Unstable and Non–ST-Segment Elevation Myocardial : Part I. Initial Evaluation and Management, and Hospital Care STEPHEN D. WIVIOTT, M.D., and , M.D., in Study Group, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts

Each year, more than 1 million patients are admitted to U.S. hospitals because of and non–ST-segment elevation myocardial infarction (UA/NSTEMI). To help standardize the assessment and treatment of these patients, the American College of and the American Association convened a task force to formulate a management guideline. This guideline, which was published in 2000 and updated in 2002, highlights recent medical advances and is a practical tool to help physicians provide medical care for patients with UA/NSTEMI. Management of suspected UA/ NSTEMI has four components: initial evaluation and management; hospital care; coronary revascularization; and hos- pital discharge and post-hospital care. Part I of this two-part article discusses the first two components of management. During the initial evaluation, the history, , electrocardiogram, and cardiac are used to determine the likelihood that the patient has UA/NSTEMI and to aid in assessment when the diagnosis is estab- lished. Hospital care consists of appropriate initial triage and monitoring. Medical treatment includes anti-ischemic therapy (, , ), antiplatelet therapy (, , glycoprotein IIb/IIIa inhibitor), and antithrombotic therapy (, low-molecular-weight heparin). (Am Fam Physician 2004;70:525-32 Copyright© 2004 American Academy of Family Physicians.)

This is part I of a he term “ coronary syndrome” important for family physicians to under- two-part article on encompasses unstable angina and stand the diagnosis, risk assessment, and unstable angina and non–ST-segment eleva- non–ST-segment elevation myocar- treatment of this syndrome. tion myocardial infarction. dial infarction (UA/NSTEMI) and To help standardize the assessment and Part II, “Coronary T ST-segment elevation myocardial infarction treatment of patients with UA/NSTEMI, Revascularization, Hospital (STEMI). UA/NSTEMI is the combination of the American College of Cardiology (ACC) Discharge, and Post- Hospital Care,” appears two closely related clinical entities (i.e., a syn- and the American Heart Association (AHA) on page 535 in this issue. drome), whereas STEMI is a distinct clinical convened a task force to produce a manage- This article exem- entity. UA/NSTEMI is characterized by an ment guideline. The ACC/AHA guideline, 1 plifies the AAFP 2004 imbalance between myocardial oxygen sup- which was published in 2000 and updated Annual Clinical Focus on ply and demand. Most often, the syndrome in 2002,2,3 divides the management of sus- caring for America’s aging develops because of decreased myocardial pected UA/NSTEMI into four components: population. resulting from coronary narrowing initial evaluation and management; hos- See page 425 for caused by nonocclusive formation pital care; coronary revascularization; and definitions of strength-of- subsequent to disruption of an atheroscle- hospital discharge and post-hospital care. recommendation labels. rotic plaque. In contrast, STEMI results from This two-part article focuses on the major an occlusive thrombus. management recommendations in the Each year, more than 5 million patients guideline, using the ACC/AHA classifica- present to U.S. emergency departments with tion of recommendations (Table 1).3 Recent chest and related symptoms.1 Approxi- advances in management are highlighted. mately 1.4 million of these patients are Part I reviews the first two components of admitted for management of UA/NSTEMI.1 management, and part II4 reviews the other Because of the scope of the problem, it is two components.

August 1, 2004 � Volume 70, Number 3 www.aafp.org/afp American Family Physician 525 Initial Evaluation and Management TABLE 1 Two important issues arise in the initial evaluation of the ACC/AHA Classification of Evidence Used patient with a suspected : the in the UA/NSTEMI Guideline likelihood that the clinical presentation represents an acute coronary syndrome (Table 2)3,5 and the risk of adverse out- Class I: conditions for which there is evidence or general 3,5 agreement that a given procedure or treatment is useful comes (Table 3). The initial clinical evaluation to address and effective both issues should include a history, a physical examination, an electrocardiogram, and a cardiac measure- Class II: conditions for which there is conflicting evidence or a divergence of opinion about the usefulness or efficacy ment (a cardiac-specific level [preferred in the 2,3 of a procedure or treatment ACC/AHA guideline ] or an MB isoenzyme of level). Data from this evaluation aid in the assess- Class IIa: weight of evidence or opinion favors usefulness or efficacy ment of risk and in decisions about the required intensity of monitoring ( versus “step-down” unit), Class IIb: usefulness or efficacy is less well established by choice of therapeutic agents, and use of cardiac catheteriza- evidence or opinion tion and revascularization. Class III: conditions for which there is evidence or general agreement that a given procedure or treatment is not RISK PREDICTION RULE useful or effective, and in some cases may be harmful The 2002 ACC/AHA guideline2,3 includes the use of a risk prediction rule for early assessment. Multiple risk scores ACC = American College of Cardiology; AHA = American Heart Asso- ciation; UA/NSTEMI = unstable angina and non–ST-segment elevation have been developed to predict the likelihood of adverse myocardial infarction. Information from reference 3. outcomes in patients presenting with UA/NSTEMI.6-8 One example is the seven-point Thrombolysis in Myo-

TABLE 2 Likelihood of Acute Coronary Syndrome Secondary to Coronary Based on Clinical Features

Likelihood of acute coronary syndrome based on clinical features

Area of assessment High Intermediate Low

Symptoms Chest or left arm pain or discomfort Chest or left arm pain Symptoms with features reproducing previously documented or discomfort other than those angina indicating intermediate or high likelihood History Known history of Patient age > 70 years, male sex, Recent use or myocardial infarction mellitus Physical examination Transient mitral regurgitation, , Manifestations of extracardiac reproduced diaphoresis, rales by palpation ECG New transient ST-segment deviation or Q waves; abnormal ST segments Normal ECG T-wave inversions with symptoms or T waves not documented to be new Cardiac biomarkers Elevated cardiac-specific troponin level or Cardiac biomarker Cardiac biomarker elevated MB isoenzyme of creatine levels not elevated levels not elevated kinase level

ECG = electrocardiogram. Adapted with permission from ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). Accessed online May 11, 2004, at: http://www.americanheart.org/presenter.jhtml?identifier=300 1260, and Braunwald E. Unstable angina: diagnosis and management. Rockville, Md.: U.S. Dept. of Health and Human Services, Service, Agency for Policy and Research, National Heart, , and Institute, 1994; clinical practice guideline no. 10; AHCPR publication no. 94-0602.

526 American Family Physician www.aafp.org/afp Volume 70, Number 3 � August 1, 2004 UA/NSTEMI

TABLE 3 Clinical Features Associated with Risk of Death or Nonfatal Myocardial Infarction in Patients with Unstable Angina

Risk of death or nonfatal myocardial infarction based on clinical features

Area of assessment High* Intermediate† Low

History Accelerating tempo of ischemic Previous myocardial infarction, — symptoms in preceding 48 hours peripheral vascular disease, , coronary artery bypass grafting, or aspirin use Character of pain Prolonged, ongoing (> 20 minutes) Prolonged angina at rest (> 20 New-onset or progressive angina at rest minutes), now resolved anginal symptoms, not Angina at rest (< 20 minutes) or occurring at rest relieved with rest or sublingual nitroglycerin Clinical findings Ischemic , new or Patient age > 70 years —

worsening mitral regurgitation, S3 gallop, hypotension, , , patient age > 75 years ECG Angina at rest, with new transient T-wave inversions, Normal ECG, or no ST-segment deviation; bundle- Q waves changes in ECG during branch block or sustained ventricular pain episode tachycardia Cardiac biomarker Cardiac-specific troponin level elevated Cardiac-specific troponin level Cardiac-specific troponin above “ limit” elevated but below “necrosis limit” level not elevated

ECG = electrocardiogram. *—Risk is high if at least one clinical feature is present †—Risk is intermediate if at least one clinical feature in the column is present and no high-risk clinical features are present. Adapted with permission from ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). Accessed online May 11, 2004, at: http://www.americanheart.org/presenter.jhtml?identifier=300 1260, and Braunwald E. Unstable angina: diagnosis and management. Rockville, Md.: U.S. Dept. of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, National Heart, Lung, and Blood Institute, 1994; clinical practice guideline no. 10; AHCPR publication no. 94-0602.

cardial Infarction (TIMI) risk score for UA/NSTEMI higher risk scores have been shown to derive greater ben- (Figure 1).6 efit from specific pharmacologic therapies (enoxaparin The TIMI risk score integrates historical factors, [Lovenox],6 platelet glycoprotein IIb/IIIa inhibitor9) and frequency of symptoms, electrocardiographic findings, an early (invasive) strategy.10 and cardiac biomarker levels.6 Higher scores are associ- ated with an increased risk of adverse outcomes such as BIOMARKERS death, (re)infarction, or recurrent requiring Recent studies have examined the role of nontraditional revascularization. The risk of these outcomes ranges biomarkers in the risk stratification of patients with acute from approximately 5 percent with a TIMI risk score coronary syndrome. High-sensitivity C-reactive protein of zero or one point to approximately 41 percent with a (hs-CRP), a marker of inflammation, has been shown risk score of six or seven points. The risk score may be to provide prognostic information in patients with acute used to help guide therapeutic decisions. Patients with coronary syndromes, independent of clinical factors and

August 1, 2004 � Volume 70, Number 3 www.aafp.org/afp American Family Physician 527 TIMI Risk Score for UA/NSTEMI TABLE 4 High-Risk Indicators Favoring an Early Invasive Strategy in Patients with UA/NSTEMI

Recurrent angina or ischemia at rest or with low-level activity, despite intensive anti-ischemic therapy Elevated cardiac-specific troponin level ( or T) New or presumably new ST-segment depression Recurrent angina or ischemia with symptoms of congestive

, an S3 gallop, pulmonary edema, worsening rales, or new or worsening mitral regurgitation High-risk findings on noninvasive testing Depressed left ventricular function (e.g., < 40% on noninvasive study) Hemodynamic instability Sustained Percutaneous coronary intervention within previous six months Previous coronary artery bypass grafting

UA/NSTEMI = unstable angina and non–ST-segment elevation myo- cardial infarction. Figure 1. Information from reference 3.

monitoring for and recurrent ischemia. Patients with high-risk indicators, such as recurrent pain or hemodynamic disturbance (Table 4),3 should be traditional markers of necrosis.11-13 B-type natriuretic admitted to a coronary care or intensive care unit capable peptide (BNP) has been associated with heart failure, as of more extensive monitoring. Therapy should include well as adverse clinical outcomes (predominantly mor- anti-ischemic, antiplatelet, and antithrombotic agents, as tality), in patients with acute coronary syndromes.14 The well as a care plan that includes consideration of an early study findings11-14 suggest that future risk stratification invasive strategy (Figure 2).3 in patients with acute coronary syndrome may involve a panel of biomarkers. ANTI-ISCHEMIC THERAPY One investigative team15 has proposed a simplified ACC/AHA class I anti-ischemic interventions include method of combining the information provided by bio- supplemental oxygen, sublingually or intravenously markers. From zero to three points are assigned, depending administered nitroglycerin for relief of recurrent isch- on the number of elevated biomarkers (cardiac-specific tro- emia and associated symptoms and, in the absence of ponin, hs-CRP, BNP). The risk of death, recurrent myocar- contraindications, an intravenously administered beta dial infarction, or congestive heart failure has been found to blocker for management of ongoing chest pain followed be 4.5 times higher when all three biomarkers are elevated by an orally administered beta blocker.2,3 Beta block- than when no biomarker is elevated.15 However, more data ers should be used cautiously in patients with marked are needed before use of hs-CRP and BNP can be recom- first-degree , second- and third- mended for risk stratification in UA/NSTEMI. degree atrioventricular block without a pacemaker, , severe left ventricular dysfunction with con- Hospital Care gestive heart failure, significant chronic obstructive Patients with UA/NSTEMI should be admitted to an pulmonary disease, and significant inpatient unit, where they should undergo continuous or hypotension.2,3

528 American Family Physician www.aafp.org/afp Volume 70, Number 3 � August 1, 2004 UA/NSTEMI

Evaluation and Management of a Patient with Probable ACS

Patient has high likelihood of ACS (see Table 2).

Administer aspirin, clopidogrel (Plavix),* beta blocker, nitrates, heparin (or low-molecular-weight heparin), platelet glycoprotein IIb/IIIa inhibitor.† Inpatient monitoring

High-risk indicators present (see Table 4) High-risk indicators absent (see Table 4)

Early invasive strategy Early conservative strategy

Angiography Recurrent ischemia, congestive heart Clinically stable failure,

Not low risk Noninvasive stress testing

Low risk

Medical therapy

*—Clopidogrel may be administered at the time of in patients with a planned early invasive strategy. †—Platelet glycoprotein IIb/IIIa inhibitors are given an ACC/AHA class I indication (see Table 1) in patients for whom catheterization is planned, and an ACC/AHA class IIa indication in patients who have high-risk indicators, such as an elevated cardiac-specific troponin level or ST-segment deviation (see Table 4), and in whom a conservative strategy is planned.

Figure 2. Evaluation and management of the patient with a high likelihood of having an acute coronary syndrome (ACS). (ACC = American College of Cardiology; AHA = American Heart Association)

Adapted with permission from ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). Accessed online May 11, 2004, at: http://www.americanheart.org/presenter.jhtml?identifier=3001260.

ANTIPLATELET THERAPY Clopidogrel. The updated ACC/AHA guideline2,3 rec- Three classes of antiplatelet agents have important roles ommends use of the thienopyridine clopidogrel (Plavix) in the management of UA/NSTEMI: aspirin, thienopyri- in patients who cannot tolerate aspirin17 (ACC/AHA class dines, and platelet glycoprotein IIb/IIIa inhibitors. I). Because of its safety profile (compared with ticlopidine Aspirin. A cornerstone of management in acute coro- [Ticlid]), clopidogrel currently is the preferred thienopyr- nary syndromes, aspirin has been shown to reduce car- idine.1 Clopidogrel is a potent antiplatelet agent that acts diovascular events by 50 to 70 percent.16 In the absence by irreversibly blocking the diphosphate of known contraindications, aspirin therapy should be receptor on the platelet surface, thereby interrupting used in all patients with suspected, probable, or definite platelet activation and aggregation. acute coronary syndrome. One of the major changes in the care of patients with

August 1, 2004 � Volume 70, Number 3 www.aafp.org/afp American Family Physician 529 UA/NSTEMI has been the ACC/AHA class I indica- tional or interventional approach and are not at high tion for use of clopidogrel in addition to aspirin in risk for bleeding. Clopidogrel therapy is recommended patients with acute coronary syndromes.2,3 This change for at least one month and may be continued for up to occurred because of the findings of recent major clinical nine months. Aspirin, unless contraindicaetd, should be trials. The Clopidogrel in Unstable Angina to Prevent continued for life. When elective coronary artery bypass Recurrent Ischemic Events (CURE) trial18 randomized grafting is planned, clopidogrel should be withheld for more than 12,000 patients with UA/NSTEMI to receive five to seven days. clopidogrel or placebo in addition to aspirin. Patients Platelet Glycoprotein IIb/IIIa Inhibitors. These agents were followed for three to 12 months. In the CURE constitute a third class of antiplatelet agents that may be trial, death, myocardial infarction, or occurred used in patients hospitalized with UA/NSTEMI. Three in 9.3 percent of the patients treated with clopidogrel, agents in this class currently are available for clinical compared with 11.5 percent of those who received pla- use: abciximab (ReoPro), which is a monoclonal anti- cebo. The improvement occurred at the cost of a small, body; and (Integrelin) and (Aggra- but significant increase in bleeding (relative risk: 27 stat), which are “small molecule” glycoprotein IIb/IIIa percent), especially in patients who underwent coronary inhibitors. These potent inhibitors of platelet aggrega- artery bypass grafting within five days of discontinuing tion are administered intravenously. clopidogrel therapy. Clinical trials have shown that platelet glycopro- In an analysis of patients undergoing percutaneous tein IIb/IIIa inhibitor therapy is beneficial in selected coronary intervention (PCI-CURE study),19 patients patients with UA/NSTEMI.20 However, benefit appears were treated with clopidogrel or placebo for a median to be greater in patients for whom an early invasive of 10 days before the intervention (all patients also strategy is planned (i.e., cardiac catheterization and received aspirin). After the intervention, patients in percutaneous coronary intervention)20,21 and patients the PCI-CURE study received open-label clopidogrel or who have elevated cardiac-specific troponin levels22 or ticlopidine for four weeks, followed by the initial study other high-risk indicators such as an elevated TIMI risk drug (clopidogrel or placebo) for an average of eight score9 or diabetes mellitus.23 In patients for whom an months. The clopidogrel-treated patients had fewer early early invasive strategy is not planned, the Global Utiliza- (30-day) and long-term cardiovascular events. tion of Strategies to Open Occluded Coronary As a result of the study findings, the 2002 ACC/AHA IV–Acute Coronary Syndromes (GUSTO IV-ACS) ran- guideline2,3 considers the use of clopidogrel in addition domized trial24 showed no benefit for abciximab com- to aspirin to have a class I indication in patients with pared with placebo. As a result of the GUSTO IV-ACS UA/NSTEMI who are undergoing an early noninterven- study findings, use of abciximab is contraindicated in patients for whom an early invasive strategy is not planned (ACC/AHA class III). The Authors Based on the combined study findings,20-23,25 platelet STEPHEN D. WIVIOTT, M.D., is an instructor of medicine at Harvard glycoprotein IIb/IIIa inhibitors have an ACC/AHA Medical School, Boston, an investigator with the Thrombolysis in class I indication in patients for whom catheterization Myocardial Infarction (TIMI) Study Group, and a member of the and percutaneous coronary intervention are planned. cardiovascular division at Brigham and Women’s Hospital, Boston. After graduating from Harvard Medical School, Dr. Wiviott com- These agents should be administered in addition to pleted a medical residency and served as chief medical resident at aspirin and heparin. An ACC/AHA class IIa recom- Brigham and Women’s Hospital. He also completed a cardiology mendation is given to the use of eptifibatide or tiro- fellowship at Johns Hopkins Hospital, Baltimore. fiban in addition to aspirin and heparin in patients EUGENE BRAUNWALD, M.D., is the Distinguished Hersey Professor with continuing ischemia, elevated cardiac-specific of Medicine at Harvard Medical School and chair of the TIMI Study troponin levels, or other high-risk features for whom Group at Brigham and Women’s Hospital. Dr. Braunwald also chairs an invasive strategy is not planned. the American College of Cardiology/American Heart Association Guidelines Committee for Unstable Angina and Non–ST-Segment ANTITHROMBOTIC THERAPY Elevation Myocardial Infarction. He is editor-in-chief of Harrison’s Principles of Internal Medicine and Heart Disease. The final component of medical therapy to consider in patients with UA/NSTEMI is antithrombotic/antico- Address correspondence to Stephen D. Wiviott, M.D., TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, agulant therapy. Unfractionated heparin results in anti- 75 Francis St., Boston, MA 02115 (e-mail: [email protected]). by facilitating the action of antithrombin Reprints are not available from the authors. which, in turn, inactivates factor IIa (thrombin), factor

530 American Family Physician www.aafp.org/afp Volume 70, Number 3 � August 1, 2004 UA/NSTEMI

Strength of Recommendations

SOR Key clinical recommendation labels References The updated ACC/AHA guideline recommends use of the thienopyridine clopidogrel (Plavix) in A 2, 3, 17 patients who cannot tolerate aspirin (ACC/AHA class I). The updated ACC/AHA guideline considers the use of clopidogrel in addition to aspirin to have a A 2, 3, 18,19 class I indication in patients with UA/NSTEMI who are undergoing an early noninterventional or interventional approach and are not at high risk for bleeding. When elective coronary artery bypass grafting is planned, clopidogrel should be withheld for five C 2, 3 to seven days. Platelet glycoprotein IIb/IIIa inhibitors have an ACC/AHA class I indication in patients for whom A 20-23, 25 catheterization and percutaneous coronary intervention are planned. These agents should be administered in addition to aspirin and heparin. Anticoagulation with unfractionated heparin or low-molecular-weight heparin for patients with A 27 UA/NSTEMI has an ACC/AHA class I indication. The heparin is to be used in addition to aspirin or clopidogrel.

ACC = American College of Cardiology; AHA = American Heart Association; UA/NSTEMI = unstable angina and non–ST-segment elevation myo- cardial infarction.

IXa, and factor Xa. Treatment with unfractionated hep- This article is one in a series developed in collaboration with the American arin has been shown to be superior to aspirin therapy Heart Association. Guest editor of the series is Sidney C. Smith, Jr., M.D., Chief Science Officer, American Heart Association, Dallas. alone in patients with UA/NSTEMI.26 Low-molecular- weight (LMW) heparin (e.g., enoxaparin) is obtained The authors indicate that they do not have any conflicts of interest. through cleavage of heparin to provide chains with Sources of funding: none reported. different molecular weights. Compared with unfrac- tionated heparin, the LMW are relatively more REFERENCES potent inhibitors of factor Xa. LMW heparins also have 1. Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hoch- a more predictable pharmacology, which means that man JS, et al. ACC/AHA guidelines for the management of patients laboratory monitoring of anticoagulation status is not with unstable angina and non-ST-segment elevation myocardial infarc- 26 tion. A report of the American College of Cardiology/American Heart needed. Anticoagulation with unfractionated heparin Association Task Force on Practice Guidelines (Committee on the 27 or LMW heparin has an ACC/AHA class I indication. Management of Patients with Unstable Angina) [published correc- One of these agents is to be used in addition to aspirin tion appears in J Am Coll Cardiol 2001;38:294-5]. J Am Coll Cardiol or clopidogrel. 2000;36:970-1062. 28 2. Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hoch- Recent trial data have shown superior results with man JS, et al. ACC/AHA guideline update for the management of the use of enoxaparin compared with unfractionated patients with unstable angina and non-ST-segment elevation myocar- heparin in patients with UA/NSTEMI. Consequently, dial infarction—2002: summary article: a report of the American Col- 2,3 lege of Cardiology/American Heart Association Task Force on Practice the guideline indicates a ACC/AHA class IIa rec- Guidelines (Committee on the Management of Patients with Unstable ommendation for the use of enoxaparin, rather than Angina). Circulation 2002;106:1893-1900. unfractionated heparin, in patients with UA/NSTEMI. 3. ACC/AHA 2002 guideline update for the management of patients with Although data are not conclusive, recent trials have unstable angina and non-ST-segment elevation myocardial infarction. A report of the American College of Cardiology/American Heart Associa- shown that LMW heparin is safe to use in combination tion Task Force on Practice Guidelines (Committee on the Management with glycoprotein IIb/IIIa inhibitors29,30 and in percuta- of Patients with Unstable Angina). Accessed online May 11, 2004, at: neous coronary intervention.31-33 http://www.americanheart.org/presenter.jhtml?identifier=3001260. 4. Wiviott SD, Braunwald E. Unstable angina and non-ST-segment-eleva- Despite the role of in UA/NSTEMI, throm- tion myocardial infarction: part II. Coronary revascularization, hospital bolytic agents have not been shown to provide benefit discharge, and post-hospital care. Am Fam Physician 2004;70:535-8. in patients with UA/NSTEMI; in fact, there is a trend 5. Braunwald E. Unstable angina: diagnosis and management. Rockville, toward worse outcomes.34-36 Consequently, thrombo- Md.: U.S. Dept. of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, National Heart, Lung, and lytic agents are contraindicated for use in the treatment Blood Institute, 1994; clinical practice guideline no. 10; AHCPR publica- of patients who have UA/NSTEMI. tion no. 94-0602.

August 1, 2004 � Volume 70, Number 3 www.aafp.org/afp American Family Physician 531 UA/NSTEMI

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532 American Family Physician www.aafp.org/afp Volume 70, Number 3 � August 1, 2004