Chapter  10:  Unstable Angina: Diagnosis and Management: Clinical Practice Guideline Number 10

Project Oversight

• Robert H. Jones, MD

• Project Director Mary and Deryl Hart

• Professor of Surgery

• Daniel B. Mark, MD, MPH

• Project Co-Director

• Author/Editor

• Associate Professor Division of Cardiology

• Nancy Archibald, MHA, MBA

• Project Manager

• Vanessa Moore

• Staff Assistant

Statistical Analysis

• L. Richard Smith, PhD

• Biostatistician

• Assistant Professor Division of Experimental Surgery

• Karen Kesler, MS

• Biostatistician

Consultants

• Robert M. Califf, MD

• Associate Professor Division of Cardiology

• Director, Cardiac Care Unit

• David B. Pryor, MD

• Associate Professor Division of Cardiology

Literature Review

• David B. Matchar, MD

• Methodologist

• Associate Professor

• Director,

• Center for Health Policy Research and Education

• Robert H. Sprinkle, MD, PhD

• Assistant Professor

• Literature Review Manager

• Center for Health Policy Research and Education

• Victor Hasselblad, PhD

• Statistician/Meta-analyst

• Associate Professor

• Center for Health Policy Research and Education

• Leslee Shaw, PhD

• Reviewer

• John S. Pauk, MD, MPH

• Reviewer

• Dean D. Blakeley, MD

• Reviewer

Computer Support

• Donald F. Fortin, MD

• Medical Consultant

• Assistant Professor Division of Cardiology

• Director, Cardiac Imaging Center

• J. Douglass Hanemann

• Technical Consultant

Patient Counseling

The panel recommends informing and involving the patient and his or her family or advocate in all important care decisions. Sufficient information describing diagnosis, prognosis, and treatment options should be given to patients to permit them to choose care alternatives they prefer.

Initial Evaluation and Treatment of Patients with Unstable Angina

Because the diagnosis of unstable angina can be quite difficult, initial evaluation of patients with symptoms consistent with ischemic pain should usually take place in a medical facility with the capability of performing an ECG and not over the telephone. In general, patients with ongoing pain should be evaluated initially in an emergency department (ED) with the capability of providing ECG monitoring, advanced cardiac life support (ACLS), intravenous (IV) pharmacologic therapy, and radiographic examinations. Patients without ongoing pain may be evaluated initially in outpatient facilities with diagnostic capabilities but without support necessary to treat the acutely unstable patient. The objective of the initial evaluation is to assess diagnostic probabilities and evaluate the short-term risk of death and other major complications. The results of this evaluation will set the pace of further care and form the basis of the working diagnosis. The two goals of initial management of patients with unstable angina are to institute immediate therapy and move the patient to a proper environment for the monitoring of complications. In many cases, stabilization progresses concurrently with patient evaluation.

Initial evaluation should be complete and treatment begun within an hour of presentation to the ED. All patients with unstable angina should receive aspirin (ASA) unless they have documented hypersensitivity or active bleeding. Those with persistent symptoms or ECG changes suggesting ongoing ischemia should also receive nitroglycerin (NTG). Beta blockers and IV heparin are indicated for patients with intermediate- and high-risk unstable angina who do not have contraindications to these drugs. Unless patients have a compelling history for acute MI accompanied by ST-segment elevation or left bundle branch block (LBBB) on the 12-lead ECG, IV thrombolytic therapy is not indicated.

Patients with unstable angina and high-risk features with persistent ischemia or hemodynamic instability should be admitted to an intensive care unit (ICU). Patients at intermediate risk may be admitted to an ICU, intermediate care unit, or other cardiac care environment. All high-risk patients and many intermediate-risk patients should have serial cardiac enzymes and ECGs to exclude the possibility of acute MI. Low-risk patients can be further evaluated and managed as outpatients. Patients with acute MI with indications for thrombolytic or other reperfusion therapy, patients with stable angina, and patients considered not to have CAD are excluded from this guideline at the conclusion of initial evaluation.

Outpatient Care

Patients judged to be at low risk when initially seen who, therefore, are not admitted to a medical facility, should have a thorough evaluation scheduled within 72 hours if a definitive evaluation cannot be completed at the time of initial presentation. At the time of subsequent evaluation, attention is directed toward further assessing the cause of the patient's symptoms, evaluating the risk of future adverse cardiac events, and providing adequate symptom relief.

Patients considered not to have CAD after this evaluation should be reassured that their symptoms are very unlikely to be due to CAD and should be evaluated appropriately to determine the cause of the symptoms. The care of patients thought to have CAD should match the severity of the process. Most patients will require some pharmacologic therapy to relieve symptoms. In addition, exercise or pharmacologic stress testing will usually be a part of this detailed workup. All patients should receive information on the modification of CAD risk factors.

Intensive Medical Management

Patients considered to have ongoing manifestations of unstable angina should receive intensive medical management. The goals of this phase of care are to relieve pain and ischemia and to prevent the progression of the underlying disease process to MI or death. ASA, heparin, nitrates, and beta blockers begun at the time of initial evaluation should be titrated to a dosage adequate to relieve ischemia but avoid hemodynamic compromise. Morphine sulfate may be necessary to help relieve severe anginal symptoms that have not resolved with initial therapy. Calcium channel blockers should not be used as initial therapy but can be added to the regimen of patients who are unable to tolerate nitrates or beta blockers or in whom these agents were not effective. Calcium channel blockers should not be given to patients with pulmonary edema or evidence of LV dysfunction. Aggressive medical management can control the presenting symptoms of most patients with unstable angina.

Careful monitoring of patients for recurrent ischemia should continue after the desired level of medical therapy has been reached. The presence of recurrent symptoms may indicate a need for a more intensive medical regimen or triage to early cardiac catheterization and revascularization. Unless complications of ischemia are noted, an optimal medical regimen should be pursued for >=24 hours before declaring it a failure. However, to use this time as an absolute requirement in the case of every patient would be inappropriate or even dangerous. Generally, if anginal symptoms persist for >1 hour after aggressive medical therapy, which includes ASA, heparin, IV nitrates, and beta blockers, the patient should be reevaluated more comprehensively to be sure there are no unaddressed precipitating factors, reconsider the possibility of noncoronary diseases that may mimic unstable angina, and reaffirm that the most appropriate diagnosis remains unstable angina and not acute MI or other more serious illness.

Progression to Nonintensive Medical Management

Patients with high- or intermediate-risk unstable angina whose symptoms have been controlled for 24 hours with intensive medical management will have progressed to a lower risk phase and are appropriate for nonintensive medical management. Patients with intermediate or low risk may be admitted directly into this phase after initial evaluation in the ED. During nonintensive medical management, the emphasis shifts from acute stabilization to the design of a maintenance medical regimen that will suppress reactivation of acute disease activity. Failure of therapy at this phase of care is indicated by recurrent angina refractory to treatment for >20 minutes or recurring more than once on nonparenteral medication. These patients are expected to return to intensive medical management. Other objectives of care often include optimization of the therapeutic regimen and noninvasive testing for risk stratification.

Noninvasive Testing

Important management decisions in patients with unstable angina revolve around ongoing risk stratification. In some patients the early clinical course will be characterized by recurrent ECG-documented ischemia. In other patients further evaluation will suggest that the initial diagnosis of unstable angina may have been incorrect. These patients, who are recognized by clinical presentation to have such a high or low probability of high-risk CAD that further risk stratification by noninvasive testing would not alter management, and patients whose other comorbid conditions make stress testing unnecessary or inappropriate have no need to undergo noninvasive testing. Unless cardiac catheterization is indicated, all other patients hospitalized for unstable angina should undergo noninvasive testing after stabilization has been achieved and prior to discharge or as soon as possible thereafter. In this context, noninvasive testing is most useful to assess the adequacy of current therapy, estimate prognosis, and guide decisions on further evaluation and management.

Cardiac Catheterization and Myocardial Revascularization

Common indications for cardiac catheterization in patients with unstable angina include: (1) failure to stabilize with adequate medical therapy; (2) recurrent unstable angina; (3) high-risk result of noninvasive test; (4) prior revascularization procedure; and (5) diagnosis or exclusion of significant CAD in patients with multiple clinical episodes of unstable angina without objective documentation of ischemia. Individual patient characteristics and preferences should temper application of these general indications to specific clinical situations.

The goal of cardiac catheterization in patients with unstable angina is to provide detailed structural information necessary to assess prognosis and select an appropriate long-term management strategy. The procedure is usually helpful in choosing between medical therapy, percutaneous transluminal coronary angioplasty (PTCA), or coronary artery bypass graft (CABG) surgery in patients with unstable angina who remain at significant risk for future cardiac events. Patients with extensive comorbidity felt not to be suitable for revascularization and patients who do not wish to consider interventional therapy should not undergo diagnostic catheterization.

Patients found at catheterization to have significant left main disease (>=50%) or significant (>=70%) three-vessel disease with depressed LV function (EF <=0.50) should undergo CABG to improve survival as well as relieve symptoms. Patients with two- or three-vessel disease with proximal severe subtotal stenosis (>=95%) of the left anterior descending coronary artery (LAD) may also experience a survival benefit from revascularization. Other patients are appropriately treated for control of anginal symptoms by CABG, PTCA, or medical therapy.

Hospital Discharge and Postdischarge Care

Patients responding to intensive and nonintensive medical therapy and patients undergoing CABG or PTCA during their admission should be instructed on appropriate activities after hospital discharge. Discharge plans should include provisions for clinical followup and risk-factor modification. Continued long-term management of the patient with unstable angina should include ASA therapy indefinitely unless contraindicated. Patients who have stable symptoms at followup may be managed as if they have stable angina.

Definition of Unstable Angina

Table 1. Three principal presentations of unstable (more...)

Table 1. Three principal presentations of unstable angina

Rest angina	Angina occurring at rest and usually prolonged > 20 minutes occurring within a week of presentation.
New onset angina	Angina of at least CCSC III severity with onset within 2 months of initial presentation.
Increasing angina	Previously diagnosed angina that is distinctly more frequent, longer in duration, or lower in threshold (i.e., increased by at least one CCSC class within 2 months of initial presentation to at least CCSC III severity).

Note: CCSC = Canadian Cardiovascular Society classification.

Table 2. Grading of angina pectoris by the Canadian (more...)

Table 2. Grading of angina pectoris by the Canadian Cardiovascular Society classification system

Class	Description of stage
Class I	Ordinary physical activity does not cause angina, such as walking, climbing stairs. Angina [occurs] with strenuous, rapid, or prolonged exertion at work or recreation.
Class II	Slight limitation of ordinary activity. Angina occurs on walking or climbing stairs rapidly, walking uphill, walking or stair climbing after meals, or in cold, or in wind, or under emotional stress, or only during the few hours after awakening. Walking more than two blocks on the level and climbing more than one flight of ordinary stairs at a normal pace and in normal condition.
Class III	Marked limitations of ordinary physical activity. Angina occurs on walking one to two blocks on the level and climbing one flight of stairs in normal conditions and at a normal pace.
Class IV	Inability to carry on any physical activity without discomfort -- angina symptoms may be present at rest.

Source: Campeau L. Grading of angina pectoris [letter]. Circulation, 54:522-523, 1976. Copyright 1976, American Heart Association, Inc. Used with permission.

Definition of Care Environments

Table 3. Definition of unstable angina care environments (more...)

Table 3. Definition of unstable angina care environments

Emergency Department (ED)
To be considered an adequate ED for patients with unstable angina, a hospital or clinic entry point or emergency chest pain center should be continuously staffed by personnel competent in performing an ECG, initial evaluation and treatment of patients with unstable angina, cardiac monitoring, and advanced cardiac life support (ACLS). Such a facility should be able to provide routine laboratory testing and radiographic studies. In remote regions of the country, where continuous availability of trained personnel is not feasible, arrangement of consultation linkages with practitioners with appropriate training using facsimile and telephone communication is recommended.
Outpatient Facility
A doctor's office, hospital associated or free-standing clinic, or other environment to be used for care of patients initially presenting with symptoms of unstable angina who are not hospitalized should have the capability to perform a 12-lead ECG and be staffed by personnel who are competent in placing a secure IV line and performing basic life support (BLS).
Intensive Care Unit (ICU)
This unit, which may also be called a coronary care unit (CCU), represents the highest level of medical intensive care available in a hospital. Typical characteristics include a nurse to patient ratio of 1:1 or 1:2; cardiac monitoring; immediate access to persons trained in ACLS; and capabilities for arterial line and pulmonary artery catheter placement, temporary pacemaker placement, and mechanical ventilation. Some, but not all, such units will have facilities for intra-aortic balloon placement. This unit can handle all forms of vasoactive continuous IV infusion. Nurses are competent in the recognition and treatment of arrhythimias and evaluation of ischemic symptoms.
Intermediate Care Unit
This unit, which may also be referred to as a cardiac monitoring or step-down unit, has a lower nurse to patient ratio, typically 1:3 to 1:5, than an ICU. It can provide continuous ECG monitoring and prompt access to personel trained in ACLS. Personnel are competent in recognition of arrhythmias and evaluation of ischemic symptoms. Patients on some forms of vasoactive drips (e.g., low dose dopamine, dobutamine, or nitroglycerin [NTG] infusion) or with a temporary pacemaker already in place may be cared for in this unit.
Standard Hospital Unit
A standard hospital unit typically has a nurse to patient ratio greater than 1:5. ECG telemetry may or may not be available, but the nurses must be competent in recognition of unstable angina and its initial management. Access to cardiac resuscitation is via a code cart on the floor and a designated code team. Nursing personnel on the floor are trained in BLS. Continuous heparin infusions may be used, but usually vasoactive drug infusions are not permitted.

Definition of Strength of Evidence Grading

Table 4. Grading of evidence

Table 4. Grading of evidence

	Strength of evidence = A	Strength of evidence = B	Strength of evidence = C
Primary evidence	Randomized controlled trials	Well designed clinical studies	Panel consensus
Secondary evidence	Other clinical studies	Clinical studies related to topic but not in an unstable angina population	Clinical studies related to topic but not in an unstable angina population

Often, the most basic patient management questions and the most well-accepted care strategies are the most difficult to test. For example, no randomized clinical trials are likely to be conducted to evaluate the importance of a medical history and physical examination in patients with unstable angina. Therefore, the strength of evidence grade does not always reflect the importance of the recommendation to patient care. The specific language used to formulate each recommendation conveys panel opinion of both the clinical importance attributed to the topic and the strength of evidence available.

Unstable Angina in the Spectrum of Coronary Artery Disease

CAD is the most important cause of death and disability in the United States. Only about 10 percent of patients with CAD have unstable angina as their initial presentation if patients who experience an MI are retrospectively excluded. However, patients with established CAD (either chronic stable angina or prior MI) commonly cycle through unstable phases. As a clinical syndrome, unstable angina shares ill-defined borders with chronic stable angina, a presentation with lower risk, and with acute MI, a presentation with higher risk. Unstable angina occurs in a variety of clinical scenarios, including in patients without known CAD, with prior stable CAD, soon after MI, and following myocardial revascularization by CABG or PTCA. Patients presenting with unstable angina may undergo any of the diagnostic and therapeutic procedures used for other CAD patients. Therefore, recommendations for the management of patients with unstable angina of necessity address questions pertinent to patients with any mode of presentation of CAD.

Despite the fact that death rates for CAD are decreasing ( Gillum and Feinleib, 1988; Feinleib, 1984), hospital discharge rates for this disorder appear to have stabilized since 1979 ( Feinleib, Havlik, Gillum et al., 1989). The number of hospitalizations for which the principal diagnosis was unstable angina (ICD-9-CM 411.1) increased from 130,000 in 1983 to 570,000 in 1991 ( Graves, 1993; National Center for Health Statistics, 1985). Nearly 60 percent of persons admitted to the hospital with unstable angina as their primary diagnosis were older than age 65, and 46 percent were women. The number of hospitalizations for unstable angina is greater for men than women in all age groups under 75 years of age. The ratio appears to reverse between the ages of 75 to 84, and more women than men are hospitalized for unstable angina over the age of 85 ( Feinleib, Havlik, Gillum et al., 1989). This reversal in hospitalizations reflects the larger representation of women than men in advanced age populations and is not due to a change in the relative incidence of CAD diagnosis in men and women in this age group.

Process of Unstable Angina

Precipitating conditions for unstable angina may be those that increase myocardial oxygen demand (e.g., physical exertion) or reduce myocardial oxygen supply (e.g., anemia, development of a platelet-rich thrombus on a fissured plaque, or spasm of an epicardial coronary artery). Unstable angina most often results from disruption of an atherosclerotic plaque and a subsequent cascade of pathologic processes that decrease coronary blood flow ( Davies and Thomas, 1984; Falk, 1989; Fuster, Badimon, Badimon et al., 1992; Sherman,Litvack, Grundfest et al., 1986). Most patients who die during unstable angina do so because of sudden death or an intervening MI. Therefore, no pathologic endpoint can be used to define unstable angina.

Unstable angina is often associated with significant angiographic progression of coronary atherosclerotic disease ( Moise, Theroux, Taeymans et al., 1984). Patients with unstable angina do have more complex lesions and more coronary thrombus on coronary arteriograms than patients with stable angina ( Ahmed, Bittl, and Braunwald, 1993). However, no coronary angiographic findings are pathognomonic of unstable angina. The disorder is often angiographically indistinguishable from non-Q-wave MI ( Ambrose, Hjemdahl-Monsen, Borrico et al., 1988; Arbustini, Grasso, Diegoli et al., 1991).

Time-Dependent Mortality Risks of Unstable Angina

Figure 1: Outcomes of 21,761 medically treated patients (more...)

   Figure 1: Outcomes of 21,761 medically treated patients at Duke University Medical Center, 1985-1992, grouped by ischemic heart disease diagnosis on admission

Source: Unpublished data, Duke Cardiovascular Databank.

(see Figure 1)

Figure 2: Outcomes of medically treated patients with (more...)

   Figure 2: Outcomes of medically treated patients with unstable angina

Source: Published data as shown in Table 5 and unpublished data, Duke Cardiovascular Databank.

Table 5. Reported mortality of unstable angina

Table 5. Reported mortality of unstable angina

Letter in Figure 2	Primary study	Definition for entry	Patients entered	Study interval	Deaths/100 patients/month
A	Clinical trial: lidocaine vs. placebo	EMT diagnoses of possible acute MI	1,427	Prehospital, presenting to paramedics	4.2
B	Multicenter Chest Pain Trial	Increasing New onset	3,465	Presenting at ED	2.6
			458	Postdischarge to approximately 2.3 years	1.0
C	Natural history of angina patients	Increasing	4,698	Presenting at ED	5.0
				ICU discharge to 1 year	0.2
D	Clinical trial: aspirin vs. heparin	Increasing ECG changes	484	First 3 days of ICU admission	2.0
E	Clinical trial: nifedipine	Rest Increasing	133	ICU admission to 2 weeks	6.0
	vs. propranolol plus nitrate			2 weeks post-admission to 6 months	0.4
F	Reaction to discontinuing heparin	Increasing New onset ECG changes	403	Day 7-11 of ICU admission	1.6
G	Prognostic significance of ECG	Rest Increasing New onset	911	ICU admission to 1 year	0.2
H	Clinical trial: propranolol vs. diltiazem	Increasing New onset ECG changes	100	Discharge to 1 month post-presentation	4.8
I	Outcome of unstable angina	Rest Increasing	196	Discharge to 4 months	0.75
J	Describe events for ICU patients	Rest Increasing No enzymes	4,698	ICU discharge to 1 year	0.5
K	Smoking outcomes	None	157	Months 2-6 postpresentation	1.0
L	Clinical trial: Enalapril vs. placebo	Ejection fraction < 35%	6,797	Screening to average of 40 months	0.5
M	Clinical trial: Antihyper-tensives vs. placebo	Age > 60 SBP > 160 DBP < 90	5,736	Screening to average of 4.5 years	0.06

Key: A: Hargarten, Aprahamian, Stueven et al., 1986; B: White, Lee, Cook et.al., 1990; C: Karlson, Herlitz, Pettersson et al., 1993; D: Theroux, Waters, Qiu et al., 1993; E: Muller, Turi, Pearle et al., 1984; F: Theroux, Waters, Lam et al., 1992; G: Nyman, Areskog, Areskog et al., 1993; H: Theroux, Taeymans, Morissette et al., 1985; I: Wilcox, Freedman, McCredie et al., 1989; J: Cairns, Singer, Gent et al., 1989; K: Daly, Mulcahy Graham et al., 1983. L: Yusef, Pepine, Garces et al., 1992; M: SHEP Cooperative Research Group, 1991.

Figure 2

Figure 1

are overlaid on the Duke data by straight lines that depict the average mortality (height of the line) over the specific time interval (the beginning and ending of the line). These data demonstrate the mortality of unstable angina to be greatest at time of hospital admission and to rapidly decline over the 2 months thereafter.

Diagnosis of Unstable Angina

In patients without a known history of CAD, consideration of the diagnosis of CAD demands assessment of whether the patient's presentation, with its constellation of specific symptoms and signs, is most consistent with CAD or with an alternative disease process.

ECG Findings Useful for Establishing the Likelihood of CAD

Careful examination of the ECG is crucial in the diagnosis of unstable angina ( Rouan, Lee, Cook et al., 1989). A recording made during an episode of the patient's presenting symptoms is particularly valuable, although an asymptomatic recording can be quite informative as well. Importantly, transient ST- or T-wave changes that develop during a symptomatic episode at rest and resolve when the patient becomes asymptomatic strongly suggest unstable angina and a very high likelihood of underlying severe CAD. Patients whose current ECG suggests acute IHD have added diagnostic accuracy if a prior ECG is available for comparison ( Lee, Cook, Weisberg et al., 1990).

Table 6. ECG findings useful for establishing the likelihood (more...)

Table 6. ECG findings useful for establishing the likelihood of coronary artery disease

Finding	Most likely cause	Alternate causes
ST-segment elevation > 1 mm in two or more contiguous leads	Acute MI	Acute pericarditis Early repolarization Left ventricular aneurysm Coronary spasm
ST-segment depression > 1 mm	Ischemia or acute MI	Normal heart Hyperventilation LV hypertrophy with strain Digitalis Hypokalemia Hypomagnesemia
Inverted T-waves in two or more contiguous leads (> 1 mm in leads with dominant R waves, or marked symmetrical precordial T-wave inversion)	Ischemia or acute MI	Normal heart Central nervous system disease Hypertrophic cardiomyopathy

ST-segment and T-wave changes are the primary elements upon which an ECG diagnosis of acute ischemia is based (see Table 6).

ST-segment elevation >=1 mm in two or more contiguous leads strongly suggests the diagnosis of acute MI and possible candidacy for reperfusion therapy. ST-segment depression typically signifies ischemia or non-Q-wave infarction. Acute reperfusion therapy is usually not indicated for patients with this finding, except for those with acute posterior infarction manifesting the most marked ST-depressions in V₁-V₃. Inverted T-waves may also indicate ischemia or non-Q-wave infarction, especially with T-waves inverted >=1 mm in leads with dominant R-waves. Marked symmetrical precordial T-wave inversion strongly suggests acute ischemia, particularly that due to a proximal LAD stenosis. Established Q-waves >=0.04 seconds are less helpful in the diagnosis of unstable angina, although they do indicate a high likelihood of significant CAD with prior MI. Isolated Q-waves in lead III may be a normal finding.

Nonspecific ST- and T-wave changes, usually defined as ST-deviation or T-wave inversion <=1 mm, are less helpful than the foregoing findings. In the Multicenter Chest Pain Study, when such findings were present, approximately one-fourth of the patients had acute IHD (predominantly unstable angina) ( Lee, Cook, Weisberg et al., 1985), but this was lower than the prevalence of such disease in the ED population overall. Thus, these nonspecific changes actually lowered the likelihood of MI and unstable angina, but not enough to reliably exclude either diagnosis. In the Multicenter Acute Ischemia Predictive Instrument Trial ( Pozen, D'Agostino, Selker et al., 1984), findings were similar. Along with elevation or depression of ST segments of 1 mm or more, even ST segment "straightening" (horizontal or downsloping ST segment with slight depression suggesting acute ischemia) was found to be significantly predictive of the presence of acute ischemia.

A completely normal ECG in the ED does not exclude the possibility of acute IHD, since 1 to 6 percent of such patients will eventually prove to have had an acute MI, and 4 percent or more will be found to have unstable angina ( McCarthy, Wong, and Selker, 1990; Rouan, Lee, Cook et al., 1989). In the Multicenter Acute Ischemia Predictive Instrument Trial ( Pozen, D'Agostino, Selker et al., 1984), 6 to 7 percent of ED patients with acute ischemia were found to be sent home. In a followup study ( McCarthy, Beshansky, D'Agostino, Selker, 1993) that included a search of the National Death Index, it was found that this 6 to 7 percent false-negative discharge rate included 2 percent of ED patients with acute MI who had been sent home. A study by the Multicenter Chest Pain Group showed a 4 percent false-negative discharge rate for acute MI ( Rouan, Lee, Cook et al., 1989).

Determination of Prognosis in Patients with Unstable Angina

Since patients with unstable angina as a group are at increased risk of cardiac death and nonfatal MI, assessment of prognosis often sets the pace of initial evaluation and treatment of patients with suggestive symptoms. For all modes of presentation of IHD, a strong relationship exists between indicators of likelihood of CAD and prognosis. Those patients with a high likelihood of CAD are at a greater risk of an untoward cardiac event than patients with a lower likelihood of CAD. Therefore, assessment of the likelihood of CAD is the beginning point for determining prognosis in a patient presenting with symptoms suggestive of unstable angina. The two other important elements for prognostic assessment are the recent tempo of the patient's clinical course, which relates to the short-term risk of future cardiac events, principally acute MI, and the patient's likelihood of survival should an acute ischemic event occur.

Clinical and ECG Findings Related to Short-Term Prognosis in Patients with Unstable Angina

The tempo of the patient's disease is judged from the cardiac history and ECG and from an examination of the patient during a symptomatic episode. The key elements of the history are: the current frequency of episodes, the change in frequency over the last 2 months (and particularly the last week), any increase in severity or duration of symptoms and in particular occurrence of episodes lasting >20 minutes, progression from effort or stress-related symptoms to symptoms occurring at rest, new onset of nocturnal symptoms, or a significant decrease in the amount of stress or effort necessary to provoke symptoms ( Califf, Mark, Harrell et al., 1988; De Servi, Ghios, Ragni et al., 1985). New onset angina is an adverse prognostic event ( Roberts, Califf, Harrell et al., 1983), but its risk is defined by other variables from the history, such as the tempo, frequency, and severity of symptoms ( Califf, Mark, Harrell et al., 1988; White, Lee, Cook et al., 1990).

Table 8. Short-term risk of death or nonfatal myocardial (more...)

Table 8. Short-term risk of death or nonfatal myocardial infarction in patients with unstable angina

High risk	Intermediate risk	Low risk
At least one of the following features must be present:	No high-risk feature but must have any of the following:	No high- or intermediate- risk feature but may have any of the following features:
Prolonged ongoing (>20 mins) rest pain	Prolonged (> 20 mins) rest angina, now resolved, with moderate or high likelihood of CAD	Increased angina frequency, severity, or duration
Pulmonary edema, most likely related to ischemia	Rest angina (> 20 mins or relieved with rest or sublingual nitroglycerin)	Angina provoked at a lower threshold
Angina at rest with dynamic ST changes > 1 mm	Nocturnal angina	New onset angina with onset 2 weeks to 2 months prior to presentation
Angina with new or worsening MR murmur Angina with S3 or new/worsening rales	Angina with dynamic T-wave changes New onset CCSC[1] III or IV angina in the past 2 weeks with moderate or high likelihood of CAD	Normal or unchanged ECG
Angina with hypotension	Pathologic Q waves or resting ST depression < 1 mm in multiple lead groups (anterior, inferior, lateral)
	Age > 65 years

[1] CCSC = Canadian Cardiovascular Society classification.

Note: Estimation of the short-term risks of death and nonfatal MI in unstable angina is a complex multivariable problem that cannot be fully specified in a table such as this. Therefore, the table is meant to offer general guidance and illustration rather than rigid algorithms.

Entry into Medical Care Directed by the Guideline

Stabilization and Initial Evaluation

Patients meeting criteria for unstable angina should receive ASA therapy, 160 to 324 mg, as described below, unless contraindications are present. Patients without pain but with definite ischemic ECG changes should be treated during this initial phase as if they have ongoing pain. Patients without ongoing pain or ischemic ECG changes should be further risk-stratified. About one-half of these patients will be known to have CAD for which they have received prior treatment. Management decisions for these patients with known CAD are similar to those for patients without known CAD but with a high likelihood of having CAD.

Details of past medical care most likely to impact on current management decisions include prior assessments of LV function and coronary anatomy, prior revascularization procedures, and recent medication history. The current historic information of greatest importance in these patients is their assessment of the severity and tempo of their symptoms in the context of their prior history. Patients who feel that their symptoms are similar to those experienced during a prior major cardiac event and patients who have undergone coronary angioplasty or a bypass operation within the past year and have intermediate- or high-risk features deserve hospital admission for more thorough evaluation in most cases. Patients with known LV dysfunction or CHF represent another group that should usually be admitted to the hospital. Patients who are at or near maximal medical treatment and who have been symptomatic over the preceding 24 hours deserve hospital admission. Others who should be admitted include patients with a symptom duration >=1 hour (even without ECG changes), patients with a history of rest pain lasting >20 minutes within the past week, or patients with a two-class worsening of angina ( Goldman, Cook, Brand et al., 1988). All low-risk patients with known CAD usually can be managed as described in Chapter 3. Hospitalization may be reasonable in some low-risk patients with known CAD, such as those with other diseases that might confound outpatient management and patients who live in areas remote from an appropriate health care facility.

Patients without known CAD and a high likelihood of CAD are managed initially as if they have high-risk unstable angina. For all other patients without known CAD, the pattern of recent symptoms defines the urgency with which further evaluation should proceed to determine the likelihood of CAD as a cause of symptoms. Patients with an intermediate likelihood of CAD for whom another cause of current symptoms cannot be determined who also appear to be at intermediate risk are usually best managed by hospitalization in a standard or intermediate care bed. Patients with an intermediate likelihood of CAD but low risk deserve further evaluation for the cause of their symptoms. In some cases, it will be logistically reasonable to proceed with a more definitive evaluation in the ED. Alternatively, patients who have been asymptomatic for >24 hours can reasonably be referred to an outpatient facility for definitive workup. However, in most situations, this evaluation should be completed within 72 hours, and patients should always be advised to return to the ED immediately for reevaluation if symptoms recur, worsen, or fail to respond to prescribed symptomatic therapy. A trial of sublingual NTG may provide useful diagnostic information in some of these patients. All patients should be instructed to observe and later report the influence of medication and activity on symptoms experienced during the interval prior to more definitive evaluation.

Patients with a low likelihood of CAD, especially those with a history of intermediate-risk features who currently do not have ongoing pain, ECG change, or hemodynamic instability, should be evaluated carefully for other causes of the presentation including: musculoskeletal chest pain>= gastrointestinal (GI) disorders, such as gastritis, peptic ulcer disease, or cholecystitis; intrathoracic disease, such as esophageal spasm, pneumonia, pleurisy, pneumothorax, or pericarditis; neuropsychiatric disease, such as hyperventilation; or panic disorder. Patients who are found to have evidence of one of these alternative diagnoses should be excluded from management by this guideline and referred appropriately for followup care. Stable angina may also be diagnosed in this setting, and patients with this diagnosis are excluded from further management by this guideline. Patients for whom a specific diagnosis cannot be made on the brief initial examination should undergo a more definitive evaluation. This evaluation may proceed in the ED or outpatient facility if time permits. Occasionally, admission to a standard hospital unit is required for definitive evaluation of patients with complex presentations.

Definitive evaluation of patients with a low likelihood of CAD and low risk is less urgent than it is for patients at higher risk. If time is not adequate in the ED setting to evaluate these low-risk patients sufficiently to arrive at an alternate diagnosis or to differentiate unstable angina from stable angina, patients should be referred for outpatient evaluation, generally within 72 hours, as described in Chapter 3.

Initial Treatment of Patients with Unstable Angina

Initial General Care

Recommendation: Patients with unstable angina and ongoing rest pain should be placed at bed rest during the initial phase of medical stabilization (strength of evidence = C).

Recommendation: Patients with obvious cyanosis, respiratory distress, or high-risk features (see Table 8) should receive supplemental oxygen. A finger pulse oximetry or arterial blood gas determination should be used to confirm adequate arterial oxygen saturation and continued need for supplemental oxygen (strength of evidence = C).

Recommendation: As soon as the diagnosis of unstable angina is made, patients should be placed on continuous ECG monitoring for ischemia and arrhythmia detection (strength of evidence = C).

The severity of symptoms of unstable angina will dictate some of the general patient care that should be employed during initial treatment of patients with a diagnosis of unstable angina. Patients should be placed on bed rest while ischemia is ongoing but can be mobilized to a chair and bedside commode once they become symptom-free. Subsequent activity restriction should be focused on preventing recurrent symptoms and may be liberalized as judged appropriate as patients respond to treatment. Patients with cyanosis, respiratory distress, or high-risk features (see Table 8) should receive supplemental oxygen, and adequate blood arterial saturation should be confirmed by direct measurement or pulse oximetry. No evidence is available to support the common medical practice of administering oxygen to all patients with acute chest pain syndromes in the absence of signs of respiratory distress. Although routine use of oxygen during initial evaluation would not appear to cause much harm, more selective use of oxygen for patients with questionable respiratory status or those with documented hypoxemia by finger pulse oximeter is a preferable strategy. All patients with unstable angina should undergo cardiac monitoring during their ED evaluation.

Initial Pharmacologic Treatment.^[1] Drugs to be considered for use at the time of initial evaluation and treatment of patients with symptoms suggestive of unstable angina include ASA, heparin, nitrates, and beta blockers. The certainty of diagnosis, severity of symptoms, hemodynamic state and medication history will determine the choice and timing of drugs used in individual patients. Treatment with an indicated drug should begin in the ED and not be delayed until hospital admission. The aggressiveness of drug dosage will depend on the severity of symptoms and, for many drugs, will require modification throughout the subsequent hospital course. Principles of drug use are not altered by the care environment in which the drug is administered.

Table 9: Summary of drugs commonly used in the emergency (more...)

Table 9: Summary of drugs commonly used in the emergency department to treat patients with symptoms suggestive of unstable angina

Drug category	Clinical condition	When to avoid[1]	Usual dose (low-high)
Aspirin	Diagnosis of unstable angina or acute MI	Hypersensitivity, active bleeding, severe bleeding risk	324 mg (160-324)
Heparin	Unstable angina in high-risk category and some intermediate-risk patients	Active bleeding, history of heparin-induced thrombocytopenia, severe bleeding risk, recent stroke	80 units/kg IV bolus with constant IV infusion at 18 units/kg/hr titrated to maintain aPTT between 46 and 70 seconds[2]
Nitrates	Ongoing pain or ischemia	Hypotension	Sublingual (1-3 tablets)[3] IV (5-100 µg/min)
Beta Blockers	Diagnosis of unstable angina	PR ECG segment > 0.24 seconds, 2° or 3° AV block, heart rate <60, systolic blood pressure < 90 mmHg shock, left ventricular failure with CHF, severe reactive airway disease	Oral dose appropriate for specific drug IV metoprolol (1-5 m slow IV every 5 minutes to 15 mg total) IV propranolol 0.5 to 1.0 mg IV atenolol 5 mg every minutes to 10 mg total
Narcotics	Persistent pain following initial therapy with nitrates and beta blockers	Hypotension, respiratory depression, confusion, obtundation	Morphine sulfate 2 to 5 mg IV

[1] Allergy or prior intolerance contraindication for all.

[2] Dose regimen assumes a mean control aPTT of 30 seconds and a therapeutic goal of 1.5 to 2.5 times control.

[3] Patients with symptoms suggestive of unstable angina and ongoing pain should be given sublingual NTG 0.3 to 0.4 every 5 minutes until discomfort is relieved, three tablets have been given, or limiting symptoms or signs develop. If discomfort is still present after three tablets, IV NTG should be started promptly at a dose of 5 micro-/min and titrated up to 75 to 100 micro-g/min or limiting side effects.

Note: Some of the recommendations in this guideline suggest the use of agents for purposes or in doses other than those specified by the Food and Drug Administration (FDA). Such recommendations are made after consideration of concerns regarding nonapproved indications. Where made, such recommendations are based on more recent clinical trials or expert consensus.

To avoid redundancy, a detailed description of the use of each drug will be presented only once in this guideline, although modifications of drug use required during other phases of care will be mentioned when appropriate. Because ASA and heparin are the drugs that should be considered early in the treatment of unstable angina, their use is described in this chapter. Nitrates, beta blockers and narcotics are often begun in the ED, but their use at maximum dosage and the importance of response to these agents for determining the need for alternate therapies in individual patients often occurs in the intensive care environment. For this reason the use of nitrates, beta blockers, and morphine is discussed in detail in Chapter 4. Table 9summarizes indications, contraindications, and usual dosage of drugs commonly used in the ED to treat patients with unstable angina.

Recommendation: IV thrombolytic therapy is not indicated in patients who do not have evidence of acute ST-segment elevation or left bundle branch block (LBBB) on their 12-lead ECG (strength of evidence = A).

Figure 4: Influence of thrombolysis on myocardial infarction (more...)

   Figure 4: Influence of thrombolysis on myocardial infarction in patients presenting with unstable angina

Source: Saran, Bhandari, Narain et al., 1990; Karlsson, Berglund, Bjorkholm et al., 1992; Screiber, Rizik, White et al., 1992; Bar, Verheught, Col et al., 1992; Ambrose, Torre, Sharma et al., 1992; Freeman, Langer, Wilson et al., 1992; Charbonnier, Bernadet, Schiele et al., 1992; TIMI-IIIB, in press.

The failure of IV thrombolytic therapy to improve clinical outcomes in the absence of acute MI with ST-segment elevation or LBBB has now been clearly demonstrated ( TIMI IIIA, 1993; TIMI IIIB, in press). A meta-analysis by Duke University staff of recent studies of thrombolytic therapy in unstable angina patients shows no benefit of thrombolysis versus standard therapy for the reduction of acute MI. Thrombolytic agents had no significant effect and actually increased the risk of MI by 1.7 percent (95% confidence interval [CI] 2.4-5.8%) (Figure 4). Consequently, such therapy is not recommended for unstable angina patients managed according to this guideline.

The distinction between unstable angina and acute MI often cannot be definitively made during the initial evaluation. Patients with ECG changes diagnostic of epicardial injury (i.e., >=1 mm ST-elevation in two or more contiguous leads, or ST-depression in V1-V3) or LBBB with a consistent history should be managed as if they have an acute MI, including prompt administration of ASA, beta blockers, and reperfusion therapy. In most large trials of reperfusion therapy, such patients have a >=95 percent prevalence of acute MI. In the Multicenter Chest Pain Study, however, only about 80 percent of patients meeting these criteria had acute MI ( Lee, Weisberg, Brand et al., 1989).

Recommendation: All patients with the diagnosis of unstable angina should receive regular ASA 160 to 324 mg as soon as possible after presentation unless a definite contraindication is present, such as evidence of ongoing major or life-threatening hemorrhage, a significant predisposition to such hemorrhage (e.g., recent bleeding peptic ulcer disease), or a clear history of severe hypersensitivity to ASA (strength of evidence = A).

The recommendation for an initial ASA to be given in the ED is based on the efficacy of this therapy in independently reducing mortality in patients with acute MI enrolled in the second International Study of Infarct Survival (ISIS-2) trial (1988). Those data, combined with the recognition that a definitive distinction between acute MI and unstable angina is frequently not possible at the time of acute presentation, led to the recommendation to initiate ASA immediately in appropriate patients. No randomized trials or other studies compare immediate with a more delayed initiation of ASA in unstable angina.

Some of the strongest evidence available about the long-term prognostic effects of medical therapy on coronary disease outcomes pertains to ASA. ASA inhibits the formation of thromboxane A2, thereby diminishing platelet aggregation promoted by some but not all physiologic stimuli. Since platelets are one of the main participants in the thrombotic consequences of disruption of a coronary plaque, platelet inhibition is a plausible mechanism for clinical benefit. In unstable angina, ASA has been shown to have significant benefit for stabilizing an acutely unstable coronary plaque, producing reductions in mortality and MI rates of 50 percent or more.

Four randomized trials clearly demonstrated the benefit of ASA in the long-term treatment of unstable angina. The Veterans Administration (VA) Cooperative Study Group in 1983 compared the effects of 324 mg of ASA given once a day for 12 weeks with the effects of placebo in 1,266 male veterans admitted with unstable angina ( Lewis, Davis, Archibald et al., 1983). At the conclusion of the 12-week study period, there was a 51 percent reduction in the rate of nonfatal acute MI in the ASA group (3.4% vs. 6.9%, p=0.005) and a 51 percent reduction in the rate of death or acute MI in the ASA group (5% vs. 10.1%, p=0.0005). Although the difference in the mortality rates of the ASA and placebo groups was not significant at 12 weeks, there was a significant 43 percent reduction in the mortality rate of the ASA-treated group at 1-year followup (5.5% vs. 9.6%, p=0.008).

A group of Swedish investigators reported the effects of ASA (75 mg/day) compared with the effects of placebo in 796 men admitted with either unstable angina or non-Q-wave MI ( Wallentin, 1991). Study treatment had been scheduled for 1 year, but the trial was stopped after publication of the ISIS-2 trial. All patients received at least 3 months of treatment. At 12-month followup, there was a significant 48 percent reduction in the combined rate of death and MI in the ASA group (11% vs. 21%, p=<=0.0001). However, there was no significant difference in the risk of death alone (2.7% vs. 4.5%, p=NS). ASA also reduced the incidence of recurrent angina in this trial.

Figure 5: Relative risk of death or myocardial infarction (more...)

   Figure 5: Relative risk of death or myocardial infarction in unstable angina patients treated with aspirin vs. placebo

Source: Carins, Gent, Singer et al., 1985; Lewis, Davis, Archibald et al., 1983; Theroux, Ouimet, McCans et al., 1988; Wallentin, 1991.

A Canadian multicenter trial reported in 1985 tested the effects of 325 mg of ASA given every 6 hours with the effects of placebo in 555 patients admitted to the CCU with unstable angina ( Cairns Gent, Singer et al., 1985). At an average followup point of 18 months, there was a significant 56 percent reduction in the risk of cardiac death (5% vs. 9.4%, p=0.009), although there was no difference in the followup rate of MI. A second Canadian study reported in 1988 examined the effects of 325 mg of ASA given twice per day versus those of placebo in 479 patients admitted to the CCU with unstable angina ( Theroux, Ouimet, McCans et al., 1988). The researchers reported a 28 percent reduction in the rate of MI over the first week of therapy in the ASA group (3.3% vs. 11.9%, p=0.012). There were too few deaths to analyze the effects of the treatment on this endpoint. Meta-analysis of these four studies to assess outcomes measured at greater than 3 months suggests that ASA reduces the risk of MI by 48 percent and the risk of death by 51 percent. There was a 47 percent reduction in the combined risk of death and MI as illustrated in the likelihood function in Figure 5.

No data directly compare the efficacy of different doses of ASA in patients presenting with unstable angina. However, a broad review and meta-analysis of different doses of ASA in long-term treatment of patients with CAD suggest equal efficacy of daily doses of 75-324 mg per day ( Antiplatelet Trialists' Collaboration, 1994). It appears reasonable to initiate ASA treatment in patients with unstable angina with a dose of at least 160 mg as used in the ISIS-2 (1988) trial. Thereafter, an ASA dose of 80-324 mg could be used for long-term therapy.

Recommendation: IV heparin should be started as soon as a diagnosis of intermediate- or high-risk unstable angina is made (strength of evidence = A). The initial dose is 80 units/kg by IV bolus followed by a constant infusion of 18 units/kg/hr, maintaining the activated partial thromboplastin time (aPTT) at 1.5 to 2.5 times control.

There is clear and compelling evidence that IV heparin started early in the course of unstable angina reduces the risk of subsequent MI and recurrent unstable angina. Heparin exerts its anticoagulant effect by markedly accelerating the action of circulating antithrombin III, a proteolytic enzyme that inhibits thrombin and several other activated factors in the clotting cascade. Thus, heparin acts to prevent thrombus propagation but does not lyse existing thrombi (Hirsh, 1991).

Five randomized trials of heparin use in unstable angina have been reported. Two early trials showed a benefit but must be judged inconclusive due to methodologic defects ( Telford and Wilson, 1981; Williams, Kirby, McPherson et al., 1986). A group of Swedish investigators performed a double-blind placebo-controlled trial with a 2x2 factorial design in 796 men with unstable angina or non-Q-wave infarction ( RISC Group, 1990). The active drug regimens tested were ASA 75 mg daily for >=3 months and heparin 5,000 units IV bolus every 4 hours. Drug therapy was initiated 1 to 3 days after hospital admission. This investigation did not demonstrate any therapeutic benefit of heparin alone, although patients treated with heparin and ASA combined had significantly fewer (p=0.0007) deaths and MIs than those treated with heparin alone, and fewer, but not significantly fewer, cardiac events than ASA alone ( RISC Group, 1990).

Two placebo-controlled heparin and ASA trials were performed at the Montreal Heart Institute. A 479-patient study performed between 1986 and 1988 tested treatments consisting of 650 mg of ASA immediately followed by 324 mg twice per day and a 5,000-unit IV heparin bolus followed by 1,000 units per hour in a 2x2 factorial design ( Theroux, Ouimet, McCans et al., 1988). Importantly, a double-blind placebo was used for both heparin and ASA ensuring truly unbiased assessment of efficacy. Although the study was too small to detect an effect on mortality, the risk of MI was reduced by 89 percent and the risk of recurrent refractory angina by 63 percent relative to placebo. In this study, ASA also reduced the rate of MI, but the two drugs given together were not superior to heparin alone (possibly due to the relatively small sample size and inadequate statistical power) and were associated with a slightly higher risk of serious bleeding. A more recent double-blind randomized trial from this group compared ASA (325 mg twice per day) and heparin (5,000 units IV bolus followed by a constant infusion titrated to an aPTT 1.5 to 2.5 3 control) in 484 unstable angina patients. MI (fatal or nonfatal) occurred in 0.8 percent of heparin patients and 3.7 percent of ASA patients (p=0.035). This trial was the first to clearly demonstrate the superiority of IV heparin over ASA in the acute phase of unstable angina ( Theroux, Waters, Qiu et al, 1993).

Taken together, these available trials indicate a substantial reduction in acute MI incidence from early heparin, with possible reduction of death and recurrent unstable angina. No direct data exist about the relative efficacy of bolus administration versus continuous infusion of heparin, but two randomized trials from another area of medicine suggest equivalent anticoagulant results and more bleeding complications with intermittent therapy. Thus, although continuous infusion is preferred in this guideline, centers not equipped to administer heparin by continuous infusion may substitute a regimen of 5,000 units IV bolus every 4 hours.

The efficacy of ASA and heparin in combination is suggested, but this benefit has not been unequivocally demonstrated relative to monotherapy by their complementary mechanisms of action and demonstrated value in different phases of the disease. ASA has been shown to provide benefits with an initial ED dose in patients who are later confirmed to have the diagnosis of acute MI. ASA may also prevent reactivation of acute IHD when heparin therapy is discontinued later in the hospital course. Finally, ASA has demonstrated efficacy in long-term secondary prevention. Heparin, on the other hand, is the most efficacious agent available to reduce early in-hospital ischemic events. Thus, the combination of the two agents for initial therapy in unstable angina is strongly recommended.

Treatment and Assessment of Relief of Symptomatic Ischemia

Diagnostic Assessment

All patients should have a history, physical examination, and ECG. Initial evaluation for patients without prior ED evaluation should proceed as described for low-risk patients in Chapter 2. For patients returning for followup examination of a recent ED visit, the circumstances surrounding the initial presentation and any interval symptoms since the initial examination represent the important features of the history. Evidence of a worsening symptom pattern may necessitate hospital admission for control and further diagnostic workup. This repeat evaluation should also include a further search for factors that might precipitate or exacerbate unstable angina, such as fever, tachyarrhythmias, hyperthyroidism, severe anemia, cocaine use, noncompliance with medical therapy, environmental temperature extremes, severe psychosocial stress, and changes in the level of physical exertion or lifestyle.

Patients who develop pain during the clinic visit should have a careful cardiac examination during the episode (looking for a new S₄ or S₃, new or worsening MR murmur, rales) and an immediate ECG (looking for transient changes in the ST-segment or T-wave). A therapeutic trial with sublingual NTG can be attempted after these steps if the discomfort is still present. Repeat examination and an ECG should be performed once symptoms are completely resolved.

Risk Stratification and Further Management

Table 7. Likelihood of significant coronary artery (more...)

Table 7. Likelihood of significant coronary artery disease in patients with symptoms suggesting unstable angina

High likelihood (e.g., 0.85-0.99)	Intermediate likelihood (e.g., 0.15-0.84)	Low likelihood (e.g., 0.01-0.14)
Any of the high or following features:	Absence of high likelihood features and any of the following:	Absence of intermediate likelihood features but may have:
History of prior MI or sudden death or other known history of CAD Definite angina: males > 60 or females > 70 years of age Transient hemodynamic or ECG changes during pain	Definite angina: males < 60 or females < 70 years of age Probable angina: males > 60 or females > 70 years of age Chest pain probably not angina in patients with diabetes	Chest pain classified as probably not angina One risk factor other than diabetes T-wave flattening or inversion < 1 mm in leads with dominant R waves
Variant angina (pain with reversible ST-segment elevation)	Chest pain probably not angina and two or three risk factors other than diabetes[1]	Normal ECG
ST segment elevation or depression > 1 mm Marked symmetrical T-wave inversion in multiple precordial leads	Extracardiac vascular disease ST depression 0.05 to 1 mm
	T-wave inversion > 1 mm in leads with dominant R-waves

[1] Coronary artery disease risk factors include diabetes, smoking, hypertension, and elevated cholesterol.

Note: Estimation of the likelihood of significant coronary artery disease is a complex, multivariable problem that cannot be fully specified in a table such as this. Therefore, the table is meant to illustrate major relationships rather than offer rigid algorithms.

Outpatient Treatment of Symptoms

The symptomatic therapy of patients with low-risk unstable angina not requiring hospitalization involves the use of sublingual NTG for treatment of individual anginal episodes and prophylactic therapy with an agent from one of the three major classes of antianginal drugs (nitrates, beta blockers, calcium antagonists). In general, it is reasonable to start therapy with one major antianginal, preferably in a long-acting preparation, and proceed to a second agent only if there are recurrent symptoms on optimal doses of the first agent. In addition, ASA should be a standard part of each regimen. The details of these therapies and the evidence for their use are described in Chapter 4.

Some patients who present with symptoms suggestive of unstable angina and are initially categorized as having low likelihood of CAD will continue to report symptoms suggestive of angina despite an antianginal regimen that appears appropriate. The medical provider should first review all diagnoses and management decisions and, if appropriate, obtain or repeat other noninvasive exercise or pharmacologic stress tests. Fear of heart disease or other psychological problems commonly underlies complaints of cardiovascular symptoms which are out of proportion to objective evidence of ischemia. Some patients benefit from more complete and frequent counseling and reassurance. This group of patients will often respond to cardiac rehabilitation in a structured environment with supervised exercise. A trial of simple measures is reasonable in this group of patients, but failure to respond may necessitate the decision to perform a cardiac catheterization with the intention of confirming the absence of coronary artery disease. If this is to be undertaken, patients must be informed of the reason for the procedure when they provide informed consent.

Some patients find sufficient reassurance with angiographic documentation of normal coronary arteries that their symptoms gradually dissipate. Patients who continue to have symptoms they consider to be angina despite normal coronary angiograms may have small-vessel or vasospastic coronary artery disease requiring further evaluation that is not covered by this guideline. Other patients with continued symptoms but no objective evidence of ischemia or CAD may benefit from evaluation and counseling by medical practitioners other than cardiovascular specialists.

Pharmacologic Management

Laboratory Testing

Standard criteria for diagnosis of acute MI are based on demonstrating elevation and subsequent decline of CK levels along with evolutionary changes on serial 12-lead ECGs. CK is a nonstructural muscle enzyme that catalyzes the transfer of high energy phosphate from creatinine phosphate to adenosine diphosphate (ADP). CK occurs in three isoenzyme forms: skeletal muscle (MM), brain (BB), and MB (predominantly cardiac). CK-MB, the most sensitive and specific diagnostic test for acute MI, begins to rise within 6 hours of myocardial injury and peaks at 10 to 18 hours ( Botker, Ravkilde, Sogaard et al., 1991). Total CK begins to rise at about 12 hours after symptom onset and peaks at 12 to 24 hours. Because of the rapid rise and clearance of CK-MB and total CK, timing of blood sampling is crucial in achieving maximal detection of acute MI. The literature is mixed, however, on the optimal sampling interval ( Lee and Goldman, 1986). Rapid reporting of results of serial CK-MB measurements obtained hourly for 3 hours after presentation to the ED was found to aid early decision in 376 patients evaluated for chest pain ( Young, Hedges, Gibler et al., 1991). After the admission sample, recommendations range from every 6 to every 12 hours for the first 24 hours. A sampling interval of every 6 to 8 hours is recommended to maximize sensitivity ( Brush, Brand, Acampora et al., 1988).

Patients with severe renal insufficiency have a marked reduction in the clearance of CK from the blood. Diagnosis of acute MI in these patients is based not only on finding elevated CK and CK-MB levels but also demonstrating the rise and subsequent fall in these levels in relation to an appropriate clinical event. Patients presenting more than 24 hours after symptom onset who have negative serial CK-MBs should have serial LDH isoenzyme determinations. LDH is a widely distributed cellular enzyme that catalyzes the transformation of pyruvate to lactate. It has five isoenzymes identified on electrophoresis. LDH1 is most common in myocardium, red blood cells, and the kidney. Elevation of LDH1 is usually seen within 12 to 24 hours of myocardial necrosis and may fall to nondiagnostic levels by 72 hours.

Recently, several new laboratory tests for myocardial injury have been proposed with the goal of improving on the sensitivity and specificity of CK-MB. One such group of tests involves measuring the levels of CK-MM and -MB isoforms. Another group of tests concentrates on measuring serum levels of myocardial structural proteins, particularly troponin T, troponin I, myoglobin, and myosin light chain ( Hamm, Ravkilde, Gerhardt et al., 1992; Katus, Yasuda, Gold et al., 1984). At present, none of these approaches has been established as providing more accurate diagnostic information than CK-MB. Thus, these tests are not currently recommended as part of standard practice.

Serum lipid levels (total cholesterol, triglycerides, high-density lipoprotein [HDL] cholesterol) provide an important part of the data base required for planning postdischarge management. Acute MI and other major physical stresses tend to falsely depress cholesterol and triglyceride levels, probably due to elevated circulating catecholamines. There are data, however, which show that cholesterol measured within the first 24 hours of an acute MI accurately reflects nonstress levels ( Gore, Goldberg, Matsumoto et al., 1984). This is the rationale for the recommendation for an admission determination. All patients should also have a followup determination no sooner than 8 weeks after their acute presentation ( National Institutes of Health, 1990).

Serial ECGs are performed in unstable angina to detect the evolutionary changes of acute MI, transient and persistent ischemic complications, and disturbances of rhythm or conduction. In the absence of specific clinical indications, the optimal sampling interval for ECGs is uncertain. New data from continuous ST-segment monitoring show much more dynamic activity of the ST-segment in unstable angina patients than had been previously appreciated. Such patients may be in a tenuous equilibrium between coronary thrombus propagation and lysis with resulting intermittent transient coronary occlusion, often in the absence of symptoms. The therapeutic implication of these findings is still unclear. Also, continuous ST-segment monitoring is not widely available at present. Thus, the panel recommends that after the admission ECG, repeat ECGs should be obtained at 24 hours and then at 48 hours. In addition, a repeat ECG should be obtained whenever the patient's clinical condition changes (e.g., recurrent symptoms, hypotension, arrhythmia, pulmonary edema).

Because of lower cost and greater diagnostic content, a posteroanterior and lateral chest radiograph is preferable to a portable radiograph in patients with unstable angina who are hemodynamically stable. In general, the chest radiograph does not contribute substantially to the initial management of these patients and, therefore, is reasonable to defer until other more pressing management concerns have been addressed. However, any suggestion of hemodynamic instability or inclusion of an alternate diagnosis of severe intrathoracic disease is reason for an early chest radiograph, even if it must be obtained by a portable technique.

The resting EF is one of the most potent prognostic factors in CAD. In patients who are planned for early cardiac catheterization, this measurement can be obtained by contrast ventriculography. Clinicians who opt for an early conservative strategy (defined in Chapter 7) should obtain a resting noninvasive measure of LV function within 72 hours of admission in patients with previous infarction or cardiomegaly on chest radiograph to allow for additional risk stratification and identification of high-risk patients who should be referred for early angiography. Patients with low EFs (<=0.50) should receive careful consideration for revascularization therapy because of the risk with medical therapy that increases as a function of decrease in EF. Selection of the imaging mode should be based primarily on the technology and expertise available at each site. Calculation of the EF using 2-D echocardiography is technically more difficult than by radionuclide ventriculography because of the cross-sectional nature of the images and the frequency of suboptimal sound penetration of the chest wall.

Assessment of Efficacy of Initial Medical Therapy

An early management strategy characterized by cardiac catheterization within 48 hours of presentation for high-risk unstable angina, with consideration of subsequent revascularization by PTCA or CABG, has been shown by the TIMI IIIB trial (in press) to provide equivalent freedom from cardiac death but better pain relief than a conservative strategy that utilizes interventional approaches only with documented failure of a medical regimen (evidence cited in Chapter 7). A more complete discussion of factors likely to influence choice of these alternate approaches for an individual patient appears in Chapter 7.2

Patient counseling to provide information, discuss relative risks and benefits, and learn patient preference about further treatment with the early invasive or conservative strategies is appropriate after the patient has reached a plateau of stabilization. This important counseling period should be scheduled for a time permitting medical practitioners to completely address these serious issues with several brief intervals of group discussion separated by periods of private reflection for the patient and family and/or advocate. In this elective setting, patients should not be hurried into making this major decision. Patients who choose an early invasive strategy will be managed as described in Chapter 7. The remaining patients will continue to be treated with a medical regimen appropriate for the severity of symptoms and will retain the option for invasive therapy if medical therapy proves ineffective.

Patients who desire a noninterventional strategy of early treatment of unstable angina will be started on an initial medical regimen with serial reassessments to determine the success of therapy and the occurrence of significant complications. During the initial hours of therapy, medications are titrated up to their target doses as permitted by the patient's hemodynamic state and general medical condition. Prior to achievement of the target regimen, the patient may have recurrent symptoms requiring the physician to consider whether a change in course (such as emergency catheterization) would be appropriate. In addition, once the desired level of medical therapy has been reached, recurrent symptoms may indicate a need for a still more intensive regimen or for triage to early cardiac catheterization. Thus, clinical decisionmaking at this juncture requires criteria by which the adequacy of medical therapy can be judged and failure of such therapy defined. In addition, it is necessary to understand the prognostic importance of the different manifestations of recurrent ischemia so that changes in management can be formulated based on the patient's short-term risk of adverse events.

Criteria defining the adequacy of medical therapy in unstable angina serve two roles: first, they provide the practitioner with explicit therapeutic goals to ensure that patients receive the full benefits available from such therapies; and second, they provide guidance about the conditions under which early diagnostic catheterization and subsequent revascularization should be considered. If inadequate levels of medical therapy are employed, recurrent symptoms may precipitate an otherwise avoidable referral for invasive study. On the other hand, excessively aggressive therapeutic endpoints may provoke harmful complications or needlessly delay revascularization in patients likely to benefit from this therapy.

The optimal level of medical therapy for the unstable angina patient has not yet been established. Two general approaches have been proposed to define adequate medical therapy. The first defines adequate medical therapy as maximally tolerated doses of nitrates, beta blockers, and calcium channel blockers plus ASA and heparin. The implication of this definition is that failure of medical therapy cannot be declared until each drug has been pushed up to limiting levels so that any further increment would cause hemodynamic deterioration or toxicity. The second approach is to define adequate medical therapy by arbitrary levels of each of the key therapeutic agents. For example, in addition to heparin and ASA, this criterion might require the patient to be on IV nitrates (e.g., >=50 micro-g/min) or nonparenteral nitrates (e.g., >=1 inch of ointment) and a combination of beta blockers and calcium channel blockers with a heart rate <=60 beats per minute and an SBP <=150 mmHg. Since achievement of steady state medication effects may require 24 hours or more even with parenteral administration, some criteria for adequate medical therapy also specify a minimum duration such therapy should be continued prior to referral for invasive study. Intensive medical treatment for unstable angina is usually very effective. In one recent study, only 11 of 502 patients (2%) admitted for unstable angina were found to be truly refractory to medical therapy ( Grambow and Topol, 1992).

Based on current understanding of the most prevalent pathophysiology of unstable angina (i.e., plaque rupture with thrombus formation and propagation), it is proposed that failure of medical therapy be defined in terms of continuing angina despite having an adequate anticoagulant effect with at least moderate reductions in cardiac oxygen demand through decreases in heart rate and blood pressure. Thus, for this guideline a patient will not be said to have failed (or be "refractory" to) medical therapy until he or she is receiving ASA (>=160 mg/day) and IV heparin with an aPTT of 1.5 to 2.5 times control. In addition, in the absence of limiting symptoms, IV NTG should be infused at >=50 micro-g/min (or topical NTG at >=1 inch of ointment every 6 hours for three doses followed by a 6- to 8-hour nitrate-free interval or an equivalent regimen of oral or buccal nitrates). Beta blockers should be used to keep the resting heart rate at an average of <=60 beats/minute. Significant hypertension (i.e., resting SBP >=150 mmHg) resistant to first-line medical therapy is an indication for addition of calcium channel blockers.

Although it is theoretically desirable to have this regimen in place for >=24 hours before declaring any patient a failure of medical therapy, to do so in all cases may be inappropriate or even dangerous. In particular, patients who have one or more recurrent severe, prolonged (>20 minutes) ischemic episodes particularly when accompanied by pulmonary edema, a new or worsening MR murmur, hypotension, or new ST- or T-wave changes should be considered high risk, regardless of the level of medical therapy, and triaged to early cardiac catheterization. Patients with shorter, less severe ischemic episodes without accompanying hemodynamic or ECG changes are at substantially lower risk and should be continued on medical therapy to the prespecified targets.

Evaluation and Management of Early Ischemic Complications

The major ischemic complications seen in unstable angina are acute MI, recurrent unstable angina, acute ischemic pulmonary edema, new or worsening MR, cardiogenic shock, malignant ventricular arrhythmias, and advanced AV block. Aside from maximizing the medical regimen described in the previous section and instituting appropriate adjunctive therapy (e.g., pulmonary artery pressure monitoring and inotropic therapy for shock, antiarrhythmic therapy for malignant ventricular arrhythmias, pacemaker for symptomatic high-grade AV block), the clinician should consider either insertion of an IABP or cardiac catheterization or both.

Preparation for Nonintensive Phase

The large majority of unstable angina patients will stabilize and become pain free with appropriate intensive medical therapy. Transfer from intensive to nonintensive medical management is undertaken when the patient is hemodynamically stable (including no uncompensated CHF) and ischemia has been successfully suppressed for >=24 hours. Once these criteria are satisfied, any parenteral medicines can be converted to nonparenteral regimens in preparation for this transfer. Heparin use should be reassessed after 24 hours and may be discontinued in selected patients, such as those who are found to have a clearly identified secondary cause for unstable angina (e.g., anemia). ASA is continued without interruption.

Selection of Noninvasive Tests

Noninvasive functional or stress testing refers to a series of provocative tests that use either exercise or pharmacologic means to detect ischemia or inhomogeneity in myocardial blood flow due to obstructive CAD. The exercise tests are based on the principle of using a progressive physiologic stress (usually treadmill or bicycle exercise) to increase myocardial work and oxygen demand while using some method (ECG, function, perfusion) to document objective evidence of ischemia. Provocation of ischemia at a low workload (e.g., >=5 to 6 metabolic equivalents [METs]) signifies a high-risk patient who would generally merit referral to cardiac catheterization. On the other hand, attainment of a higher workload (e.g., >=5 to 6 METs) without ischemia is associated with a better prognosis, and many such patients can be safely managed conservatively. Other patients, including those who tolerate only a low workload but have no evident ischemia or those who develop ischemia at a high workload, represent an intermediate-risk group for whom several reasonable strategies can be proposed.

Pharmacologic stress testing provides an important complement to exercise testing, particularly for the subset of patients who are unable to exercise ( Zhu, Chung, Botvinick et al., 1991). The IV-administered coronary vasodilators such as dipyridamole decrease coronary vascular resistance and thus substantially increase coronary flow. Where significant epicardial coronary stenosis exists, the increase in flow is limited relative to myocardial segments supplied by nonobstructed coronary arteries. This flow discrepancy is routinely evaluated with perfusion scintigraphy. Occasionally, these agents produce ischemia by provoking an endocardial to epicardial steal and consequent diminished endocardial blood flow in the territory of a critical coronary stenosis. In contrast, dobutamine stress testing with measurement of cardiac function or perfusion acts by increasing myocardial oxygen demand in a fashion similar to exercise.

The greatest experience with these agents is in patients who are unable to exercise. In general, their prognostic value appears equivalent to exercise testing with imaging although there are few direct comparison studies of prognostic stratification with the two approaches. However, the known prognostic information derived from maximal exercise level attained argues for use of pharmacologic stress testing as an alternative to exercise testing only for specific indications.

No empirical data or theoretical arguments have yet established that LV function during exercise or pharmacologic stress provides more valuable prognostic information than a perfusion scan or vice versa. Both the extent of CAD and the degree of LV dysfunction are important for selection of appropriate therapy. Studies directly comparing prognostic information from multiple noninvasive tests for ischemia in patients after stabilization of unstable angina are hampered by small sample size ( Amanullah, Bevegard, Lindvall et al., 1992; Marmur, Freeman, Langer et al., 1990).

Two relatively large studies addressed the prognostic value of exercise testing in unstable angina to predict death and MI. The Multicenter Myocardial Ischemia Research Group recently reported the results of a 23-month followup study of the prognostic value of noninvasive testing in 936 stable CAD patients who had an MI (70%) or unstable angina (30%) hospitalization within the 6-month period prior to testing ( Moss, Goldstein, Hall et al., 1993). Noninvasive testing involved rest, ambulatory, and exercise ECG and stress thallium-201 scintigraphy. The outcome event tested was a composite of death (n=22), nonfatal MI (n=53), or unstable angina (n=125). In the primary analysis, only ST depression on the resting ECG was an independent prognostic factor. Both exercise ECG ST-depression (p=0.29) and reversible thallium defects (p=0.05) showed univariate trends towards a worse prognosis. Ambulatory ECG changes were not significant predictors of outcome in this population (p=0.93). Additional prespecified analyses revealed that the combination of exercise ST depression >0.10 mV and an exercise duration <9 minutes (modified Bruce protocol) identified patients at a 3.4-fold (<6 minutes) to 1.9-fold (6-9 minutes) increase in risk of cardiac events. With the exercise thallium, a reversible defect and increased lung thallium uptake indicated a 2.8-fold increase in risk; a reversible defect alone signified a 1.2-fold increase in risk.

The RISC study group evaluated the use of predischarge symptom-limited, bicycle exercise testing in 740 men admitted with unstable angina (51%) or non-Q-wave MI (49%) ( Nyman, Larsson, Areskog et al., 1992). Multivariate analysis showed that the extent of ischemic ST depression (number of positive leads) and low maximal workload were independent predictors of 1-year, infarct-free survival.

Table 10. Noninvasive studies in patients with unstable (more...)

Table 10. Noninvasive studies in patients with unstable angina reporting at least 10 cardiac events (cardiac death or myocardial infarction) during followup

	Study	Inclusion criteria	Low risk	High risk
A	Moss, Goldstein, Hall et al, 1993	30% Unstable angina 26% Non-Q-wave MI	893	23
B	Swahn, Areskog, Berglund et al, 1987	All unstable angina	247	145
C	Severi, Orsini, Marraccini et al, 1988	All unstable angina	199	175
D	Madsen, Thomsen, Mellemgaard et al, 1988	All unstable angina	118	98
E	Nyman, Larsson, Aresko et al, 1992	All unstable angina	366	374
F	Krone, Dwyer, Greenberg et al, 1989	All non-Q-wave MI	85	7
A	Moss, Goldstein, Hall et al, 1993	30% Unstable angina 26% Non-Q-wave MI	876	20
D	Madsen, Thomsen, Mellemgaard et al, 1988	All unstable angina	129	29
G	Gibson, Beller, Gheorghiade et al, 1986	36% Non-Q-wave MI 64% MI	133	108
H	Younis, Byers, Shaw et al, 1989	58% Unstable angina 42% MI	14	54

Figure 10: Noninvasive testing for risk stratification (more...)

   Figure 10: Noninvasive testing for risk stratification in patients with unstable angina

Source: Studies summarized in Table 10.

Figure 10

In low-risk patients, it is unclear that an imaging modality adds importantly to a standard treadmill test. Thus, selection of the test to use with an individual patient should rest primarily on patient characteristics, knowledge of local availability, and interpretation expertise. Because of simplicity, lower cost, and widespread familiarity with performance and interpretation, the standard ECG treadmill is the most reasonable test to select in patients able to exercise who have a normal resting ECG. Patients with an abnormal baseline ECG that would interfere with interpretation of the exercise results should have an imaging modality added to their test. Patients unable to exercise should have a pharmacologic stress test. The optimal testing strategy in women remains less well defined than in men. All major forms of exercise testing have been reported as less accurate for diagnosis in women. At least a portion of the lower reported accuracy derives from a lower pretest likelihood of CAD in populations of women compared with men. The relative accuracy of noninvasive testing for prognosis in women and men has not been adequately studied. Until data are reported to clarify this issue, it is reasonable to use noninvasive testing for prognosis in women as freely as in men with proper consideration of the influence of sex on the pretest likelihood of CAD.

The stress test using a standard protocol can be performed as soon as appropriate indications are present and the patient has stabilized clinically. In 1991, Larsson, Areskog, Areskog and colleagues compared the results of a symptom-limited exercise test performed before discharge at 3 to 7 days after an episode of unstable angina or non-Q-wave infarction with the results of a similar test 1 month later in 189 patients. The diagnostic and prognostic value of both tests was similar, but the earlier test identified events occurring over the first month which represented one-half of all events during the first year. This study illustrates the importance of early noninvasive testing for risk stratification of patients with unstable angina.

Use of Noninvasive Test Results in Patient Management

Noninvasive tests are most useful in patient management decisions when risk can be stated in terms of events over time. A large population of patients must be studied to derive and test equations needed to accurately predict risk for individual patients. No noninvasive study has been reported in a sufficient number of patients after stabilization of unstable angina to develop and test the accuracy of a multivariable equation to report test results in terms of absolute risk. Therefore, data borrowed from studies of patients with stable angina must be used if risk is to be reported as events/time. Although the pathologic process evoking ischemia may be different in the two subgroups, it is likely that use of prognostic nomograms derived on groups of patients with stable angina would also be predictive of risk in patients with recent unstable angina after stabilization. Using this untested assumption, the much larger literature derived from populations that include patients with both stable and unstable angina provides equations for risk stratification which convert physiologic changes observed during noninvasive testing into statements of risk expressed as events over time.

Figure 11: Nomogram of the prognostic relations embodied (more...)

   Figure 11: Nomogram of the prognostic relations embodied in the treadmill score

(Figure 11)

Cardiac Catheterization

This guideline proposes two alternative definitive treatment strategies termed "early invasive" and "early conservative." Randomized trial data did not support the inherent superiority of either strategy based on medical outcomes (TIMI IIIB, in press). The decision about which strategy to pursue for a given patient should be based on the patient's estimated risk (Chapter 1), available facilities, and patient preference. These strategies are defined below.

The principal data upon which these recommendations are based are the TIMI IIIB (in press) results. This study randomized 1,473 patients with unstable angina requiring hospital admission to early (18-48 hours) invasive or early conservative strategies. At 42 days, 15.5 percent of the early invasive patients had died, had a nonfatal MI, or had a positive 6-week exercise test versus 17.7 percent of the early conservative patients (p=0.26). Ninety-seven percent of the invasive group underwent diagnostic catheterization (as assigned) compared with 64 percent of the conservative group (p < 0.001). Revascularization by 42 days had been performed in 61 percent of the invasive group and 49 percent of the conservative group (p <0.001). In addition, conservatively treated patients had a significantly higher use of antianginal medications and more hospital readmissions by the 6-week followup.

Although data are not available to permit a formal cost-effectiveness analysis of these alternate strategies, any savings realized initially in the group not receiving cardiac catheterization appear to be largely offset by the need for longer hospitalization initially and for subsequent care. Unless continued followup of these patients shows late survival benefit for patients treated by the early invasive strategy, the aggressiveness of early use of cardiac catheterization and revascularization procedures would appear to be best determined by the preferences of the individual patient with unstable angina.

Patients who present with intermediate- or high-risk unstable angina and a history of a prior PTCA within the past year have a high incidence of restenosis which often can be effectively treated by repeat angioplasty. Noninvasive testing is not sufficiently accurate to detect restenosis in these patients, and coronary angiography without preceding functional testing is generally indicated. Patients with prior CABG surgery and intermediate- or high-risk unstable angina represent a second group for whom a strategy of early coronary angiography is generally indicated. In patients with recent bypass, early graft stenosis frequently can be treated with angioplasty. The complex interplay between progression of native coronary disease, development of graft atherosclerosis with ulceration and embolization, and the potential for noncardiac chest pain all argue for a greater need to visualize coronary arteries by catheterization in patients with prior bypass surgery than in patients with similar presenting symptoms but no prior procedure.

Patients with CAD and known or suspected poor LV function, such as patients with known prior Q-wave MIs or those who have had prior measurements of LV function or who present with CHF, have sufficient probability of benefit from revascularization procedures to merit direct coronary angiography without preceding functional testing.

Confirmation of normalcy in patients presenting frequently with symptoms of unstable angina and no objective evidence of ischemia represents another valid indication for cardiac catheterization. Identification and management of this patient group is described more fully in Chapter 3.

In unstable angina, results of catheterization typically show the following profile: (1) normal coronary arteries or insignificant CAD in 10 to 20 percent, (2) significant (i.e., >50%) left main disease in 5 to 10 percent, (3) three-vessel disease in 20 to 25 percent, (4) two-vessel disease in 25 to 30 percent, and (5) single-vessel disease in 30 to 35 percent. In the TIMI IIIB (in press) early invasive strategy, no significant CAD >60 percent obstruction was found in 19 percent of patients, one-vessel disease in 38 percent, two-vessel disease in 29 percent, three-vessel disease in 15 percent, and left main disease (>50 percent obstruction) in 4 percent. Lesions are often eccentric with irregular borders in patients with unstable angina, and irregular lesion morphology has correlated with an increased risk of ischemia, MI, and cardiac death ( Bugiardini, Pozzati, Borghi et al., 1991).

Discovery that a patient does not have significant obstructive CAD can help avert improper "labeling" and prompt a search for the true cause of symptoms. High-risk patients with two-vessel disease including patients with severe proximal LAD involvement, and those with severe three-vessel or left main disease should be considered for CABG. Many other patients will have less severe lesions that do not put them at high risk of cardiac death but can have a substantial negative impact on their quality of life. As compared with high-risk patients, low-risk patients will receive negligible or very modestly increased chances of long-term survival with CABG. Therefore, quality of life and patient preferences will be given more weight than strict clinical outcomes in selecting a treatment strategy. Low-risk patients whose symptoms do not respond well to maximal medical therapy and who experience a significant negative impact on their quality of life and functional status may be considered for revascularization. Patients in this group who are unwilling to accept the increased short-term procedural risks to gain long-term benefits or who are quite satisfied with their existing capabilities should be managed medically at first and followed carefully as outpatients. Other patients willing to accept the risks of revascularization and wishing to improve their functional status or to decrease symptoms may be considered appropriate candidates to undergo early elective revascularization.

It is not possible presently to define an arbitrary extent of comorbidity that would in every case make referral for cardiac catheterization and further invasive procedures inappropriate. As a general principle, the potential benefits of catheterization and revascularization must be carefully weighed against the risks which may be significantly greater in patients with significant comorbidity. This decision is further complicated because even when CABG surgery is not an option, high-risk patients may benefit from a palliative PTCA or other interventional procedure.

The case of the high-risk patient with significant comorbidities calls for especially thoughtful discussion between the health care practitioner, patient, and family. The decision for or against revascularization should be made on a case-by-case basis, and all parties should be in mutual agreement. Patients and families should understand that the presence of significant comorbidities can alter the revascularization risk-to-benefit ratio and negatively influence patient outcomes.

Examples of extensive comorbidity within the spirit of this recommendation include:

• Advanced or metastatic malignancy with a projected life expectancy <=1 year.

• Intracranial pathology contraindicating the use of systemic anticoagulation.

• End-stage hepatic cirrhosis with symptomatic portal hypertension (e.g., encephalopathy, visceral bleeding).

More difficult decisions involve patients with significant comorbidity but not as significant as described above. Examples of this group of patients include those with:

• Moderate or severe renal insufficiency.

• Hepatic cirrhosis with functional hepatic insufficiency.

The nature of the facility performing the catheterization also can be an important consideration in this evaluation. Specifically, the availability of interventional cardiologists experienced in high-risk and palliative PTCA should be considered, as should the availability of an experienced cardiac surgeon able and willing to take on complex, high-risk cases.

Revascularization

Revascularization is used to improve prognosis, relieve symptoms, and improve functional capacity in patients with obstructive CAD. In general, the indications for revascularization in the unstable angina patient who has been stabilized are the same as for stable angina, but the impetus for some form of revascularization is stronger than in stable angina. Moreover, long-term survival rates after CABG are similar for unstable angina patients who present with rest angina, increasing angina, new onset angina, or post-MI angina (Rahimtoola, Nunley, Grunkemeier et al., 1983).

CABG and PTCA are the two revascularization strategies available, and implicit in this guideline is the understanding that the initial treatment selection will be modified or supplemented when necessitated by changes in the patient's condition. Thus, subsequent referrals of a PTCA patient to CABG surgery or of a CABG surgery patient to PTCA (i.e., therapeutic crossovers) are integral parts of the initial treatment strategy. However, excessive crossover rates suggest inappropriate treatment selection, inadequate technical results, or both. Furthermore, although the percutaneous intervention strategy is referred to in this guideline as "PTCA," it should be recognized that this term refers to a family of techniques including standard balloon angioplasty, perfusion balloon (prolonged dilatation) angioplasty, atherectomy, laser angioplasty, and intracoronary stenting. Thus, once the decision has been made to attempt percutaneous coronary revascularization, a further decision is required about the optimal mode(s) of such intervention.

The TIMI-IIIB (in press) results comparing early invasive versus early conservative catheterization and revascularization have been described in the cardiac catheterization section of this chapter. Two randomized trials compared medical and surgical therapy in unstable angina. The National Cooperative Study Group randomized 288 patients between 1972 and 1976 at nine academic centers ( Russell, Moraski, Kouchoukos, 1978). The Veterans Administration Cooperative Study randomized 468 patients between 1976 and 1982 at 12 VA hospitals ( Luchi, Scott, and Deupree, 1987; Parisi, Khuri, Deupree et al., 1989; Scott, Luchi, and Deupree, 1988; Sharma, Deupree, Khuri et al., 1991). Both studies included patients with progressive or rest angina accompanied by ST- and T-wave changes. Patients over age 70 or with a recent MI were excluded. The VA study included only men.

In the National Cooperative Study, hospital mortality was 3 percent for medicine and 5 percent for CABG surgery (p=NS). Followup to 30 months failed to show any differences in survival between the therapies. In the VA study, survival to 2 years was the same for medicine and CABG surgery overall and in subgroups defined by number of diseased vessels. A post-hoc analysis of patients with depressed LV function, however, showed a significant survival advantage with CABG surgery. All randomized trials of CABG surgery versus medicine (including those in stable angina) have found improved symptom relief and functional capacity with CABG surgery. Long-term followup in these trials has suggested that by 10 years there is a significant attenuation of both symptom relief and survival benefits from CABG surgery. However, these randomized trials reflect an earlier technical era for both CABG surgery and medicine. Improvements in anesthesia and surgical techniques, including internal mammary artery grafting to the LAD artery and improved intraoperative myocardial protection with cold potassium cardioplegia, are not reflected in these trials. Also, the routine use of heparin and ASA in the acute phase and the range of therapeutic agents available represent significant differences in current practice from the era in which these trials were performed.

Three published and two unpublished randomized trials of PTCA have now been reported, but only one of these, the Randomized Intervention Treatment of Angina (RITA), enrolled unstable angina patients. The VA Angioplasty Compared with Medicine (ACME) trial tested PTCA versus medicine in single-vessel disease and found improved functional status and quality of life at 6 months in the PTCA arm ( Parisi, Folland, Hartigan et al., 1992). The RITA trial enrolled 1,011 patients in the United Kingdom with one-, two-, or three-vessel disease that had equal chance of revascularization success with either PTCA or CABG ( RITA, 1993). Approximately 60 percent of the enrolled patients were reported to have angina at rest prior to randomization. An interim analysis at 2.5 years of followup has shown equivalent hard cardiac events (death, MI) and a much higher repeat revascularization rate in the PTCA arm. The German Angioplasty Bypass Surgery Investigation (GABI), which randomized 358 patients with multivessel CAD and > class II angina to CABG or multivessel PTCA, recently reported that at 6-month followup, the primary endpoint (angina rates) was similar, and there was no significant difference in the rates of hard cardiac events (death, MI) between the CABG and PTCA groups. Initial results have recently been presented for the Coronary Artery Bypass Revascularization Investigation (CABRI) trial involving 1,054 multivessel CAD patients randomized to PTCA or CABG. The Emory Angioplasty vs. Surgery Trial (EAST) also reported, but has not published, outcomes in 392 patients with multivessel disease, including a majority of patients with unstable angina, randomized between PTCA and CABG. The reported results of these two unpublished trials do not differ substantially from the reported results of the RITA trial.

One large registry compared 5-year survival with medicine, PTCA, and CABG in 9,263 CAD patients with unstable angina (defined as symptoms requiring hospital admission for control and to rule out MI) treated between 1984 and 1990 ( Mark, Nelson, Califf et al., in press). In this nonrandomized comparison, extensive statistical adjustments were used to control for prognostically important baseline differences created by treatment selection. For patients with three-vessel disease or two-vessel disease with a proximal severe (>=95%) LAD artery stenosis, surgical survival at 5 years was significantly better than medicine, and a similar trend in favor of CABG was found in comparison with PTCA. In less severe two-vessel CAD, revascularization improved survival relative to medicine, and there was a trend for PTCA to provide better survival results (due to lower procedural mortality) than CABG. In one-vessel disease, all therapies were associated with high 5-year survival rates with very small differences among groups.

The available data can be used to formulate some general principles about the proper role of revascularization in acute IHD. The first general principle is the more extensive the CAD, the larger the benefit in survival realized from revascularization ( Califf, Harrell, Lee et al., 1989). In the most severe forms of CAD (e.g., left main disease, three-vessel disease), CABG provides the best long-term survival results. In intermediate forms of CAD (e.g., two-vessel disease), revascularization provides improved survival relative to medicine, although the absolute survival benefit is smaller than in three-vessel disease. In general, the patient with high-risk two-vessel disease (as defined by impaired LV function, older age, or coexisting vascular disease) will have improved survival with CABG surgery as compared with other patients who have two-vessel disease and similar anatomy. For other two-vessel disease patients, PTCA may provide modest survival benefits relative to medicine. In the least severe CAD patients (i.e., one-vessel disease), observational data have shown good survival associated with medical therapy, PTCA, and CABG. The primary treatment choice is usually between medicine and PTCA, with CABG reserved for those patients with large areas of myocardium at risk, those who fail medical therapy, or those who are technically unsuitable for PTCA.

The second general principle is that survival benefits of revascularization are magnified on the absolute scale by factors that increase overall medical risk, especially LV dysfunction and advanced age. In particular, multivessel CAD benefits from CABG are substantially larger on an absolute scale in patients with depressed LV function. These factors tend to increase the procedural risks of revascularization somewhat but offer proportionally greater long-term benefits than can be expected with medical treatment ( Califf, Harrell, Lee et al., 1989; McCormick, Schick, McCabe et al., 1985).

Discharge Medical Regimen

The use of and rationale for different medical agents have been described earlier in this guideline. In most cases, the inpatient medical regimen used in the nonintensive phase will be continued postdischarge. The need for continued medical therapy after discharge relates to potential prognostic benefits (primarily shown for ASA and beta blockers), control of symptoms (nitrates and calcium antagonists), and treatment of major risk factors, such as hypertension, hyperlipidemia, and diabetes mellitus. Thus, selection of a medical regimen will be individualized to the specific needs of each patient and the events that have occurred in hospital.

Discharge of a patient from the hospital often requires a team effort from the medical staff (physicians, nurses, dietitians, pharmacists, rehabilitation specialists, physical and occupational therapists). Use of instruction sheets can help to document and reinforce the instructions given but should not be used in lieu of in-person instruction.

Postdischarge Followup

Clinical information available at discharge has been shown by Cox analysis to predict death within 1 year in 515 survivors of hospitalization for non-Q-wave MI, including persistent ST-segment depression, CHF, advanced age, and ST-segment elevation ( Schechtman, Capone, Kleiger et al., 1989). Patients with all high-risk markers present had a 14-fold increase in mortality compared with patients with all markers absent. Patients recognized to be at high risk for a cardiac event after discharge deserve earlier and more frequent followup than low-risk patients.

It is presently unclear whether patients who come through an episode of unstable angina without complications are at increased risk for future episodes of unstable angina, but their overall risk for death or MI is similar to that of other CAD patients with their characteristics who have not had unstable angina. The last element in the management of unstable angina, therefore, is a followup clinic visit at the point when the patient's disease activity has returned to the baseline level.

Use of Medications

Monitoring Symptoms

Either formal or informal telephone followup can serve to reinforce in-hospital learning, provide reassurance, and answer the patient's questions. Beckie (1989) found that bypass patients in a telephone followup program telephoned their physicians less frequently and had fewer readmissions, lower anxiety, and higher CAD knowledge scores compared with the control group.

Where personnel and budget resources allow, the health care team may consider establishing such a followup system in which nurses telephone patients approximately once a week for the first 4 weeks after discharge. This structured program would gauge the progress of the patient's recovery, reinforce the CAD education taught in hospital, address patient questions and concerns, and monitor progress in meeting risk behavior modification goals.

Activity Level and Lifestyle Changes

The health care team should work with patients and their families to set specific goals for risk-factor reduction. In some cases, the family may be able and willing to support the patient further by also making changes in risk behaviors (e.g., cooking low-fat meals for the entire family, exercising together).

Particular attention should be paid to smoking cessation. Daly, Mulcahy, Graham, and colleagues (1983) measured the long-term effects of smoking on patients with unstable angina. For men under 60 years of age, those who continued to smoke had a risk of death from all causes 5.4 times that of men who stopped smoking (p <0.05).

More specific recommendations on risk-factor modification and cardiac rehabilitation are beyond the scope of this guideline.

Very often patients will not ask their physicians or other health care providers about resuming sexual activity after their hospitalization. When appropriate, patients need to be reassured that sexual activity is still possible, and it is not likely to result in death or recurrent symptoms.

Consultant

• Douglass A. Morrison, MD

• Director

• Cardiac Catheterization Laboratory Denver Veterans Affairs Medical Center

Peer Reviewers

• Cary W. Akins, MD

• Associate Clinical Professor of Surgery

• Massachusetts General Hospital

• Boston, MA

• Gregory L. Angstman, MD

• Consultant, Kasson-Mayo Family Practice Clinic

• Kasson, MN

• David Baker, MD, MPH

• Assistant Professor of Medicine

• Harbor-UCLA Medical Center

• Consultant,

• RAND Corporation

• Los Angeles, CA

• George A. Beller, MD

• Chief, Division of Cardiology

• University of Virginia Health Sciences Center

• Charlottesville, VA

• Daniel S. Berman, MD

• Professor of Medicine

• UCLA School of Medicine

• Co-Chairman

• Department of Imaging Cedars-Sinai Medical Center

• Los Angeles, CA

• [1]Being listed in this section does not necessarily imply endorsement of the guideline.

• Virginia Trotter Betts, JD, MSN, RN

• President

• American Nurses Association

• Washington, DC

• Robert O. Bonow, MD

• Goldberg Professor of Medicine

• Chief, Division of Cardiology

• Northwestern University Medical School

• Chicago, IL

• Catherine Borbas, PhD, MPH

• Executive Director

• Healthcare Education and Research Foundation

• St. Paul, MN

• J. David Bristow, MD

• Professor of Medicine,

• Emeritus Oregon Health Sciences University

• Portland, OR

• James E. Calvin, MD

• Associate Professor of Medicine

• Director, Coronary Care Unit

• Rush-Presbyterian-St. Luke's Medical Center

• Chicago, IL

• Stephen V. Cantrell, MD

• Associate Director, Emergency Medical Services

• Denver General Hospital

• Denver, CO

• Walter Harry Caulfield, Jr, MD

• Executive Director

• Permanente Medical Group, Inc.

• Oakland, CA

• Bernard R. Chaitman, MD

• Professor of Medicine

• Chief, Cardiology Division

• St. Louis University Health Sciences Center

• St. Louis, MO

• Kanu Chatterjee, MB

• Lucie Stern Professor of Cardiology

• Director, Cardiac Care Unit

• Associate Chief of Cardiology

• University of California, San Francisco

• San Francisco, CA

• W. Randolph Chitwood, MD

• Professor and Chief, Division of Cardiothoracic Surgery

• Vice Chairman, Department of Surgery

• East Carolina University

• Greenville, NC

• Lawrence H. Cohn, MD

• Professor of Surgery

• Harvard Medical School

• Chief, Division of Cardiac Surgery

• Brigham & Women's Hospital

• Boston, MA

• C. Richard Conti, MD

• Professor of Medicine

• Chief, Division of Cardiology

• University of Florida

• Gainesville, FL

• William C. Dalsey, MD

• Chairman, Department of Emergency Medicine

• Albert Einstein Medical Center

• Associate Professor of Medicine

• Temple University Medical School

• Blue Bell, PA

• George A. Diamond, MD

• Professor of Medicine

• University of California,

• Los Angeles

• Director, Cardiac Stress Laboratory

• Cedars-Sinai Medical Center

• Los Angeles, CA

• Donald B. Doty, MD

• Clinical Professor of Surgery

• University of Utah

• Chairman, Cardiovascular and Thoracic Surgery

• LDS Hospital

• Salt Lake City, UT

• Kathleen Dracup, RN, DNSc

• Professor of Nursing

• University of California, Los Angeles

• Los Angeles, CA

• T. Bruce Ferguson, MD

• Associate Professor of Surgery

• Washington University School of Medicine

• St. Louis, MO

• Francis M. Fesmire, MD

• Clinical Instructor

• University of Tennessee College of Medicine

• Chattanooga, TN

• Richard G. Fosburg, MD

• Chief of Staff

• Scripps Memorial Hospital

• LaJolla, CA

• Victor F. Froelicher, MD

• Clinical Professor of Medicine

• Stanford University School of Medicine

• Palo Alto, CA

• Erika Sivarajan Froelicher, RN, PhD

• Professor and Chair, Department of Physiological Nursing

• School of Nursing University of California, San Francisco

• San Francisco, CA

• Timothy J. Gardner, MD

• William M. Measey Professor of Surgery

• Chief, Division of Cardiothoracic Surgery

• University of Pennsylvania Medical Center

• Philadelphia, PA

• Bernard J. Gersh, MB, ChB, DPhil

• W. Proctor Harvey Teaching Professor of Cardiology

• Chief, Division of Cardiology

• Georgetown University Medical Center

• Washington, DC

• Raymond J. Gibbons, MD

• Professor of Medicine

• Mayo Clinic

• Rochester, MN

• Robert A. Guyton, MD

• Chief, Cardiothoracic Surgery

• Emory University School of Medicine

• Atlanta, GA

• Stephen F. Hamilton, PharmD

• Associate Professor of Pharmacy Practice

• University of Oklahoma, College of Pharmacy

• Oklahoma City, OK

• George L. Hicks, Jr, MD

• Chair, Division of Cardiothoracic Surgery

• University of Rochester Medical School

• Rochester, NY

• Adolph M. Hutter, MD

• Associate Professor of Medicine

• Harvard Medical School

• Chair, Medical Intensive Care Coordinating Committee

• Massachusetts General Hospital

• Boston, MA

• George C. Kaiser, MD

• Professor of Surgery

• St. Louis University

• Chief of Cardiac Surgery

• St. Louis University Medical Center

• St. Louis, MO

• Stephen Karas, Jr, MD

• Associate Clinical Professor of Medicine

• University of California, San Diego

• La Jolla, CA

• Anthony L. Komaroff, MD

• Professor of Medicine

• Harvard Medical School

• Chief, Division of General Medicine

• Brigham & Women's Hospital

• Boston, MA

• Marvin A. Konstam, MD

• Professor of Medicine and Radiology

• Tufts University School of Medicine

• Director, Adult Cardiac Catheterization Laboratory

• New England Medical Center

• Boston, MA

• Lucian L. Leape, MD

• Adjunct Professor of Health Policy

• Harvard School of Public Health

• Boston, MA

• H. Eugene Lindsey, Jr, MD

• Harvard Community Health Plan

• Brookline, MA

• Larry M. Lopez, PharmD

• Professor of Pharmacy

• University of Florida College of Pharmacy

• Gainesville, FL

• James H. Moller, MD

• Professor of Pediatrics

• University of Minnesota

• President,

• American Heart Association

• Minneapolis, MN

• Barbara A. Murphy, MD

• Assistant Professor of Surgery Emergency Medicine

• Duke University Medical Center

• Durham, NC

• Ira S. Nash, MD

• Instructor in Medicine

• Harvard Medical School Cardiac Unit Massachusetts General Hospital

• Boston, MA

• Linda M. Nicolson, RN, MSN, CEN, MICN

• Clinical Nurse Specialist

• Emergency Department Grossmount Hospital

• La Mesa, CA

• William C. Nugent, MD

• Chair, Section of Cardiothoracic Surgery

• Dartmouth-Hitchcock Medical Center

• Lebanon, NH

• Stephen G.Pauker, MD

• Professor of Medicine

• Tufts University School of Medicine

• Chief, Division of Clinical Decision Making

• New England Medical Center

• Boston, MA

• Douglas Payne, MD

• Professor and Acting Chair Department of Cardiothoracic Surgery

• New England Medical Center

• Boston, MA

• Carl J. Pepine, MD

• Professor of Medicine

• Co-Director, Division of Cardiovascular Medicine

• University of Florida

• Gainsville, FL

• W. Gerald Rainer, MD

• Clinical Professor of Surgery

• University of Colorado Health Sciences Center

• Denver, CO

• Nancy S. Redeker, PhD, MSN, RNC

• Assistant Professor School of Nursing

• Rutgers, The State University of New Jersey

• Newark, NJ

• James L. Ritchie, MD

• Professor of Medicine

• University of Washington School of Medicine

• Chief, Cardiovascular Disease Section

• Seattle Veterans Affairs Medical Center

• Seattle, WA

• John F. Robb, MD

• Assistant Professor of Medicine

• Dartmouth Medical School

• Director, Cardiac Catheterization Laboratories

• Dartmouth-Hitchcock Medical Center

• Lebanon, NH

• Nicholas P. Rossi, MD

• Professor, Division of Cardiothoracic Surgery

• University of Iowa Hospitals and Clinics

• Iowa City, IA

• Richard O. Russell, Jr, MD

• Alabama Heart Institute

• Birmingham, AL

• John Rutherford, MD

• Professor of Medicine

• Chief, Cardiovascular Disease Service

• University of Texas Southwestern Medical Center

• Dallas, TX

• Thomas J. Ryan, MD

• Professor of Medicine and Chief of Cardiology

• Boston University School of Medicine

• Boston, MA

• Deeb N. Salem, MD

• Professor of Medicine

• Tufts University School of Medicine

• Chief, Division of Cardiology

• New England Medical Center

• Boston, MA

• Daniel G. Sayers, MD

• Clinical Assistant Professor of Surgery Emergency Medicine Bowman Gray

• School of Medicine

• Winston-Salem, NC

• Theodore L. Schreiber, MD

• Co-Director, Interventional Cardiology

• William Beamont Hospital

• Royal Oak, MI

• Paul M. Schyve, MD

• Senior Vice President

• Joint Commission on the Accreditation of Healthcare Organizations

• Oakbrook Terrace, IL

• Stewart M. Scott, MD

• Consulting Professor of Surgery

• Duke University School of Medicine

• Chief, Surgical Service

• Ashville Veterans Affairs Medical Center

• Ashville, NC

• Harry P. Selker, MD

• Associate Professor of Medicine

• Tufts University School of Medicine

• Director, Center for Cardiovascular Health Services Research

• New England Medical Center

• Boston, MA

• David J. Shulkin, MD

• Assistant Professor of Medicine

• University of Pennsylvania

• Director, Clinical Outcome Assessment and Quality Management

• University of Pennsylvania Medical Center

• Philadelphia, PA

• Robert J. Stomel, DO

• Chief, Division of Cardiology

• Botsford General Hospital

• Farmington Hills, MI

• Kathleen A. Stringer, PharmD

• Assistant Professor

• School of Pharmacy University of Colorado Health Sciences Center

• Denver, CO

• Richard Scott Stuart, MD

• Assistant Professor of Cardiac Surgery

• Johns Hopkins Hospital

• Baltimore, MD

• Judith L. Swain, MD

• Chief, Cardiovascular Division

• Hospital of the University of Pennsylvania

• Philadelphia, PA

• Pierre Theroux, MD

• Clinical Research Professor

• University of Montreal

• Chief, Coronary Care Unit

• Institut de Cardiologie de Montreal

• Montreal, Canada

• Robert A. Vogel, MD

• Herbert Berger Professor of Medicine

• University of Maryland School of Medicine

• Head, Division of Cardiology

• University of Maryland Medical Center

• Baltimore, MD

• Andrew S. Wechsler, MD

• Stuart McGuire Professor and Chairman Department of Surgery

• Professor of Physiology

• Medical College of Virginia Virginia Commonwealth University

• Richmond, VA

• Sylvan L. Weinberg, MD

• Clinical Professor of Medicine

• Wright State University School of Medicine

• Chairman, Section of Cardiology

• Good Samaritan Hospital

• Dayton, OH

• Gayle R. Whitman, RN, MSN

• Director, Cardiac Nursing

• Cleveland Clinic

• Cleveland, OH

• David M. Witter, Jr

• President and CEO

• Academic Medical Centers Consortium

• Rochester, NY

• Douglas L. Wood, MD

• Vice-Chair, Department of Internal Medicine

• Mayo Clinic

• Rochester, MN

• Percy Wootton, MD

• Member, Board of Trustees

• American Medical Association

• Richmond, VA

Pilot Reviewers

• David M. Abbey, MD

• Assistant Clinical Professor

• University of Colorado Health Sciences Center

• Fort Collins, CO

• Jonathan S. Appelbaum, MD

• Plainfield Medical Center

• Moosup, CT

• Alan R. Aronson, MD

• Vernon Hills, IL

• William T. Belt, Jr, MD

• University of Texas Health Center

• Tyler, TX

• William B.A. Bentley, MD

• Las Vegas, NV

• Gregory B. Buck, MD

• Wauwatosa, WI

• Donald E. Casey, Jr, MD

• Kingman, AZ

• John G. Casey, MD

• Dallas, TX

• Thomas F. Claffey, MD

• South Portland, ME

• Donna Ruth Cooper, MD

• Cambridge, MA

• Lee J. Cordova, MD

• Oregon City, OR

• David G. Covell, MD

• Pasadena, CA

• Joseph A. DiPoala, Sr, MD

• Rochester, NY

• Stephen Epstein, MD

• Fort Worth, TX

• Matthew N. Fine, MD

• Oroville, CA

• Nick Fitterman, MD

• Huntington, NY

• Paul A. Gitman, MD

• Manhasset Hills, NY

• Edward H. Greenberg, MD

• Internal Medicine Center to Advance Research and Education

• Hollywood, FL

• Michael A.W. Hattwick, MD

• Annandale, VA

• Robert M. Kohn, MD

• Clinical Professor of Medicine

• SUNY Buffalo

• Buffalo, NY

• Richard H. Kosterlitz, MD

• Associate Professor of Medicine

• University of Oregon Health Sciences Center

• Portland, OR

• Mark A. LaPorta, MD

• Miami Beach, FL

• Leonardo V. Lopez, MD

• Miami, FL

• Floyd L. Lummus, MD

• Tupelo, MS

• Michael Martonick, MD

• Arlington, WA

• Sebastian A. Mazzotta, MD

• Canton-Potsdam Hospital

• Canton, NY

• A.T. Pagter, Jr, MD

• Tryon, NC

• Neil H. Parker, MD

• UCLA School of Medicine

• Los Angeles, CA

• Jay I. Pomerantz, MD

• Pittsford, NY

• Herbert P. Reinhardt, MD

• Oklahoma City, OK

• Roger A. Renfrew, MD

• Skowhegan, ME

• John S. Santa, MD

• Medical Director

• BC/BS of Oregon

• Portland, OR

• Bernard R. Shochet, MD

• Baltimore, MD

• Laurence J. Shapiro, MD

• University of California, Irvine

• Newport Beach, CA

• Robert B. Sklaroff, MD

• Rydal, PA

• Gary M. Smith, MD

• Ferriday, LA

• Kenneth W. Stubbs, MD

• Natchez, MS

• T. Eugene Temple, Jr, MD

• Director of Medical Education

• Riverside Regional Medical Center

• Newport News, VA

• Donald F. Terry, MD

• Wichita Falls, TX

• Kenneth L. Wehr, MD

• Taft Place Medical Center

• Hamilton, OH

• Andrew Wormser, MD

• New Haven, CT

• Steven A. Yarrows, MD

• Chelsea, MI

• Don J. Young, MD

• Sandusky OH

• J. Michael Zylka, MD

• Director of Medicine

• St. Louis County

• Webster Groves, MO

AHCPR Staff

• Harriett V. Bennett, BA

• Public Affairs Specialist

• Barbara Fleming, MD, PhD

• Project Officer

• Mary L. Grady, BS

• Managing Editor

Publication Design

• Candace Cato, BA

• Designer Typography and Design

• U.S. Government Printing Office

• Janice E. Sterling, BA

• Designer Typography and Design

• U.S. Government Printing Office