific guidelines (2). If STEMI is present, as determined by an electrocardiogram performed within minutes of arrival in the ED, the decision to treat with fibrinolytic therapy or PCI must be made within the following 10 min. The history and physical examination should be directed at ascertaining previous occurrences of MI or UA; presence of hypertension, diabetes, or other vascular disease (peripheral or cerebral); and risk of bleeding (2). Rapid restoration of flow to the occluded artery by timely reperfusion therapy is essential for improving survival in patients with STEMI (2). A desirable goal is a door-to-fibrinolysis time of ⬍ 30 min and a door-toballoon time of ⬍ 90 min. In addition to restoring blood flow, the goal of reperfusion is also to minimize further ischemic damage; hence, the regimen in STEMI patients must also include adjunctive treatments that limit recurrent events. Routine therapy in patients with STEMI includes the use of supplemental oxygen, nitrates, morphine analgesia, aspirin, and beta-blockers. Patients who are not candidates for fibrinolytic or mechanical reperfusion are managed exclusively with antiplatelet and anticoagulant therapies, albeit with poorer outcomes compared with reperfusion therapy.

Reperfusion Therapy The choice of reperfusion—pharmacologic or mechanical—is dictated by many considerations including time from onset of symptoms, risk of STEMI, risk of bleeding, and availability of and time required for transport to a skilled PCI facility (Table 1) (2). Large, controlled trials have established the survival benefit of fibrinolytic therapy (23). Reperfusion with fibrinolytic agents is of greatest benefit when performed within the first hour, but confers benefits if performed up to 12 h after the onset of symptoms (23,24). Because hemorrhage poses an important risk with fibrinolytic therapy, fibrinolysis is contraindicated in patients with uncontrolled hypertension or a history of intracerebral hemorrhage or ischemic stroke (2). Use of ancillary therapies may also influence the bleeding risk. Currently available fibrinolytic agents are all plasminogen activators. Accelerated alteplase or reteplase when used with intravenous heparin lead to early coronary reperfusion and may have some advantage over streptokinase (25,26). Further improvements in flow rates can be obtained by administering GP IIb/IIIa antagonists with fi-

Table 1. Assessment of Reperfusion Options for Patients with STEMI Step 1: Assess time and risk Time since onset of symptoms Risk of STEMI Risk of fibrinolysis Time required for transport to a skilled PCI laboratory* Step 2: Determine if fibrinolysis or an invasive strategy is preferred If presentation is ⬍ 3 h and there is no delay to an invasive strategy, there is no preference for either strategy Fibrinolysis is generally preferred if: Early presentation (ⱕ 3 h from symptom onset and delay to invasive strategy) Invasive strategy is not an option Catheterization laboratory occupied/not available Vascular access difficulties Lack of access to a skilled PCI laboratory* Delay to invasive strategy Prolonged transport (Door-to-balloon) ⫺ (door-to-thrombolysis) is ⬎ 60 min† Medical contact-to-balloon or door-to-balloon is ⬎ 90 min An invasive strategy is generally preferred if: Skilled PCI laboratory available with surgical backup* Medical contact-to-balloon or door-to-balloon is ⬍ 90 min (Door-to-balloon) ⫺ (door-to- thrombolysis) is ⬍ 60 min High risk from STEMI Cardiogenic shock Killip class is ⱖ 3 Contraindications to fibrinolysis Includes increased risk of bleeding and ICH Late presentation The symptom onset was ⬎ 3 h ago Diagnosis of STEMI is in doubt * Operator experience a total of ⬎ 75 primary PCI cases per year, and team experience is a total of ⬎ 36 primary PCI cases per year. † The estimated delay to the implementation of the invasive strategy is ⬎ 1 h vs. initiation of fibrinolytic therapy immediately. Reproduced with permission from (2): ACC/AHA Guidelines for the Management of Patients with ST-elevation Myocardial Infarction. © 2004, American Heart Association, Inc. STEMI ⫽ ST-elevation myocardial infarction; PCI ⫽ percutaneous coronary intervention; ICH ⫽ intracranial hemorrhage.

brinolytic agents (half-dose); however, combination therapy has been associated with an increased risk of major bleeding compared with reteplase or tenecteplase therapy in the absence of a GP IIb/IIIa inhibitor (6,27). Pharmacologic reperfusion is a safe and effective therapeutic option for patients who present to the ED early (within 3 h of symptom onset), do not have access to catheterization facilities, or have a low risk of STEMI (Table 1) (2). Mechanical reperfusion is recommended if a skilled PCI facility is available, if the patient has left ventricular dysfunction, is in cardiogenic shock, or presented late to the ED, or if fibrinolysis is contraindicated. A detailed discussion of the advantages of primary PCI can be found elsewhere (2).

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Figure 2. Sites of antithrombotic drug action (28,31). Antithrombotic agents are identified by a gray background. ADP, adenosine diphosphate; GP, glycoprotein; UFH, unfractionated heparin; LMWH, low–molecular-weight heparin.

Ancillary Therapy Thrombin plays a central role in the formation of a thrombus and directly or indirectly leads to generation of fibrin, activation of platelets, and stabilization of the clot (28). Revascularization interventions such as fibrinolysis and PCI are also associated with a hyperthrombotic state, underscoring the need for antiplatelet and antithrombin therapy during these procedures (29,30). Medical management with anticoagulants and platelet inhibitors is therefore important for preventing the occurrence or recurrence of thrombotic complications in patients with ACS (31). Pharmacologic therapy with antithrombotic agents (anticoagulants, DTIs, antiplatelet agents) is recommended for patients experiencing plaque disruption and thrombus formation to prevent ischemic complications such as death, MI, or recurrent MI (Figure 2) (2). All patients with STEMI, regardless of the reperfusion strategy, should receive aspirin indefinitely even if other antiplatelet agents are administered. Because thrombin is a key activator of the coagulation pathway and of platelets, antithrombin therapy is important as ancillary therapy in all patients with STEMI for establishing and maintaining patency of the infarct-related artery, regardless of receipt of reperfusion therapy. UFH is recommended in patients undergoing fibrinolytic therapy, and recommendations vary with the type of fibrinolytic agent used (2). There is a clear rationale for the use of UFH with fibrin-specific agents, such as alteplase, reteplase, and tenecteplase, because these agents have little systemic activity and do not produce addi-

tional anticoagulants. By contrast, the need for conjunctive anticoagulation remains uncertain with non-specific fibrinolytic agents such as streptokinase, anistreplase, and urokinase, which generate fibrin degradation products that have considerable anticoagulant activity. In these patients, UFH confers a very modest mortality benefit, but increases the risk of bleeding (25,32–34). LMWH may be an acceptable alternative to UFH in younger patients (⬍ 75 years) receiving fibrinolytic therapy, provided they have adequate renal function (2).

RECENT ADVANCES IN FIBRINOLYSIS AND ADJUNCTIVE ANTITHROMBOTIC THERAPY IN PATIENTS WITH STEMI Since the publication of the ACC/AHA clinical practice guidelines for STEMI in 2004, several clinical trials have been conducted that could effectively change how physicians manage their patients. A review of recent trial data and their clinical implications are discussed below. Aspirin significantly reduces the odds of vascular mortality and reinfarction in patients with acute MI (2,35). The benefits of adding clopidogrel to a standard fibrinolytic regimen, including aspirin, were investigated in the CLARITY-TIMI-28 trial in 3491 patients with STEMI (Table 2) (36). The addition of clopidogrel improved rates of patency of the infarct-related artery, without increasing bleeding complications. The COMMIT/CCS-2 study, which assessed ischemic events (death, recurrent MI, or stroke) in 46,000 patients in China, similarly concluded that the addition of clopidogrel (75 mg daily)

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Table 2. Summary of Recent Trials of Antithrombotic Agents in Patients with STEMI Patient Population

Comparators

Efficacy Outcomes

CLARITY (36)

Patients with STEMI receiving fibrinolytic therapy, aspirin, and heparin (if needed) (n ⫽ 3491)

Clopidogrel (300 mg loading dose, followed by 75 mg once daily) Placebo

ExTRACT (38)

Patients with STEMI undergoing fibrinolysis and antiplatelet therapy (aspirin; clopidogrel, at physician’s discretion) (n ⫽ 20,506)

OASIS-6 (41)

Patients with STEMI (n ⫽ 12,092)

Enoxaparin for up to 8 days ● ⬍ 75 years of age: 30 mg i.v. bolus, then 1 mg/kg SQ BID ● ⱖ 75 years of age: 0.75 mg/kg BID ● Creatinine clearance ⬍ 30 mL/min: 1 mg/kg QD UFH (weight adjusted) for at least 48 h Fondaparinux (2.5 mg QD) for 8 days Usual care X Placebo if UFH was not indicated or X UFH (weight adjusted) for 48 h followed by placebo for up to 8 days

Primary X Composite of artery occlusion (TIMI flow grade of 0/1), all-cause mortality, or recurrent MI: clopidogrel (15.0%) vs. placebo (21.7%); p ⬍ 0.001 Secondary X Incidence of artery occlusion: clopidogrel (11.7%) vs. placebo (18.4%); p ⬍ 0.001 X Composite endpoint (death from CV causes, recurrent MI, or recurrent ischemia leading to urgent revascularization) at 30 days: clopidogrel (14.1%) vs. placebo (11.6%); p ⫽ 0.03 Primary X Composite endpoint of death or MI at 30 days: enoxaparin (9.9%) vs. UFH (12.0%); p ⬍ 0.001 Secondary X Composite endpoint of death, non-fatal MI, or urgent revascularization at 30 days: enoxaparin (11.7%) vs. UFH (14.5%); p ⬍ 0.001

Primary X Composite endpoint of death or reinfarction at 30 days: fondaparinux (9.7%) vs. control (11.2%); p ⫽ 0.008 X Death at day 30: fondaparinux (7.8%) vs. control (8.9%); p ⫽ 0.03 X Reinfarction at day 30: fondaparinux (2.5%) vs. control (3%); p ⫽ 0.06 Secondary X Reduction in composite endpoint with fondaparinux was observed at day 9 and up to final follow-up at 6 months Post hoc subgroup analysis of composite endpoint (fondaparinux vs. control, respectively) X No reperfusion therapy: 12.2% vs. 15.1%; p ⫽ 0.003 X Fibrinolytic therapy: 10.9% vs. 13.6%; p ⫽ 0.003 X Primary PCI: 6.0% vs. 4.9%; p ⫽ ns

Safety Outcomes

Clinical Implication

X Major bleeding: clopidogrel (1.3%) vs. placebo (1.1%); p ⫽ ns X Intracranial hemorrhage: clopidogrel (0.5%) vs. placebo (0.7%); p ⫽ ns

Clopidogrel improved flow in the infarct-related artery and reduced complications in patients with STEMI undergoing fibrinolysis

X Major bleeding: enoxaparin (2.1%) vs. UFH (1.4%); p ⬍ 0.001 X Death in patients with major bleeding episode: enoxaparin (38%) vs. UFH (32%); p ⫽ ns

Net clinical benefit (composite of death, non-fatal MI, and non-fatal major bleeding) at 30 days favored enoxaparin (10.1% vs. UFH, 12.3%; p ⬍ 0.001) Treatment with enoxaparin throughout hospitalization was superior to treatment with UFH for 48 h in patients with STEMI undergoing fibrinolytic therapy Enoxaparin therapy was associated with an increased risk of bleeding Net clinical benefit (composite rate of death, MI, and severe bleeding) at 9 days, 30 days, and 6 months favored fondaparinux over control; p ⫽ ⬍ 0.005 In patients with STEMI who were not undergoing PCI, fondaparinux reduced mortality and reinfarction without increased bleeding or stroke

X Rate of severe bleeding episodes at 9 days: fondaparinux (1%) vs. control (1.3%); p ⫽ ns X Rate of fatal bleeding at 9 days: fondaparinux (0.6%) vs. control (0.8%); p ⫽ ns

STEMI ⫽ ST-elevation myocardial infarction; TIMI ⫽ Thrombolysis in Myocardial Infarction; UFH ⫽ unfractionated heparin; MI ⫽ myocardial infarction; CV ⫽ cardiovascular; i.v. ⫽ intravenous; SQ ⫽ subcutaneous; BID ⫽ twice daily; QD ⫽ once daily; ns ⫽ non-significant; PCI ⫽ percutaneous coronary intervention; mg ⫽ milligram; kg ⫽ kilogram.

C. V. Pollack and A. D. Goldberg

Trial

Medical Management of ACS

to aspirin therapy reduced the risk of ischemic events from 10.1% to 9.3%, a reduction that would prevent ⬃10 major vascular events per 1000 patients treated (37). Although UFH has been the antithrombin agent of choice for pharmacologic and mechanical reperfusion in patients with STEMI, its limitations have led to investigation of alternative antithrombin therapies such as enoxaparin and fondaparinux as adjuncts to fibrinolysis in patients with STEMI. In the ExTRACT-TIMI 25 study, patients with STEMI undergoing fibrinolysis received adjunctive therapy with UFH (for 48 h) or the LMWH enoxaparin (for up to 8 days); an alternative enoxaparin-dosing regimen was used in patients 75 years of age or older or those with significant renal impairment (Table 2) (38). Despite an increased rate of major bleeding, the overall net clinical benefit of enoxaparin therapy outweighed that of UFH; treatment with enoxaparin corresponded to a relative risk reduction of 14 –18% (p ⬍ 0.001), suggesting that enoxaparin therapy in addition to fibrinolysis is superior to current therapy (i.e., UFH). Enoxaparin was also shown to be superior to UFH in reducing the risk of death or recurrent MI in patients who underwent subsequent PCI (enoxaparin [10.7%] vs. UFH [13.8%]; p ⫽ 0.001) (39). Fondaparinux is a synthetic polysaccharide that mimics the 5-sugar sequence of UFH and LMWH that binds antithrombin and causes rapid and predictable inhibition of Factor Xa; fondaparinux allows for oncedaily administration (40). OASIS-6 investigated the efficacy and safety of fondaparinux (2.5 mg once daily for 8 days) vs. usual care (placebo in patients in whom UFH was not indicated or UFH for up to 48 h followed by placebo for up to 8 days) in a broad range of patients with STEMI (Table 2) (41). This trial showed a significant reduction in the composite primary endpoint of mortality or reinfarction with use of fondaparinux when compared with usual care (9.7% vs. 11.2%, respectively; p ⫽ 0.008). This benefit was detectable early and was sustained until the end of the study. A consistent and significant reduction in mortality was obtained throughout the study with fondaparinux, due entirely to a reduction in cardiac deaths with no difference in non-cardiac deaths. A post hoc subgroup analysis showed fondaparinux was also superior to placebo or UFH in patients who received no reperfusion therapy or fibrinolytic therapy, but not primary PCI. This reduction occurred without the increase in bleeding or hemorrhagic stroke observed with other antithrombotic and antiplatelet agents (6,27,42). To date, OASIS-6 is the first STEMI trial to demonstrate a mortality benefit without an increased risk of bleeding (41).

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KEY FEATURES OF CURRENT TREATMENT OF UA/NSTEMI The goal of management of patients with UA/NSTEMI is to provide relief of ischemia and prevent adverse outcomes (1). Regardless of the approach selected (that is, early conservative or early invasive), the 2002 ACC/ AHA UA/NSTEMI guidelines recommend that all patients with probable ACS should receive anti-ischemic and antithrombotic therapy, with ongoing risk stratification to identify patients for whom an invasive strategy is appropriate. The basic pharmacologic therapy recommended for relief of ischemic symptoms in all patients with ACS includes nitrates, morphine, beta-blockers, calcium channel blockers, and angiotensin-converting enzyme inhibitors. Pharmacologic antithrombotic therapies, including antiplatelet and anticoagulant agents, are administered to reduce ischemic complications such as death, MI, or recurrent MI in patients with non-ST-segment elevation (NSTE) ACS (1). Table 3 provides an overview of the recommended use of these therapies in patients with UA/NSTEMI. Platelet inhibitors prevent the activation and aggregation of platelets and are key to the prevention of thrombosis. The platelet inhibitors currently in clinical use encompass three different classes of agents with distinct mechanisms of action—aspirin, thienopyridines (i.e., clopidogrel), and platelet GP IIb/IIIa inhibitors. Anticoagulants such as heparin are also a fundamental therapy for treating ACS. Heparin (UFH or LMWH) reduces ischemia by potentiating the effects of circulating antithrombins and preventing thrombus propagation (43). The intensity of therapy can be tailored to individual risk, with combination therapy (aspirin, UFH, and a GP IIb/IIIa inhibitor) advocated for patients with continuing ischemia or other high-risk features, or if an early interventional approach is planned (1). The early conservative strategy relies on non-invasive evaluation of ischemia, with catheterization and revascularization recommended only if ischemia recurs or remains unresolved (1). This strategy, which spares the use of invasive procedures with their attendant risks and costs, is recommended only for patients at low risk for ischemic complications. Pharmacologic interventions recommended with this strategy include a combination of aspirin, clopidogrel, and LMWH or UFH. In addition, tirofiban or eptifibatide is recommended in patients with continuing ischemia, positive cardiac biomarker levels, or other high-risk features who are not anticipated to undergo PCI. With an early invasive strategy, coronary angiography and revascularization (PCI or CABG) are performed within 48 h of symptom onset (21). Studies have indicated that a more aggressive approach for high-risk

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Table 3. Key Recommendations for Antithrombotic Therapy in Patients with UA/NSTEMI (1) Therapy Platelet inhibitors Aspirin Clopidogrel

GP IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban)

Anticoagulants Unfractionated heparin

Recommendation (1)

Comments

X Administer immediately on presentation to the ED X Use as alternative to aspirin in patients with aspirin sensitivity or gastrointestinal intolerance to aspirin X Use in addition to aspirin if noninterventional approach is planned X Use in patients who undergo PCI but withhold in patients scheduled for CABG X Administer any of these agents with aspirin and heparin to patients in whom an interventional approach is planned X Use eptifibatide or tirofiban in patients receiving only pharmacologic therapy (21) X Do not use abciximab as first-line medical treatment (21)

X Benefit of aspirin for reducing cardiac event rates is well established from clinical trials (1,50,51) X Clopidogrel is an ADP antagonist that prevents platelet aggregation (52) X Addition of clopidogrel to aspirin in the CURE trial resulted in 18% reduction in primary outcome of death, MI, or stroke (53)

X Use in addition to antiplatelet therapy in patients managed conservatively

Low-molecular-weight heparin

X Enoxaparin is the preferred anticoagulant in patients with NSTE ACS unless CABG is planned within 24 h

Direct thrombin inhibitors (bivalirudin, argatroban)

X Not recommended for the treatment of patients with UA/NSTEMI

X GP IIb/IIIa inhibitors block the GP IIb/IIIa receptor that binds fibrinogen to allow platelet activation (54)

X Limitations include variable anticoagulant effects and requirement for frequent monitoring (29) X Production of anti-heparin antibodies in ⬃1% of patients can lead to thrombocytopenia and thrombosis (55) X Advantages over UFH include better bioavailability and more predictable pharmacokinetics (29) X A pooled study showed that enoxaparin was consistently superior to UFH in patients managed conservatively (48); however, increased bleeding is a cause for concern (21,47) X Less likely to cause heparin-induced thrombocytopenia, but a platelet count is recommended every other day during therapy (55) X Currently, direct thrombin inhibitors are approved for use only in patients undergoing interventional procedures (56,57)

UA ⫽ unstable angina; NSTEMI ⫽ non-ST-segment elevation myocardial infarction; ED ⫽ Emergency Department; PCI ⫽ percutaneous coronary intervention; CABG ⫽ coronary-artery bypass grafting; GP ⫽ glycoprotein; ADP ⫽ adenosine diphosphate; MI ⫽ myocardial infarction; UFH ⫽ unfractionated heparin.

NSTEMI patients, including coronary angiography and mechanical revascularization, can significantly reduce short-term and long-term mortality (10,44). Additional studies, including REPLACE-2, ISAR-REACT, and STEEPLE, have recently addressed pharmacotherapy for patients undergoing PCI (17–19). A discussion of these strategies is beyond the scope of the current review, which is confined to the medical management of ACS.

EMERGING CLINICAL TRIAL DATA AND IMPLICATIONS FOR THE MEDICAL MANAGEMENT OF PATIENTS WITH NSTE ACS Combination therapy with aspirin or clopidogrel, GP IIb/IIIa inhibitors, and an anticoagulant is recommended

for pharmacologic treatment of patients with high-risk NSTE ACS (1). Due to the potentially higher bleeding risk associated with this combination, a number of recent trials have compared the safety and efficacy of LMWH or UFH used in combination with GP IIb/IIIa inhibitors in these patients. INTERACT was a small open-label study that showed that, when combined with aspirin and the GP IIb/IIIa inhibitor eptifibatide, enoxaparin was safer and equivalent or more effective than UFH in patients with NSTEMI (45). A to Z was a larger openlabel study that assessed the safety and efficacy of enoxaprin vs. UFH when administered with the GP IIb/IIIa inhibitor tirofiban, and SYNERGY compared outcomes in high-risk patients with NSTEMI treated with either enoxaparin or UFH and managed with an early invasive strategy (46,47). Details of the design and outcomes of A to Z and SYNERGY are presented in Table 4. In addi-

Trial

Patient Population

Comparators

Efficacy Outcomes

Safety Outcomes

Clinical Implication

A to Z (46)

Patients with NSTEMI receiving tirofiban and aspirin (n ⫽ 3987) X 55% intended for early invasive treatment X 43% underwent catheterization or primary PCI

Enoxaparin (1 mg/kg BID) UFH (weight adjusted)

X Composite of all-cause mortality, new MI, or refractory ischemia at 7 days: enoxaparin (8.4%) vs. UFH (9.4%), p ⫽ ns; non-inferiority criterion met X Composite event rate in patients managed conservatively: enoxaparin (6.7%) vs. UFH (8.0%); p ⫽ ns X All components of primary and secondary composite endpoints favored enoxaparin, except death

X Transfusion rate: enoxaparin (1.0%) vs. UFH (0.8%); p ⫽ ns; X Any TIMI bleeding: enoxaparin (3.0%) vs. UFH (2.2%); p ⫽ ns; X TIMI major bleeding: enoxaparin (0.9%) vs. UFH (0.4%); p ⫽ 0.05

SYNERGY (47)

Patients with high-risk NSTEMI managed with an early invasive strategy (n ⫽ 10,027)

Enoxaparin (1 mg/kg BID) UFH (weight adjusted)

Primary X Composite of all-cause mortality or nonfatal MI within 30 days: enoxaparin (14.0%) vs. UFH (14.5%); p ⫽ ns

OASIS-5 (49)

Patients with NSTEMI (n ⫽ 20,078)

Fondaparinux (2.5 mg QD) Enoxaparin (1 mg/kg BID)

Primary X Composite of death, MI, or refractory ischemia at 9 days: fondaparinux (5.8%) vs. enoxaparin (5.7%), p ⫽ ns; non-inferiority criteria met Secondary X Rate of death or MI after 9 days: fondaparinux (4.1%) and enoxaparin (4.1%) X 30-day mortality: fondaparinux (2.9%) vs. enoxaparin (3.5%); p ⫽ 0.02 X 6-month mortality: fondaparinux (5.8%) vs. enoxaparin (6.5%); p ⫽ 0.05 X Composite efficacy at 9 days (no revascularization subgroup): fondaparinux (3.3%) vs. enoxaparin (3.5%)

X Major bleeding (TIMI criteria): enoxaparin (9.1%) vs. UFH (7.6%); p ⫽ 0.008 X GUSTO severe bleeding: enoxaparin (2.7%) vs. UFH (2.2%); p ⫽ ns X Transfusion rate: enoxaparin (17.0%) vs. UFH (16.0%); p ⫽ ns X Major bleeding at 9 days: fondaparinux (2.2%) vs. enoxaparin (4.1%); p ⬍ 0.001 X Total bleeding: fondaparinux (3.3%) vs. enoxaparin (7.3%) X Catheter-related thrombosis: fondaparinux (0.9%) vs. enoxaparin (0.4%); p ⫽ 0.001 X Major bleeding at 9 days (no revascularization subgroup): fondaparinux (1.0%) vs. enoxaparin (3.0%)

There was a consistent but non-significant 10 –15% reduction of risk with enoxaparin across entire population and in higher-risk subgroups Enoxaparin was comparable to UFH in patients with NSTEMI receiving concomitant antiplatelet therapy with tirofiban and aspirin Enoxaparin was a safe and effective alternative to UFH in high-risk patients with early intended invasive strategy

Medical Management of ACS

Table 4. Summary of Recent Trials of Antithrombotic Agents in Patients with NSTE ACS

Composite of efficacy and safety outcomes revealed an advantage with the use of fondaparinux (7.3% vs. enoxaparin, 9%; p ⬍ 0.001) Fondaparinux provided similar short-term antiischemic benefits as enoxaparin, with significantly less bleeding and improved long-term mortality and morbidity

NSTE ACS ⫽ non-ST-elevation acute coronary syndrome; PCI ⫽ percutaneous coronary intervention; BID ⫽ twice daily; UFH ⫽ unfractionated heparin; MI ⫽ myocardial infarction; QD ⫽ once daily; ns ⫽ non-significant; TIMI ⫽ Thrombolysis in Myocardial Infarction; GUSTO ⫽ Global Use of Strategies to Open Occluded Coronary Arteries; mg ⫽ milligram; kg ⫽ kilogram.

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tion, a meta-analysis evaluating six randomized controlled trials (including A to Z, INTERACT, and SYNERGY) compared outcomes in 22,000 patients receiving enoxaparin or UFH for the treatment of ACS (48). The analysis showed a significant reduction in the combined endpoint of death or non-fatal MI at 30 days with enoxaparin (10.1% vs. 11% with UFH; number needed to treat, 107), but there were no differences in 30-day mortality or rates of blood transfusion or major bleeding. A number of the trials listed above as well as those included in the meta-analysis involved treatment with enoxaparin or UFH before randomization, and subsequent subanalyses have suggested that “switching” from one antithrombin therapy to another could potentially mask the efficacy of enoxaparin and increase the risk of bleeding by “stacking” anticoagulant efficacy; however, the potential impact of “switching” has yet to be fully validated (47,48). OASIS-5 was a large multicenter trial evaluating more than 20,000 patients with NSTEMI that assessed whether fondaparinux would preserve the anti-ischemic benefits of enoxaparin while reducing bleeding (49). Primary efficacy outcome events occurred in similar proportions of patients receiving fondaparinux and enoxaparin, showing that the agents have similar short-term efficacy (Table 4). However, mortality at both 30 days and 6 months was reduced significantly with fondaparinux, a difference attributed almost entirely to the reduced incidence of major bleeding with fondaparinux. It should be noted that a proportion of patients in both the fondaparinux and enoxaparin arms of the study received UFH before administration of study drug that, in light of the switching hypothesis highlighted by the SYNERGY trial, could have contributed to the inferiority of enoxaparin; this issue remains unresolved. In addition, fondaparinux was associated with a significantly higher rate of guidingcatheter thrombosis than enoxaparin after PCI. The net clinical benefit was in favor of fondaparinux when a combined efficacy and safety endpoint was calculated (7.3% vs. 9.0%, respectively). Thus, in patients with UA/NSTEMI, fondaparinux provided similar shortterm anti-ischemic benefits as enoxaparin, but its significantly reduced potential to cause bleeding improved long-term mortality and morbidity. Patients who did not undergo revascularization and who received fondaparinux had a similar rate of ischemic events and a 67% reduction in the rate of major bleeding events compared with those receiving enoxaparin; fondaparinux is therefore an attractive option as an anticoagulant for short-term medical treatment of patients with ACS.

C. V. Pollack and A. D. Goldberg

CONCLUSIONS Short- and long-term outcomes in patients presenting with symptoms of ACS can be improved significantly with prompt evaluation, accurate diagnosis, and appropriate selection of treatment strategies. Recent trials suggest that other anticoagulants including the LMWH enoxaparin or the selective Factor Xa inhibitor fondaparinux may be acceptable alternatives to UFH. A metaanalysis that compared the use of enoxaparin and UFH in patients presenting with NSTEMI demonstrated a significant reduction in ischemic events with enoxaparin without an increased rate of bleeding (48). In a head-to-head study with enoxaparin, fondaparinux was shown to offer similar protection from cardiovascular-related death and MI in patients with NSTEMI, but with a lower risk of major bleeding and an improved mortality benefit (49). For patients who present to the ED early, do not have access to catheterization facilities, or have a low risk of STEMI, pharmacologic reperfusion can be a safe and effective therapeutic option. Adjunctive pharmacotherapy with aspirin and anticoagulants such as UFH also may be used in patients receiving fibrinolytic therapy. There is overwhelming support for the use of clopidogrel in patients with STEMI who are managed pharmacologically. Treatment with enoxaparin was shown to be superior to standard therapy with UFH in patients undergoing fibrinolysis, but was accompanied by an increased risk of bleeding (38). In patients diagnosed with STEMI, fondaparinux dramatically reduced long-term mortality without an increased risk of major bleeding or stroke, although the benefit was limited to patients not undergoing direct PCI (41). Therefore, fondaparinux is an attractive alternative for the medical management of NSTEMI or STEMI patients who do not undergo immediate interventional procedures (41).

Disclosure of Potential Conflict of Interest—Charles V. Pollack, Jr., MA, MD, has received grant support from GlaxoSmithKline, and has served as a speaker for sanofi-aventis, ScheringPlough, and Bristol-Myers Squibb.

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