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Antithrombotic Therapy for Acute Coronary Syndromes Sarah A. Spinler, Stephanie M. Inverso, Janet H. Dailey, and Mark J. Cziraky

Received December 17, 2003, and in revised form February 20, 2004. Accepted for publication February 23, 2004.

ABSTRACT Objectives: To review the role of antithrombotic therapy for treatment of acute coronary syndromes (ACS) in the hospital setting. Data Sources: Recent (1995–2003) published scientific literature, as identified by the authors through Medline searches, using the terms acute coronary syndromes, antithrombotic, antiplatelet, clinical trials, and reviews on treatment. Study Selection: Recent systematic English-language review articles and reports of controlled randomized clinical trials were screened for inclusion. Data Synthesis: For the patient with ST-segment elevation (STE) ACS, nonenteric-coated aspirin should be initiated immediately, if possible before arrival at the emergency department. In-hospital treatment is aimed at rapidly re-establishing coronary patency by means of percutaneous coronary intervention (PCI) or thrombolysis, preventing cardiac complications, and improving survival. Patients undergoing primary PCI should receive a glycoprotein IIb/IIIa receptor inhibitor, unfractionated heparin (UFH), and clopidogrel (Plavix— Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership) if bypass surgery is not urgently indicated; those undergoing thrombolysis should receive UFH. For the patient with non–ST-segment elevation (NSTE) ACS, beta-blockers, nitrates (also indicated for STE myocardial infarction), antiplatelet agents, and antithrombin therapy (UFH or low-molecular-weight heparin) are provided in standard care. Aspirin should be commenced immediately and continued indefinitely; in addition, clopidogrel is recommended for patients who are medically managed and those undergoing PCI. Glycoprotein IIb/IIIa receptor inhibitors (tirofiban [Aggrastat—Guilford Pharmaceuticals], eptifibatide [Integrilin— Millennium Pharmaceuticals], and abciximab [ReoPro—Lilly]) are of benefit in reducing ischemic complications in patients undergoing PCI. Conclusion: Early reperfusion with thrombolytics or primary PCI is required in patients presenting with STE ACS. Early invasive management is recommended for high-risk patients with NSTE ACS; for lower-risk patients, either early invasive or early conservative therapy is recommended. Keywords: Cardiovascular medicine, acute coronary syndromes, glycoprotein IIb/IIIa receptor blockers, anticoagulants, antiplatelet agents, hospitalized patients.

Sarah A. Spinler, PharmD, FCCP, is Associate Professor of Clinical Pharmacy, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, Philadelphia, Pa. At the time of this writing, Stephanie M. Inverso, PharmD, was Assistant Professor at Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, Philadelphia, Pa.; she is currently Clinical Pharmacy Specialist in Cardiology, Cooper Medical Center, Camden, N.J. Janet H. Dailey, PharmD, is Clinical Assistant Professor of Pharmacy Practice, College of Pharmacy, University of Florida, Gainesville. Mark J. Cziraky, PharmD, FAHA, is Executive Vice President, Health Core Inc., Newark, Del. Correspondence: Sarah A. Spinler, PharmD, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, 600 South 43rd Street, Philadelphia, PA 19104. Fax: 215-596-8586. E-mail: [email protected] Continuing education credits: See learning objectives and test questions at the end of this article, which is number 202-000-04-148-H01 in APhA’s educational programs. CE answer sheets are located inside the back cover of this supplement. To take the CE test for this article online, go to www.pharmacist.com/educa tion.cfm, and follow the links to the APhA CE center. Disclosure: Dr. Spinler is a member of National Pharmacy Cardiovascular Council and has served as a consultant to Bristol-Myers Squibb and Aventis; Dr. Dailey is a member of the National Pharmacy Cardiovascular Council and is supported by BristolMyers Squibb/Sanofi Pharmaceuticals Partnership. The authors declare no other conflicts of interest or financial interests in any product or service mentioned in this article, including grants, employment, gifts, stock holdings, or honoraria. Acknowledgments: To the National Pharmacy Cardiovascular Council for administrative support. Funding: This project was supported by an unrestricted educational grant from Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership to the National Pharmacy Cardiovascular Council.

J Am Pharm Assoc. 2004;44(suppl 1):S14–S27.

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C

oronary artery heart disease (CAD) remains the leading cause of death in the United States, with acute myocardial infarction (MI) being the leading cause of coronary deaths. Each year, approximately 640,000 Americans experience MIs, and more than 7.6 million people in the United States have a history of MI.1 Atherosclerosis is a generalized and progressive process affecting medium- and large-sized arteries and can begin in childhood.2 Stable atherosclerotic plaques may encroach on the lumen of the artery and cause chronic ischemia, resulting in symptoms of stable angina pectoris or intermittent claudication, depending on the vascular bed affected.3 Atherothrombosis, which involves rupture of an atherosclerotic plaque and subsequent formation of an occlusive arterial thrombus composed of fibrin and platelets, underlies the pathophysiology of acute coronary syndromes (ACS), including MI (Figure 1).4 Plaques more likely to rupture are those with a thin fibrous cap, a large lipid core, fewer smooth muscle cells, and more macrophages.5 Patients with ACS—unstable angina, non–ST-segment elevation (NSTE) MI, or ST-segment elevation (STE) MI— have plaque rupture or superficial plaque injury with either occlusive or nonocclusive thrombi. This underlying disease process is

AT A GLANCE Synopsis: Percutaneous coronary interventions (PCIs) are increasingly the mainstay of therapy for managing patients who present with myocardial infarction and other types of acute coronary syndromes. However, only about one seventh of hospitals in the United States perform procedures such as coronary artery bypass grafts, leading to a plethora of clinical decisions about how best to manage patients immediately and during transfer. This article reviews the in-hospital care for patients with ST-segment elevation and non–ST-segment elevation acute coronary syndromes, and the authors present a useful section on how pharmacists should monitor patients on drugs such as aspirin, thienopyridines, and glycoprotein IIb/IIIa inhibitors. Analysis: Despite the prominence of interventional cardiology in re-establishing coronary blood flow in patients with these conditions, pharmacotherapy is critically important before, during, and after PCIs. However, the literature presented in this article is complicated—with many different patient types, diseases and drugs under evaluation— and clinicians must be sure that the evidence they are reviewing applies to the specific patient being treated. Like an orchestra conductor, the secret of care is to bring just the right medications, doses, and interventions together to maximize the patient’s chances of having a positive outcome in this delicate clinical situation.

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Figure 1. Initiation, progression, and complication of human coronary atherosclerotic plaque.

Longitudinal section depicts the evolution of human atherogenesis from a healthy artery (1) to atheroma associated with clinical manifestations of thrombosis or stenosis (5–7). Transverse sections depict (1) healthy artery; (2) recruitment of inflammatory leucocytes; (3) fibrofatty stage, with transformation of macrophages into lipid-laden foam cells; (4) weakening of fibrous cap of plaque; (5) rupture of fibrous cap and exposure of thrombogenic lipid core, leading to thrombus formation on the nonocclusive atherosclerotic plaque; (6) healing response marked by collagen deposition and smooth muscle cell proliferation, leading to advanced fibrous, calcified plaque; and (7) superficial erosion of advanced stenotic lesion, leading to mural thrombus formation. REPRODUCED WITH PERMISSION FROM LIBBY P. CURRENT CONCEPTS OF THE PATHOGENESIS OF THE ACUTE CORONARY SYNDROMES. CIRCULATION. 2001;104:365–72.

common to ACS, ischemic stroke, and peripheral arterial disease. Previously, patients were classified as having either Q-wave or non–Q-wave MI, a differential diagnosis that usually took several hours or days to reach. Newer terminology calls for the diagnosis of STE or NSTE ACS, with the latter category including unstable angina and non–Q-wave MI. ACS thus encompasses unstable angina and both STE and NSTE MI (abbreviated as STEMI and NSTEMI, respectively). In this article, we describe the use of antithrombotic therapies in the management of the various types of ACS.

Diagnosis and Triage Diagnostic testing for ACS is initiated when a patient presents with substernal chest discomfort at rest or on minimal exertion, or a change in their pattern of stable angina. The priority for a patient with suspected ACS is to obtain a 12-lead electrocardiogram (ECG) within the first 10 minutes of presentation. With STE, the patient has a very high likelihood of having an MI and dying during the hospitalization. If the patient does not have ST-segment elevation, they are classified as having suspected NSTEMI or unstable angina (Figure 2).6,7 Further risk stratification of the patient with NSTE ACS involves evaluating the patient’s medical history, including age, cardiovascular risk factors, prior use of aspirin, number of chest pain attacks within the past 24 hours, and prior history of significant coronary artery disease. Patients with several unfavorable characteristics are at increased risk of death, acute MI (AMI), and Supplement to the Journal of the American Pharmacists Association

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Figure 2. Differentiation of ST-segment elevation (STE) and non–ST-segment elevation (NSTE) acute coronary syndrome (ACS).

sion, resulting from thrombus formation on the underlying atheromatous plaque, is the cause of ACS, antiplatelet and anticoagulant therapy form one of the cornerstones of treatment. Treatment of ACS should follow evidence-based guidelines, with early initiation of therapies in or even before arrival to the emergency department.

In-Hospital Management of STE Acute Coronary Syndromes

ABBREVIATIONS AND SYMBOLS: MI = MYOCARDIAL INFARCTION; IHD = ISCHEMIC HEART DISEASE; ECG = ELECTROCARDIOGRAM; * = TROPONIN I AND C.

recurrent ischemic chest pain within the next 30 days.8 Patients with ST-segment depression are at lower risk than those with STE but are at higher risk than those with no or nonspecific ECG changes.7 Troponin I and T isoforms are integral myocardial proteins involved in the contraction of the heart, and elevated concentrations of either isoform are useful markers of myocardial damage. Thus, blood troponin I or T concentrations should be measured to check for myocardial necrosis arising from an infarction. Patients with elevated blood troponin levels are at higher risk of death or reinfarction. An elevated troponin level confirms the diagnosis of infarction in a patient presenting with chest discomfort, even if the ECG is not changed.7 Troponin concentrations can be obtained within 20–40 minutes of presentation and can be used to stratify patients by risk. In patients presenting with STE ACS, the initial troponin concentration may not necessarily be elevated if the patient presents very early in the course of their infarction. Therefore, clinicians do not need to wait for troponin results to determine initial treatment of STE ACS patients. In patients with NSTE ACS, certain high-risk features may be identified, including, multiple cardiac risk factors, ST-segment depression, elevated troponin levels, or signs of acute decompensated heart failure. These patients with NSTE ACS, as well as patients with STE ACS, are generally admitted to a coronary intensive care unit or an intensive care step-down unit for treatment and telemetric monitoring for arrhythmias. Patients with NSTE ACS who have one or no risk factors and do not have a raised troponin concentration are evaluated for noncardiac causes of chest pain. They may not even be admitted to hospital or may undergo a stress test for further risk stratification.7 Patients with STE ACS have a higher likelihood of complete occlusion of one or more of the coronary arteries than patients without ST-segment elevation.6 Because coronary arterial occluS16

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Goals of Therapy The goals of therapy for the STE ACS patient are to improve survival, re-establish coronary artery blood flow as soon as possible, monitor for and prevent complications such as arrhythmias and heart failure, and relieve chest discomfort. Medications administered to patients with STE ACS include aspirin, clopidogrel (Plavix—Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership), thrombolytics, glycoprotein IIb/IIIa receptor inhibitors, beta-blockers, and angiotensin-converting enzyme (ACE) inhibitors. Administration of calcium-channel blockers is reserved for patients with refractory ischemia and/or contraindications to a beta-blocker.

Aspirin and Clopidogrel Aspirin is one of the most simple and rapid ways to reduce mortality in STE ACS. A dose of 162–325 mg of nonenteric-coated aspirin should be initiated before arrival at the hospital, if possible. In the International Study of Infarct Survival 2 (ISIS-2) trial, aspirin combined with unfractionated heparin (UFH) reduced the rate of cardiovascular death by 25% and recurrent infarction or stroke by 50% each, compared with placebo plus UFH.9 The efficacy was similar to that of streptokinase.9 Therefore, some 25 lives are saved for every 1,000 STE ACS patients treated with aspirin. Aspirin and thrombolysis are synergistic in terms of reduction in cardiovascular mortality.9 According to the current American College of Cardiology/American Heart Association (ACC/AHA) guidelines, clopidogrel should be initiated in patients who have a true aspirin allergy (such as anaphylaxis or rash, but not simple gastrointestinal upset). Clopidogrel is administered as a 300 mg oral loading dose followed by 75 mg per day.10 Whether initiation of clopidogrel 75 mg with aspirin on the first day of a confirmed STE or NSTE AMI reduces 30-day cardiovascular events is the subject of an ongoing 40,000-patient trial (the Second Chinese Cardiac Study; CCS-2), which is expected to conclude this year.11

Antithrombins UFH has been less well studied in STE ACS patients. Trials without routine aspirin administration suggest that UFH results in 35 fewer deaths per 1,000 patients treated, while the addition of www.japha.org

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UFH to aspirin results in 5 fewer deaths per 1,000 patients treated. However, the addition of UFH to aspirin causes 3 additional bleeds per 1,000 patients treated.12 Nevertheless, UFH is assigned a class I recommendation by the ACC/AHA for treating STE ACS patients. An intravenous 60 U/kg bolus is recommended (maximum 4,000 U), followed by continuous infusion of 12 U/kg/hour (maximum 1,000 U/hour).6 Enoxaparin (Lovenox—Aventis), a low-molecular-weight heparin (LMWH), has also been studied in several STE ACS trials but has not yet been incorporated into professional association guidelines. The largest enoxaparin trial, Assessment of the Safety and Efficacy of a New Thrombolytic regimen (ASSENT)-3, reported a reduction in the composite endpoint of 30-day mortality, in-hospital reinfarction, or refractory ischemia, when enoxaparin was administered as a 30 mg intravenous bolus followed by 1 mg/kg subcutaneous injection (with the first two doses capped at 100 mg) in combination with tenecteplase (TNKase—Genentech), compared with UFH in combination with tenecteplase.13 The incidence of major bleeding was not different between enoxaparin- and UFH-treated patients. Smaller angiographic trials have suggested similar or higher patency rates of the infarct-related coronary artery with enoxaparin compared with UFH, in patients treated with alteplase (Activase—Genentech), tenecteplase, or streptokinase (Streptase—Aventis).14 A meta-analysis of six clinical trials of enoxaparin combined with a thrombolytic agent for STE ACS involving more than 6,000 demonstrated a reduction in reinfarction and recurrent angina with enoxaparin compared with UFH.14 The incidences of major bleeding and intracranial hemorrhage were similar with enoxaparin and UFH. However, analysis of the recent ASSENT-3 PLUS trial suggests that the incidence of intracranial hemorrhage may be higher with enoxaparin than with UFH in patients older than 75 years.15 Caution should be exercised when using enoxaparin in elderly patients treated with thrombolytics until the results of a large ongoing randomized trial comparing enoxaparin with UFH (Thrombolysis in Myocardial Infarction-25; TIMI-25) are known. In this ongoing trial of more than 20,000 patients, the dose of enoxaparin is reduced for patients older than 75 years by omitting the intravenous bolus and reducing the subcutaneous dose to 0.75 mg/kg every 12 hours. Currently, enoxaparin has not been studied in primary percutaneous coronary interventions for STE ACS.

Thrombolytics According to the Fibrinolytic Therapy Trialists’ (FTT) Collaborative, 37 lives are saved for every 1,000 anterior wall STE ACS patients treated with thrombolysis, and 8 lives are saved for every 1,000 inferior wall STE ACS patient treated with thrombolysis.16 Cautions and contraindications to thrombolytic use are given in Table 1. The reduction in mortality decreases as the time from onset of chest discomfort increases. Therefore, only patients presenting Vol. 44, No. 2, Suppl. 1

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within 12 hours of the onset of chest discomfort are eligible for thrombolysis. The benefits must also be weighed against the risk of bleeding and especially against the approximately 1% risk of intracranial hemorrhage.10 Because of delays in presentation and other contraindications, only 21% of STE patients currently receive thrombolytics.17 If the patient meets eligibility criteria for thrombolytic therapy and does not have an absolute contraindication, the ACC/AHA practice guidelines recommend that thrombolysis be initiated within 30 minutes of presentation.6 Many institutions have difficulty meeting this standard, but data from hospitals participating in the National Registry of Myocardial Infarction suggest an average “door-to-needle” time of 37.8 minutes.17

Primary Percutaneous Coronary Intervention Immediate percutaneous coronary intervention (PCI), with balloon angioplasty with or without placement of an intracoronary stent, is the preferred method to open an occluded coronary artery in patients with STE ACS. The current ACC/AHA guidelines suggest that primary PCI for STE ACS should be performed within 90 ± 30 minutes of presentation.10 As the time of complete occlusion increases, the extent of infarction increases. Therefore, the earlier that coronary blood flow is re-established, the smaller will be the area of infarction and the higher the patient’s chance of survival. Alternatively, coronary artery patency can be re-established by administering a thrombolytic agent such as alteplase, reteplase, tenecteplase, or streptokinase, which converts plasminogen to plasmin to lyse the occluding clot. An advantage of PCI over thrombolysis is that complete opening of the artery occurs in a greater percentage of patients treated with PCI. Meta-analyses of randomized clinical trials suggest that mortality is reduced to a greater extent with primary PCI than with thrombolytic therapy,18–20 especially in patients presenting with cardiogenic shock.21 The Danish Multicenter Randomized Trial on Thrombolytic Therapy Versus Acute Coronary Angioplasty in Acute Myocardial Infarction 2 (DANAMI-2) reported a lower combined endpoint of death, myocardial infarction, or stroke with primary PCI than with thrombolytics, in STE patients presenting to hospital within 12 hours of the onset of chest pain.22 Lower event rates occurred with primary PCI even in patients transferred from their presenting hospital to a primary PCI center, providing the transfer was completed within 2 hours of presentation to the first facility. The disadvantage of PCI is that only 13% of all hospitals in the United States are presently equipped to perform the procedure. According to the National Registry of Myocardial Infarction, the rates of primary PCI have risen from 2.4% to 7.3% of patients presenting with STE ACS.17 In patients receiving an intracoronary stent for primary PCI, clopidogrel (added to aspirin) should be administered as a 300 mg loading dose followed by 75 mg/day for at least 30 days.10

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Table 1. Contraindications and Precautions for Thrombolysis in Myocardial Infarctiona Contraindications • Previous hemorrhagic stroke at any time; other strokes or cerebrovascular events within the past year • Known intracranial neoplasm • Active internal bleeding (does not include menses) • Suspected aortic dissection Cautions/relative contraindications • Severe uncontrolled hypertension on presentation (blood pressure > 180/110 mm Hg)b • History of prior cerebrovascular accident or known intracerebral pathology not covered in contraindications • Current use of anticoagulants in therapeutic doses (INR ≥ 2–3); known bleeding diathesis • Recent trauma (within 2–4 weeks), including head trauma or traumatic or prolonged (> 10 minutes) CPR or major surgery (< 3 weeks) • Noncompressible vascular punctures • Recent (within 2–4 weeks) internal bleeding • For streptokinase/anistreplase: prior exposure (especially within 5 days to 2 years) or prior allergic reaction • Pregnancy • Active peptic ulcer • History of chronic severe hypertension Reproduced with permission from Ryan TJ et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction: 1999 update: a report of the ACC/AHA Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction), www.acc.org. Abbreviations: INR = international normalized ratio; CPR = cardiopulmonary resuscitation. a b

Viewed as advisory for clinical decision making and may not be all-inclusive or definitive. Could be an absolute contraindication in low-risk patients with myocardial infarction.

Adjuvant Glycoprotein IIb/IIIa Receptor Inhibitors

Glycoprotein IIb/IIIa receptor inhibitors (tirofiban [Aggrastat— Guilford Pharmaceuticals], eptifibatide [Integrilin—Millennium Pharmaceuticals], and abciximab [ReoPro—Lilly]) block the final common pathway of platelet aggregation by preventing cross-linking of platelets via fibrinogen. Abciximab is the most extensively studied glycoprotein IIb/IIIa receptor blocker in STE ACS patients. Despite favorable effects in primary PCI where abciximab has a class I recommendation,10,23 results of glycoprotein IIb/IIIa receptor inhibitor trials in combination with thrombolytics in STE ACS patients have not been favorable. In the ASSENT-3 trial, abciximab plus half-dose tenecteplase and low-dose UFH reduced the combined endpoint of death, AMI, and recurrent ischemia, compared with full-dose tenecteplase and UFH; however, the risk of major bleeding doubled.13 In the large Global Use of Strategies to Open Occluded Arteries (GUSTO-V) trial, abciximab combined with half-dose reteplase and reduced-dose UFH was associated with similar mortality but increased major bleeding compared with full-dose reteplase plus UFH.24 Both of these trials showed a tendency towards a doubling of risk of intracranial hemorrhage in older patients treated with abciximab. Both trials also demonstrated reduced reinfarction rates with abciximab, however. Therefore, additional trials evaluating PCI in patients receiving thrombolytic agents and glycoprotein IIb/IIIa receptor inhibitors are planned.

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Summary: Antithrombotic Therapy for STE ACS Patients with STE ACS should receive early aspirin treatment, preferably before hospital arrival. Once the patient is in the hospital, a decision regarding thrombolysis versus primary PCI should be made. Patients undergoing primary PCI should receive abciximab, UFH and, if urgent bypass surgery is not indicated, clopidogrel. Patients receiving thrombolysis with alteplase, reteplase, or tenecteplase should receive UFH.6 The roles of clopidogrel, enoxaparin, and other glycoprotein IIb/IIIa receptor inhibitors, such as eptifibatide, in STE ACS are still evolving.

In-Hospital Management of NSTE Acute Coronary Syndromes Patients admitted to hospital with NSTE ACS are treated with multiple medications, including beta-blockers, nitrates, ACE inhibitors, antiplatelet agents, and antithrombin therapy (Figure 3). As in STE ACS, calcium-channel blockers are reserved for patients with refractory ischemia and/or contraindication to ACE inhibitors.7,25 All NSTE ACS patients should receive 160–325 mg of nonenteric coated aspirin as soon as possible after symptoms begin, and aspirin therapy (75–325 mg/day) should be continued indefinitely.7 In patients with a true aspirin allergy (anaphylactic reaction or rash), clopidogrel may be substituted as an antiplatelet agent. It www.japha.org

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Figure 3. Strategies for management of non–ST-segment elevation acute coronary syndromes.

REPRODUCED WITH PERMISSION FROM BODEN WE, PEPINE CJ. INTRODUCTION TO OPTIMIZING MANAGEMENT OF NON–ST-SEGMENT ELEVATION ACUTE CORONARY SYNDROMES. HARMONIZING ADVANCES IN MECHANICAL AND PHARMACOLOGIC INTERVENTION. J AM COLL CARDIOL. 2003;41(4 SUPPL S):S1–6. ABBREVIATIONS: ACE = ANGIOTENSIN-CONVERTING ENZYME; ACS = ACUTE CORONARY SYNDROMES; ASA = ASPIRIN; CABG = CORONARY ARTERY BYPASS GRAFT SURGERY; CAD = CORONARY ARTERY DISEASE; CCU = CARDIAC CARE UNIT; CHF = CONGESTIVE HEART FAILURE; ECG = ELECTROCARDIOGRAM; GP = GLYCOPROTEIN; LBBB = LEFT BUNDLE BRANCH BLOCK; LMWH = LOW MOLECULAR WEIGHT HEPARIN; MPI = MYOCARDIAL PERFUSION IMAGING; TIMI = THROMBOLYSIS IN MYOCARDIAL INFARCTION; UFH = UNFRACTIONATED HEPARIN.

should be given as a 300 mg oral loading dose followed by a 75 mg daily oral dose thereafter. Clopidogrel is also recommended for use with aspirin in patients who will be medically managed, as well as those who will undergo coronary angiography and PCI. The duration of clopidogrel therapy is variable, with the practice guidelines recommending that therapy be continued for up to 9 months. Although ticlopidine is also effective, adverse events (notably neutropenia) limit its use. In addition to antiplatelet therapy with aspirin and/or clopidogrel, antithrombin therapy should also be initiated with either UFH or a LMWH (enoxaparin or dalteparin [Fragmin—Pfizer]). The advantages of using the LMWH are decreased nonspecific protein binding, longer half-life (allowing for twice-daily subcutaneous dosing), and the lack of required laboratory monitoring compared with UFH. UFH is usually administered as a bolus of 60–70 U/kg (up to 5,000 U), followed by a continuous infusion of 12–15 U/kg/hour. Adjustments in the rate of infusion are based on an activated partial thromboplastin time (aPTT) of 1.5–2 times the control. Dalteparin is administered subcutaneously 120 IU/kg (up Vol. 44, No. 2, Suppl. 1

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to 10,000 IU) every 12 hours; enoxaparin is administered subcutaneously 1 mg/kg every 12 hours. In the 2002 ACC/AHA practice guideline update, enoxaparin is specifically recommended over UFH.7 Use of LMWH during catheterization and coronary angiography is controversial because anticoagulation status cannot currently be assessed easily. Two options exist for patients who will undergo catheterization: continue LMWH throughout the procedure, or discontinue LMWH and use UFH during the procedure.7,26 For patients who undergo PCI between 8 and 12 hours since the last subcutaneous dose, a 0.3 mg/kg supplemental intravenous dose of enoxaparin is administered in the cardiac catheterization laboratory at the time of PCI.26 Glycoprotein IIb/IIIa receptor inhibitors also have a role in managing NSTE ACS. These agents are recommended to reduce ischemic complications in patients already receiving aspirin and heparin and in whom PCI will be performed. Tirofiban and eptifibatide can be administered to high-risk patients for medical management when intervention is not planned.7 However, most of the Supplement to the Journal of the American Pharmacists Association

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Table 2. Early Invasive Versus Early Conservative Strategies for Non–ST-Segment Elevation Acute Coronary Syndromes: Summary of Results of Five Randomized Trials

No. Patients Trial TIMI IIIB VANQWISH

Primary Endpoint

Invasive

Conservative

Invasive

Conservative

740

733

Death/MI/positive ETT at 6 weeks

16.2

18.1

.33

Death/MI at 12 months

24.0

18.6

.05

9.4

12.1

.031

15.9

19.4

.025

Death/MI/refractory angina at 4 months

9.6

14.5

.001

Death/MI at 12 months

7.6

8.3

462

458

FRISC II

1,222

1,235

Death/MI at 6 months

TACTICS

1,114

1,106

Death/MI/rehospitalization for ACS at 6 months

895

915

RITA 3

% Patients Reaching Primary Endpoint P value

.58

Abbreviations: TIMI = Thrombolysis In Myocardial Infarction28; VANQWISH = Veterans Affairs Non–Q-Wave Infarction Strategies in Hospital2; FRISC = Fragmin and fast Revascularization during InStability in Coronary artery disease.0; TACTICS = Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy.31; RITA = Randomized Intervention Trial of unstable Angina32; MI = myocardial infarction; ETT = exercise tolerance test; ACS = acute coronary syndrome.

benefit from these agents is seen in the population of patients who receive PCI.27 Abciximab is not recommended in patients who will not undergo PCI.7 Early invasive management is recommended for high-risk patients with NSTE ACS. Patients may undergo angiography with revascularization, if indicated. For lower-risk patients, early conservative management may be used, and angiography is reserved for patients with recurrent ischemia or a positive exercise stress test. In patients with lower risk, either early invasive or early conservative therapy is recommended.7 The relative benefits of the different approaches are discussed in the next section.

Interventional Therapy Versus Conservative Medical Management Five large randomized trials have compared the relative benefits of early invasive therapy and conservative medical management in NSTE ASC patients. The results have been somewhat conflicting, as summarized in Table 2. The TIMI (Thrombolysis In Myocardial Infarction) IIIB trial assessed the effects of an early invasive strategy on clinical outcomes in patients with unstable angina or non–Q-wave myocardial infarction.28 The primary endpoint was the composite of death, MI, or a positive exercise tolerance test (ETT) at 6 weeks, and was similar between the invasive and conservative treatment groups. There were no significant differences in the individual components of the primary endpoint between the two groups. In the subgroup of patients aged 65 years and older, the composite of death or MI occurred more frequently in patients randomized to the conservative strategy (14.8% versus 7.9%; P = .02). VANQWISH (Veterans Affairs Non–Q-Wave Infarction Strategies in Hospital) compared an early invasive approach with a conservative approach for treating patients with non–Q-wave MI.29 Early invasive management consisted of routine coronary S20

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angiography with subsequent revascularization. Conservative management consisted of medical therapy and noninvasive procedures. The primary endpoint was the composite of death or MI during a minimum of 12 months of follow-up, and a significant advantage was demonstrated for conservatively treated patients (P = .05; Table 2). There was no difference in all-cause mortality between the groups. The authors concluded that early invasive treatment in these patients confers no benefit and may in fact increase the risk of poor outcomes in the first year. The FRISC II (Fragmin and fast Revascularization during InStability in Coronary artery disease) trial evaluated an early invasive strategy compared with a noninvasive strategy in patients presenting with NSTE ASC on “optimum background antithrombotic medication.”30 Early invasive management consisted of coronary angiography within “a few” days and revascularization within 7 days of the start of antithrombotic therapy. The primary endpoint of this trial, a composite of death or MI after 6 months, was significantly lower in the invasive strategy group (Table 2). MI in the invasive therapy group was significantly reduced (7.8% versus 10.1%; P = .045), but mortality rates were not significantly different. Major and minor bleeding occurred with slightly greater frequency in the patients treated invasively. The TACTICS (Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy) trial, with a primary endpoint of death, nonfatal MI, or rehospitalization for ACS at 6 months, compared angina patients using early intervention and conservative treatment approaches.31 Early intervention consisted of coronary angiography 4–48 hours after randomization, with revascularization when appropriate. The primary endpoint (death, MI, or recurrent hospitalization at 6 months) was significantly lower in the early intervention group (Table 2). This benefit was also seen at 30 days and was most evident in intermediate- or high-risk patients. Major bleeding occurred more commonly in patients in the invasive therapy group (5.5% versus 3.3%; P < .01). www.japha.org

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RITA (Randomized Intervention Trial of unstable Angina) 3 compared early angiography/revascularization with conservative management in patients with NSTE ASC.32 The trial had two primary endpoints (Table 2). The first primary endpoint (death, AMI, or refractory angina at 4 months) occurred more frequently in patients in the conservative group (P = .001), but the second endpoint (death or MI at 12 months) was not significantly different between the two treatment groups (P = .58). Therefore, most data support an early invasive management strategy (angiography leading most often to revascularization with PCI or coronary artery bypass graft surgery) for intermediate- and high-risk patients with NSTE ACS.

Combination Antiplatelet Therapy Clopidogrel and Aspirin

The CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) trial compared clopidogrel plus aspirin versus aspirin alone in patients on aspirin therapy presenting with NSTE ACS.33 Patients were randomized to either clopidogrel (300 mg orally as a loading dose and 75 mg/day orally thereafter; n = 6,259) or placebo (n = 6,303) for a mean of 9 months. Aspirin (75–325 mg/day) was initiated at the same time. Two primary endpoints were examined: the composite of death from cardiovascular causes, nonfatal MI, or stroke, and the composite of all of the above endpoints plus refractory ischemia. Fewer patients in the clopidogrel group than the placebo group experienced a 20% relative risk reduction for the first primary endpoint (9.3% versus 11.4%; P < .001) and a 14% relative risk reduction for the second primary endpoint (16.5% versus 18.8%; P < .001). Of the individual components of these endpoints, significant differences were seen only in the rates of MI (specifically Q-wave MI) and refractory ischemia during hospitalization. In patients with a history of revascularization, a benefit was seen in those randomized to clopidogrel. Major bleeding was more common in patients receiving clopidogrel than placebo (3.7% versus 2.7%; P = .001), but the incidence of life-threatening major bleeding was not significantly different between the groups. The CURE trial concluded that clopidogrel combined with aspirin significantly reduced complications in patients with NSTE ACS, but at the expense of an increased risk of bleeding. A major limitation of this trial was a very high rate of temporary (about 45%) and permanent (about 20%) discontinuation of study medication. In addition, few patients in this trial received concomitant treatment with glycoprotein IIb/IIIa inhibitors. The PCI-CURE (Percutaneous Coronary Intervention–Clopidogrel in Unstable angina to prevent Recurrent Events) study was a prospectively planned, retrospective analysis of patients from the CURE trial who underwent PCI.34 Of the 12,562 patients enrolled in the CURE trial, 2,658 underwent PCI at the discretion of their physician (1,313 in the clopidogrel group and 1,345 in the placebo group). In the per-protocol analysis of these patients, the primary endpoint occurred significantly less often in the patients receiving Vol. 44, No. 2, Suppl. 1

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clopidogrel (4.2% versus 7.2%; P = .005), a difference that was also seen in patients who received stents (3.5% versus 6.1%; P = .016). The incidence of MI was significantly reduced among clopidogrel patients receiving PCI at both 30 days and the end of follow-up. The reduction in the composite endpoint was most likely secondary to the reduction in MI (specifically Q-wave MI). Pretreatment with clopidogrel in patients receiving aspirin reduced ischemic events in patients undergoing PCI. In this subgroup, minor but not major bleeding events occurred more often. Glycoprotein IIb/IIIa Inhibitors and Aspirin

PRISM-PLUS (Platelet Receptor Inhibition in ischemic Syndrome Management in Patients Limited by Unstable Signs and symptoms) investigated the use of tirofiban in patients with NSTE ASC.35 Patients had had angina at rest or with minimal exertion in the past 12 hours and had new ECG changes consistent with ischemia or elevated cardiac enzymes. The primary endpoint was the composite of death, MI, refractory ischemia, or rehospitalization for unstable angina at 7 days. Patients were randomized in the placebo-controlled trial to either tirofiban (0.6 mcg/kg/min for 30 minutes followed by 0.15 mcg/kg/min; n = 345), tirofiban (0.4 mcg/kg/min for 30 minutes followed by 0.1 mcg/kg/min) plus adjusted dose UFH (n = 773), or adjusted dose UFH only (n = 797). All patients also received aspirin 325 mg/day. Because of an increased event rate in the patients receiving tirofiban alone, that arm of the trial was stopped prematurely. At 7 days the mortality in the tirofiban alone group was 4.6%, compared to 1.1% in the UFH alone group, and 1.5% in the tirofiban and UFH group. The composite endpoint of death, MI, refractory ischemia, or rehospitalization for unstable angina was significantly lower in the combination group at 7 days (12.9% versus 17.9%; P = .004), and also at 30 days (18.5% versus 22.3%; P = .03). This difference resulted from reduction in MI and refractory ischemia. Major bleeding occurred in 3% of patients in the UFH group and 4% of patients in the combination group (P = .34). Bleeding leading to early discontinuation of study medication was seen in 1.3% of patients in the UFH group and 3.5% of patients in the combination group (P = .004). The PRISM-PLUS trial concluded that combined tirofiban and UFH decreased ischemic complications in patients with NSTE ACS. The benefit was greatest in patients undergoing angioplasty. The PURSUIT trial tested the hypothesis that platelet inhibition with eptifibatide would have an incremental benefit beyond that of aspirin and heparin in patients with nonpersistent STE ACS.36 A total of 10,948 patients were randomized to eptifibatide (180 mcg/kg loading dose and 1.3 or 2.0 mcg/kg/min infusion for up to 72 or 96 hours) or placebo, each administered with standard treatment (aspirin and heparin). The primary endpoint was the composite of death and nonfatal MI occurring up to 30 days after the index event. Compared with placebo, eptifibatide reduced the incidence of death/nonfatal MI by 9.6% (14.2% versus 15.7%; P = .04); this benefit was apparent by 96 hours and persisted for 30 days. Supplement to the Journal of the American Pharmacists Association

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Unfractionated Heparin Versus LMWHs

The FRIC (FRagmin In unstable Coronary artery disease) trial compared subcutaneous dalteparin and intravenous UFH in NSTE ACS patients receiving aspirin, in an acute phase (1–6 days) and a prolonged treatment phase (6–45 days).37 Participants presented within 72 hours of the last episode of chest pain with temporary or persistent ST-segment depression and/or temporary or persistent T-wave inversions in two or more adjacent leads. Patients were randomized to open-label treatment with either dalteparin (120 IU/kg subcutaneously every 12 hours) or UFH (5,000 U intravenous bolus followed by 1,000 U/hour adjusted to maintain aPTT 1.5 times the control). UFH infusions were continued for at least 48 hours and were then changed to 12,500 U subcutaneously every 12 hours. All patients received 75–165 mg/day aspirin. In the prolonged treatment phase, patients were randomized to receive either dalteparin (7,500 IU/day subcutaneously) or placebo. During the acute phase, 731 patients received initial treatment with UFH and 751 patients with dalteparin. During the prolonged treatment phase, 562 patients received dalteparin and 564 received placebo. The composite of death, MI, or recurrent angina was not significantly difference between the groups at day 6 (7.6% for UFH versus 9.3% for dalteparin; P = .33). During the prolonged treatment phase, placebo and dalteparin produced similar rates of the composite endpoint of death, MI, or recurrent angina, and in the individual components of this primary endpoint. Adverse events were uncommon in the acute and prolonged phases; the only difference between the groups was a higher incidence of minor bleeding in the dalteparin group during the prolonged phase. The FRIC trial demonstrates that dalteparin administered every 12 hours is well tolerated and an effective alternative to UFH in NSTE ACS patients receiving aspirin. However, the data do not support the use of prolonged lower-dose dalteparin in these patients. The use of enoxaparin in NSTE ACS patients was evaluated in two prospective, randomized trials: ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-wave Coronary Events) 38 and TIMI IIB,39 and in a prospectively planned metaanalysis of these trials.40 The ESSENCE trial evaluated safety and efficacy of enoxaparin compared with UFH in NSTE ACS patients; the TIMI IIB trial examined acute enoxaparin use compared with UFH and also extended use of lower-dose enoxaparin compared with placebo. All patients in both trials received aspirin 100–325 mg/day. Patients in the ESSENCE trial had experienced chest pain at rest for 10 minutes or more within the last 24 hours and had evidence of coronary artery disease (ST-segment changes or T-wave changes in two contiguous leads, documented history of myocardial infarction or revascularization, or test results suggestive of coronary artery disease). Participants were randomized to either subcutaneous enoxaparin 1 mg/kg every 12 hours (n = 1,607) or intravenous UFH (5,000 U bolus followed by continuous infusion, titrated to aPTT 55–85 seconds; n = 1,564). Therapy was continued for 2 to 8 days. The primary endpoint was the composite of death, MI, or recurS22

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rent angina at 14 days, which occurred in 19.8% of patients treated with UFH and 16.6% of patients treated with enoxaparin (P = .02). A significant difference was also seen at 30 days (23.3% versus 19.8%; P = .02) and at 1 year (32% versus 35.7%; P = .022), but no difference was seen at 48 hours. No significant differences in major bleeding were observed at 30 days, but significantly more minor bleeding events occurred in enoxaparin-treated patients (7.2% with UFH versus 11.9% with enoxaparin; P < .001). TIMI IIB enrolled patients with ischemic chest pain for 5 minutes or more within the previous 24 hours. Initially, patients were included if they had either a history of coronary artery disease, STsegment changes, or elevated cardiac enzymes. The protocol was later changed to include only those with ST-segment changes or elevated cardiac enzymes. TIMI IIB used a similar protocol to the ESSENCE trial, but subcutaneous enoxaparin treatment (n = 1,953) was preceded by a 30 mg intravenous bolus, and UFH patients (n = 1,957) received a 70 U/kg intravenous UFH bolus followed by 15 U/kg/hour continuous infusion (titrated to aPTT 1.5–2.5 times the control). Therapy was continued for 3 to 8 days. Patients who received UFH in the acute phase of TIMI IIB received placebo in the outpatient phase; those who received enoxaparin in the acute phase received enoxaparin in the outpatient phase. The primary endpoint of TIMI IIB was the composite of all-cause mortality, recurrent MI, or urgent revascularization at day 8 of the acute phase and day 43 of the outpatient phase. This endpoint was reached less frequently in UFH patients than enoxaparin patients (12.4% versus 14.5%; P = .048) at 8 days. Enoxaparin showed significant advantages at 48 hours, 14 days, and 43 days. Approximately 60% of patients in each group of the TIMI IIB trial progressed to the outpatient phase. No additional benefit was observed when enoxaparin therapy was continued for 35 additional days. No significant difference in the incidence of major hemorrhage was observed between UFH and enoxaparin at 72 hours or at the end of the hospital stay in the TIMI IIB trial. Significantly fewer minor hemorrhages were seen with UFH than with enoxaparin (72 hours: 5.1% versus 2.3%, P < .001; end of hospital stay: 9.1% versus 2.5%, P < .001). A meta-analysis of ESSENCE and TIMI IIB reported similar findings to the original trials.40 The incidence of major hemorrhage did not differ significantly between the groups. Minor hemorrhages were significantly more common in enoxaparin-treated patients (4.3% versus 10%; P < .001). Based on these findings, enoxaparin may be recommended over UFH in patients with NSTE ACS. As mentioned previously, the use of LMWHs during PCI is controversial. One consensus panel report provided guidelines for using enoxaparin in patients undergoing cardiac catheterization, angiography, and PCI.26 Briefly, for patients who have received at least two doses of the usual 1 mg/kg subcutaneous regimen of enoxaparin every 12 hours and whose procedure takes place within 8 hours of the last subcutaneous dose, no additional antithrombin therapy (heparin, LMWH, or bivalirudin) is administered. For patients who undergo PCI between 8 and 12 hours since the last subcutaneous dose, a 0.3 mg/kg supplemental intravenous dose of www.japha.org

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enoxaparin is administered in the cardiac catheterization laboratory at the time of PCI. For patients who have received no prior antithrombin therapy, a 1 mg/kg intravenous dose of enoxaparin is administered to patients not receiving concomitant glycoprotein IIb/IIIa receptor inhibitor therapy while 0.75 mg/kg intravenous enoxaparin is administered to patients receiving a concomitant glycoprotein IIb/IIIa receptor inhibitor.

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received either abciximab plus low-dose UFH or standard UFH alone in a placebo-controlled, randomized, double-blind design. The composite of death, MI, or urgent target vessel revascularization at 30 days was the primary endpoint, while secondary endpoints included rates of both major and minor bleeding and restenosis after 6 months.42 The study findings indicated that, in low-risk patients (non-ACS patients) undergoing elective PCI, clopidogrel obviated the need for intravenous glycoprotein IIb/IIIa receptor inhibitor treatment and its associated expense.

Adjuvant Therapy to PCI Glycoprotein IIb/IIIa Inhibitors Clopidogrel

The CREDO (Clopidogrel for the Reduction of Events During Observation) trial evaluated the safety and efficacy of clopidogrel, compared with placebo, at 1 year in patients undergoing elective PCI.41 Patients had symptomatic CAD with evidence of ischemia and were undergoing PCI. Patients were randomized to either a loading dose of 300 mg of clopidogrel (n = 1,053) or placebo (n = 1,063), and all received 325 mg/day aspirin. After PCI, all patients received clopidogrel 75 mg/day and aspirin 325 mg/day for 28 days. After the 28 days, those who received the clopidogrel loading dose continued to take clopidogrel 75 mg/day, while those who received the placebo loading dose returned to placebo. The primary endpoints were the composite of death, MI, or urgent target vessel revascularization at 28 days, and the composite of death, MI, or stroke at 1 year. The 28-day data indicated a nonsignificant reduction in the composite endpoint of death, MI, or urgent target vessel revascularization in the clopidogrel-loaded patients (per-protocol analysis: 6.8% versus 8.3%, P = .23; intention-to-treat analysis: 6.2% versus 7.8%, P = .15). In those patients who received the clopidogrel loading dose 6 hours or more before PCI, a relative risk reduction of 38.6% was demonstrated in the combined endpoint, which was of borderline significance (P = .051). For the intention-to-treat population, long-term clopidogrel therapy was associated with a significant 26.9% relative reduction in the composite endpoint of death, MI, or stroke at 1 year (8.5% clopidogrel versus 11.5% placebo; P = .02). Rates of major or minor bleeding at 28 days did not differ significantly, although patients who also received a glycoprotein IIb/IIIa inhibitor at the time of PCI showed a trend toward increased minor bleeding with clopidogrel. The CREDO trial concluded that long-term (12-month) clopidogrel therapy was more effective than short-term (28-day) therapy in reducing the risk of ischemic events after PCI, and that pretreatment with a loading dose of clopidogrel conferred no additional benefit (compared with postprocedural clopidogrel therapy) unless it was performed at least 6 hours before PCI. The Intracoronary Stenting and Antithrombotic Regimen— Rapid Early Action for Coronary Treatment (ISAR-REACT) trial investigated the efficacy and safety of a 600 mg loading dose of clopidogrel administered 2 hours or more before angiography in patients with symptomatic coronary artery disease. Patients also Vol. 44, No. 2, Suppl. 1

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EPISTENT (Evaluation of Platelet IIb/IIIa Inhibitor for STENTing) trial tested the hypothesis that stenting or balloon angioplasty plus glycoprotein IIb/IIIa inhibition would be superior to stenting plus placebo.43 The study included a total of 2,399 patients undergoing either urgent or elective percutaneous coronary revascularization for a target lesion with 60% or more stenosis, of whom 1,220 patients had a previous MI and 1,858 patients had unstable angina. Patients were randomized to three groups: stent plus placebo (n = 809), stent plus abciximab (n = 794), or balloon angioplasty plus abciximab (n = 796). All patients received aspirin 325 mg/day starting before the procedure. Patients receiving stents also received ticlopidine (Ticlid—Roche) 250 mg twice daily. Patients without stents received ticlopidine at the discretion of their physician. The primary endpoint was the composite of death, MI, or urgent revascularization at 30 days. Significantly fewer patients reached this endpoint in the stent plus abciximab (5.3%) or balloon angioplasty plus abciximab group (6.9%) than in the stent plus placebo group (10.8%) (P < .001 and P = .007, respectively; hazard ratios 0.48 and 0.63, respectively). Fewer abciximab patients experienced abrupt closure or side branch occlusion than placebo patients (P = .06 and P = .02, respectively). Major bleeding occurred in 2.2% of patients receiving stent plus placebo, 1.5% of patients receiving stent plus abciximab, and 1.4% of patients receiving balloon angioplasty plus abciximab. This trial suggested that abciximab combined with either stenting or balloon angioplasty decreases the incidence of death or MI at 30 days when compared with stenting plus placebo. The benefit of the reduction in this composite endpoint results primarily from a reduced incidence of MI. TARGET (do Tirofiban and ReoPro Give similar Efficacy Trial) compared abciximab to tirofiban in patients undergoing percutaneous coronary revascularization with stenting.44 The objective was to demonstrate that tirofiban was no less effective than abciximab in the setting of coronary stenting. Patients were included if they were to undergo stenting either electively or emergently on a lesion with 70% or more stenosis on angiography. Patients were randomized to receive either tirofiban (10 mg/kg bolus, followed by 0.15 mcg/kg/min for 18–24 hours; n = 2,398) or abciximab (0.25 mg/kg bolus, followed by 0.125 mcg/kg/min for 12 hours; n = 2,411) immediately before the revascularization procedure. All patients received aspirin 250–500 mg before the Supplement to the Journal of the American Pharmacists Association

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procedure, and continued aspirin 75–325 mg daily. Patients received clopidogrel when possible and UFH. The primary endpoint of the trial was the composite of death, MI, or urgent target vessel revascularization at 30 days, which occurred in 7.6% of tirofiban patients and 6% of abciximab patients. Statistical analysis revealed that abciximab was significantly more effective than tirofiban in reducing the incidence of cardiac ischemic events (P = .038). Major bleeding was similar between the two groups, although minor bleeding was significantly higher in patients receiving abciximab (4.3% versus 2.8%; P < .001). In summary, glycoprotein IIb/IIIa receptor antagonists are used before PCI (either tirofiban or eptifibatide) or at the time of PCI (eptifibatide or abciximab) for intermediate- and high-risk patients with NSTE ACS.

Ongoing Trials The SYNERGY trial is comparing enoxaparin and UFH in higher-risk patients with NSTE ACS undergoing PCI. The primary endpoint of this trial is the composite of 30-day death or MI. The ACUITY trial is comparing enoxaparin (with or without a glycoprotein IIb/IIIa inhibitor) and the direct thrombin inhibitor bivalirudin (Angiomax—The Medicines Company; alone or with a glycoprotein IIb/IIIa inhibitor) in intermediate- to high-risk patients with NSTE ACS undergoing PCI. The PROTECT trial is evaluating enoxaparin plus eptifibatide, UFH plus eptifibatide, and bivalirudin in patients with NSTE ACS undergoing PCI.

Summary: Antithrombotic Therapy for NSTE ACS Antiplatelet therapy is central to the management of NSTE ACS. Three classes of drugs—aspirin, thienopyridines, and glycoprotein IIb/IIIa inhibitors—have proved useful in management of NSTE ACS. Aspirin should be initiated immediately in patients presenting with symptoms of NSTE ACS and should be continued indefinitely. Clopidogrel may be substituted in patients allergic to aspirin. Aspirin and clopidogrel combination therapy is recommended for patients who are to be medically managed and those requiring coronary angiography and PCI. Antithrombin therapy should also be initiated with either UFH or a LMWH (enoxaparin or dalteparin); enoxaparin is specifically recommended over UFH. Glycoprotein IIb/IIIa inhibitors are recommended (together with aspirin and heparin) for patients who require PCI. Tirofiban and eptifibatide can additionally be used for management of high-risk patients not scheduled for PCI.

Monitoring Antithrombotic Therapy Efficacy Monitoring Patients with successful restoration of coronary artery blood flow should demonstrate resolution of chest discomfort and ECG S24

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changes. In patients treated with thrombolytics, 70% or more STsegment resolution at 90 minutes after the start of treatment correlates well with angiographic patency and with clinical outcome.45 The target aPTT for a patient receiving UFH is approximately 1.5 to 2.5 times the control value.6,7

Bleeding Administration of any antithrombotic agent increases the likelihood of bleeding. Patients receiving these therapies should have baseline and periodic complete blood counts and should be observed for bleeding. The most frequent site of bleeding is the femoral access site if coronary angiography or PCI has been performed. Antithrombotic agents should be discontinued if bleeding results in hemodynamic compromise, such as hypotension or a significant fall in hemoglobin (more than 1 g/dL) or hematocrit. Mental status should be assessed frequently (for example, every 15 minutes during infusion and hourly for the first 12 hours after infusion) in patients receiving thrombolytics, in case of intracranial hemorrhage. If significant bleeding occurs, UFH, enoxaparin, and dalteparin may be partially reversed with protamine, and thrombolytics may be reversed with blood transfusion and cryoprecipitate.46–48

Other Adverse Reactions Patients receiving a glycoprotein IIb/IIIa receptor blocker require baseline and a follow-up platelet count 4 to 6 hours after starting the infusion. The incidence of thrombocytopenia is approximately 1% to 2% with eptifibatide or tirofiban and up to 5% with abciximab.49 Diarrhea and rash are the most frequent adverse effects of clopidogrel; thrombocytopenia has been reported on rare occasions.50 Diarrhea and rash are often not noted until after hospital discharge. The most serious adverse effect of heparin therapy is heparininduced thrombocytopenia, which occurs in 1% to 3% of patients receiving UFH and in less than 1% of patients receiving LMWHs.51 This is an immune-mediated, prothrombotic effect, which may result in death, arterial or venous thromboembolism, and perhaps limb amputation. Anticoagulant therapy should be used for only a short period of time—perhaps only the first 48 hours of ACS or until PCI is performed. Platelet count should be monitored every 3 days during heparin administration.52

Conclusion An increasing number of therapies are available for ACS. Patients with STE ACS may receive primary PCI where possible, and thrombolytic therapy may be appropriate. Aspirin decreases mortality, while clopidogrel is recommended for patients allergic to aspirin. Early studies of anticoagulants such as enoxaparin showed benefits on clinical endpoints, but the issue of possible www.japha.org

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bleeding when used with thrombolytics is being examined closely in ongoing trials. Combination antiplatelet therapies such as abciximab and eptifibatide or clopidogrel with thrombolytic therapy are still under study. In patients with NSTE ACS, aspirin and clopidogrel therapy is also recommended. Studies indicate the benefits of combinations of a glycoprotein IIb/IIIa inhibitor with intracoronary stenting or balloon angioplasty, and the combination of aspirin and clopidogrel reduces complications in these patients. Enoxaparin is recommended in preference to UFH in NSTE ACS patients.

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tor with tirofiban in unstable angina and non–Q-wave myocardial infarction. N Engl J Med. 1998;338:1488–97. 36. PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med. 1998;339:436–43. 37. Klein W, Buchwald A, Hillis SE, et al. Comparison of low-molecularweight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease: Fragmin in unstable coronary artery disease (FRIC). Circulation. 1997;96:61–8. 38. Goodman SG, Cohen M, Bigonzi F, et al. Randomized trial of low molecular weight heparin (enoxaparin) versus unfractionated heparin for unstable coronary artery disease: one year results from the ESSENCE study. J Am Coll Cardiol. 2000;36:693–8. 39. Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non–Q-wave myocardial infarction: results of the thrombolysis in myocardial infarction (TIMI) IIB trial. Circulation. 1999;100:1593–601. 40. Antman EM, Cohen M, Radley D, et al. Assessment of the treatment effect of enoxaparin for unstable angina/non–Q-wave myocardial infarction: TIMI IIB-ESSENCE meta-analysis. Circulation. 1999;100:1602–8. 41. Steinhubl SR, Berger PB, Mann JT, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288:2411–20. 42. Kastrati A, Mehilli J, Schühlen H, et al. A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med. 2004;350:232–8. 43. EPISTENT Investigators. Randomized placebo-controlled and balloon angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein IIb/IIIa blockade. Lancet. 1998;352:87–92. 44. Topol EJ, Moliterno DJ, Herrmenn HC, et al. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization. N Engl J Med. 2001;344:1888–94. 45. Anderson RD, White HD, Ohman EM, et al. Predicting outcome after thrombolysis in acute myocardial infarction according to ST-segment resolution at 90 minutes: substudy of the GUSTO-III trial. Global Use of Strategies To Open occluded coronary arteries. Am Heart J. 2002;144:81–8.

CE Credit

CE Credit

To obtain 1.5 contact hours of continuing education credit (0.15 CEUs) for completing “Antithrombotic Therapy for Acute Coronary Syndromes,” complete the assessment exercise and CE registration form and return them to APhA. A statement of credit will be awarded to respondents achieving a grade of 70% or better. APhA continuing education policy provides you with two opportunities to successfully complete this continuing education examination. Please note that you will not be permitted to submit the examination a third time. Individuals completing this exercise successfully by February 24, 2007, can receive credit.

®

The American Pharmacists Association is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. The ACPE Universal Program Number assigned to this program by the accredited provider is: 202-000-04-148-H01.

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46. Agnelli G, Sonaglia F. Perspectives on antithrombotic agents: from unfractionated heparin to new antithrombotics. Haematologica. 2002;87:757–70. 47. Levy JH. Pharmacologic preservation of the hemostatic system during cardiac surgery. Ann Thorac Surg. 2001;72(suppl):S1814–20. 48. Douketis JD. Perioperative anticoagulation management in patients who are receiving oral anticoagulation therapy: a practical guide for clinicians. Thromb Res. 2002;108:3–13. 49. Vernon SM. Glycoprotein IIb/IIIa antagonists and low-molecular-weight heparin in acute coronary syndromes. Cardiol Clin. 2001;19:235–52. 50. Jarvis B, Simpson K. Clopidogrel: a review of its use in the prevention of atherothrombosis. Drugs. 2000;60:347–77. 51. Dager WE, White RH. Pharmacotherapy of heparin-induced thrombocytopenia. Expert Opin Pharmacother. 2003;4:919–40. 52. Moliterno DJ, Mukherjee D. Applications of monitoring platelet glycoprotein IIb/IIIa antagonism and low-molecular-weight heparins in cardiovascular medicine. Am Heart J. 2000;140(6 suppl):S136–42.

Learning Objectives

After reading this continuing education article, the pharmacist should be able to: ■ Compare and contrast the initial presentations, triage, objective findings, diagnosis, clinical management, and prognoses for patients presenting with ST-segment elevation and non–ST-segment elevation acute coronary syndromes. ■ Formulate a pharmaceutical care plan for a patient with STsegment elevation or non–ST-segment elevation acute coronary syndromes. ■ Describe the goals of therapy for ST-segment elevation acute coronary syndromes, and name at least three major drugs or drug classes used in its management. ■ Name at least two ways in which pharmacists should monitor antithrombotic therapy in patients with acute coronary syndromes, and name at least four specific monitoring parameters used to accomplish this.

Assessment Questions

Instructions: You may take the assessment test for this program on paper or online. CE answer sheets are located inside the back cover of this issue. For each question, blacken the letter on the answer sheet corresponding to the answer you select as being the correct one. There is only one correct answer to each question. Please review all your answers to be sure that you have blackened the proper spaces. To take the CE test for this article online, go to www.pharmacist.com/ education.cfm, and click on the “Get CE Now” box. Once you are on the CE welcome page, enter a keyword that describes this article in search box, and select this article from the list that appears. Follow the online instructions to take and submit the assessment test. 1.

In a patient presenting with chest pain at rest, the diagnosis of infarction is confirmed by: a. ST segment depression on the electrocardiogram. b. Changes on the electrocardiogram. c. Patient’s history, including the length and intensity of pain. d. Raised troponin levels. e. ST elevation on the electrocardiogram.

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Antithrombotic Therapy for ACS

2.

Goals of therapy for the management of ST-segment elevation include: a. Improved survival b. Prevention of complications c. Relief of pain d. Re-establishment of coronary patency e. All of the above alternatives are correct.

3.

Which of the following statements regarding percutaneous coronary intervention is false? a. Most hospitals in the United States are equipped to perform this procedure. b. Re-establishment of patency occurs immediately in most cases, especially if performed with 4 hours of symptom onset. c. Percutaneous coronary intervention is the preferred method to re-establish blood flow in ST-segment elevation myocardial infarction. d. Percutaneous coronary intervention includes balloon angioplasty and intracoronary stenting.

4.

5.

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8.

Which of the following statements is false? a. Compared with non–ST-segment elevation, ST-segment elevation is more likely to be associated with complete occlusion in multiple coronary arteries. b. Compared with non–ST-segment elevation, ST-segment elevation has a higher likelihood of developing into acute myocardial infarction. c. Compared with non–ST-segment elevation, ST-segment elevation is more likely to cause death during hospitalization. d. Compared with non–ST-segment elevation, ST-segment elevation has a better prognosis when troponin levels are elevated. Which of the following is not a contraindication or relative contraindication when thrombolytics are used in patients with ST-segment elevation or non–ST-segment elevation myocardial infarction? a. Diagnosis of severe hypertension b. Bleeding ulcer within the past 12 months c. Pregnancy d. Cerebrovascular accident within the past 6 months e. History of hemorrhagic stroke Characteristics of a plaque that is prone to rupture include all of the following except: a. Thick fibrous cap. b. Large lipid core. c. High concentration of macrophages. d. Few smooth muscle cells. Which of the following statements about antiplatelet therapy in ST-segment elevation acute coronary syndromes is (are) true? a. Patients should receive 162–325 mg of aspirin, preferably before arrival at the hospital. b. Enoxaparin is the preferred primary percutaneous coronary intervention. c. Abciximab is the most studied glycoprotein IIb/IIIa inhibitor for primary percutaneous coronary intervention. d. Alternatives a and c are both correct. e. All of the above alternatives are correct. Patients with non–ST-segment elevation acute coronary syndromes should be treated with which of the following medications? a. Beta-blockers b. Nitrates c. Antithrombin therapy d. Antiplatelet therapy e. All of the above alternatives are correct.

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9.

REVIEWS

Which of the following statements regarding low-molecularweight heparin use in non–ST-segment elevation acute coronary syndromes is false? a. All agents are administered once daily. b. Low-molecular-weight heparins have low nonspecific protein binding. c. Low-molecular-weight heparins have long half-lives. d. No laboratory monitoring is required for low-molecularweight heparins. e. National guidelines recommend enoxaparin over unfractionated heparin.

10. Which of the following statements regarding monitoring of patients receiving antithrombotic therapy is false? a. In patients who have had percutaneous coronary intervention, the most common site of bleeding is the femoral access site. b. Patients should have baseline and periodic blood counts. c. Antithrombotic agents should be discontinued if there is a significant fall in hemoglobin or hematocrit. d. Mental status does not need to be routinely monitored in patients receiving antithrombotic therapy. e. If significant bleeding occurs, unfractionated heparin and enoxaparin can be reversed with protamine. 11. Which of the following strategies for patients with non–ST-segment elevation acute coronary syndromes is recommended for high-risk patients? a. A “watchful waiting” strategy in which only patients with symptoms refractory to medications undergo angiography and percutaneous coronary intervention. b. An "aggressive strategy" in which most patients undergo angiography and percutaneous coronary intervention. c. A strategy in which only patients with documented myocardial infarction undergo angiography and percutaneous coronary intervention. d. A strategy in which all patients are medically stabilized and proceed to angiography and percutaneous coronary intervention following a positive stress test for ischemia. 12. In a patient with suspected myocardial infarction, which of the following aspirin products should be administered when possible before arrival at the hospital? a. Two enteric-coated aspirin tablets 325 mg b. One non–enteric-coated aspirin tablet 81 mg c. Two non–enteric-coated aspirin tablets 81 mg d. One enteric-coated aspirin tablet 325 mg e. Two non–enteric-coated aspirin tablets 325 mg 13. Which of the following agents should be substituted during the inhospital care of patients with non–ST-segment elevation acute coronary syndromes who are allergic to aspirin? a. Eptifibatide b. Acetaminophen c. Ibuprofen d. Rofecoxib e. Clopidogrel 14. The use of low-molecular-weight heparins during percutaneous coronary interventions is best described as: a. An accepted part of standard care. b. Beneficial but not yet accepted. c. Controversial. d. Of doubtful benefit. e. Contraindicated. 15. Which of the following is a common adverse effect of clopidogrel? a. Thrombocytopenia b. Rash c. Diarrhea d. Alternatives b and c are both correct.

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