ACC/AHA guidelines for coronary angiography

A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Coronary Angiography) developed in collaboration with the Society for Cardiac Angiography and Interventions

a Definitions

Patients with CAD may become symptomatic in many different ways but most commonly develop angina pectoris. In this document, angina pectoris (or simply angina) means a chest discomfort due to myocardial ischemia, often described as a transient squeezing, pressure-like precordial discomfort. Angina is generally provoked by physical effort (particularly during the postprandial state), with exposure to cold environment or by emotional stress. The discomfort on effort is relieved by rest, its duration being a matter of minutes. The ease of provocation, frequency and duration of episodes may remain relatively unchanged in individuals for extended time periods, leading to the term “stable angina pectoris.”

Not all stable chest pain syndromes are truly anginal. Various authors have subdivided stable chest pain syndromes in an attempt to link the quality of symptoms with the prevalence of significant CAD. Diamond and Forrester (84)found significant CAD at angiography in 89% of patients with typical angina but in only 50% with atypical angina and merely 16% of patients with nonanginal chest pain.

In CASS, 8,157 patients with chronic stable chest pain who underwent coronary angiography were characterized by type of symptoms reported. The CASS definitions of anginal type have become standards for much subsequent literature (85). “Definite angina” was defined as substernal discomfort precipitated by exertion and relieved by rest or nitroglycerin in <10 min. Most patients reported typical radiation to the shoulders, jaw or inner aspect of the arm. Patients with probable angina had most of the features of definite angina, but the features were atypical in some respects (e.g., radiation, unpredictable relief with nitroglycerin or duration up to 15 to 20 min). The third group had “nonspecific chest pain” that did not fit either of the above two groups. The prevalence of significant CAD in patients with definite angina, probable angina and nonspecific chest pain was 93%, 66% and 14% in men, and 72%, 36% and 6% in women (p < 0.001). The age and sex of the patients as well as the character of chest pain were important determinants of disease prevalence and severity. Coronary disease associated with high risk for adverse outcomes, that is, left main or three-vessel disease, occurred in >50% of middle-aged men and older women with definite angina and most men who had probable angina who were >60 years. In contrast, high-risk coronary disease was uncommon in both men and women with nonspecific chest pain, especially in patients <60 years.

The definition and diagnosis of angina is sometimes made more difficult by the predominance of other symptoms such as exertional dyspnea or fatigue, which may be “anginal equivalents.” Women frequently present with symptoms that do not have the features classically described in studies of large populations of middle-aged men. Furthermore, women have a higher frequency of asymptomatic ischemia (86).

Angina is further defined according to a gradient of severity as outlined by the CCS classification (87)(Appendix D). In addition, asymptomatic patients with CADare those with no symptoms to suggest myocardial ischemia in the previous six weeks(88). It is recognized that when tested, a subgroup of these patients will have transient abnormalities consistent with myocardial ischemia in the absence of symptoms. This is termed silent ischemia, and the abnormalities detected may consist of reversible ECG ST-segment shifts on exercise testing or ambulatory monitoring, perfusion abnormalities on radionuclide scans (i.e., stress ²⁰¹Tl, sestamibi, and PET) or regional wall motion abnormalities during left ventricular imaging (i.e., stress echocardiography or radionuclide ventriculography). It is appropriate to use the term ischemia in this context and to reserve the term angina to describe the subjective symptom felt by patients during episodes of myocardial ischemia. In general, these ischemic test results relate to the functional severity of CAD and are predictors of risk for future adverse outcome, independent of the perception of, or severity of symptoms. Thus, the absence of current symptoms does not necessarily mean either the absence of ischemia or the absence of an impaired prognosis. Diabetes, older age, female gender, hypertension, polyneuropathy, and cardiac transplantation, when accompanied by significant CAD, are all associated with a high frequency of ischemia or even MI without symptoms (89–92).

Patients with known CAD can be divided into two groups based on whether or not they ever had symptoms. One group includes those who were never symptomatic but in whom CAD was documented for other reasons. For example, abnormalities on a stress test led to an angiogram; the patient was a cardiac surgical candidate (e.g., valve replacement) and therefore angiography was done as a preoperative evaluation; or other clinical findings (e.g., asymptomatic MI or abnormal ECG) led to an angiogram. The other group includes those who were previously symptomatic but are currently asymptomatic (i.e., no symptoms within six weeks). This group would include, for example, those who previously had angina but are now asymptomatic; patients after symptomatic MI with no postinfarction angina; patients after revascularization (either CABG or PTCA) who now have no angina; and those who were effectively treated (i.e., drugs or activity restriction) who now have no angina. Although this grouping is convenient because it summarizes how these patients present to the clinician, there are no data to suggest that such clinical grouping, based on whether or not patients are currently symptomatic, has prognostic significance.

b Management approach for symptomatic patients

Patients with stable chest pain syndromes should undergo a thorough clinical evaluation, including classification of chest pain type into definite or probable angina or nonspecific chest pain, and identification of risk factors (age, tobacco use, dyslipidemia, hypertension, family history of premature coronary disease, activity profile, obesity, postmenopausal status and diabetes). The physical examination will usually detect evidence of other types of heart disease that can cause angina, e.g., aortic stenosis, hypertrophic cardiomyopathy or severe pulmonary hypertension. An assessment of contraindications for coronary angiography should be part of this clinical assessment. The CCS classification of angina provides a useful guide for the assessment of severity of definite or probable angina. Severe symptoms (CCS class III or IV) suggest severe CAD and are an indication for cardiac catheterization.

Optimal medical management may include nitrates, long-acting calcium channel blockers, and beta-adrenergic blocking agents, as well as attention to associated conditions such as hypertension, dyslipidemia and diabetes. Therapy is considered adequate if it includes two of the three antianginal agents used at or near maximum recommended doses in addition to antiplatelet therapy. For most patients, medical therapy is considered successful when angina has been eliminated or no longer adversely influences their lifestyle, and they are able to exercise beyond the end of stage II of the Bruce protocol without experiencing angina and ST-segment depression. Patients with definite or probable angina for whom optimal pharmacologic therapy has failed and those with an intolerance to these medications are candidates for coronary angiography. Patients who are treated medically but who demonstrate subsequent deterioration on noninvasive testing that suggests progression of disease are often considered for coronary angiography. Coronary angiography should also be considered for patients whose angina accelerates or intensifies despite adequate medical care, even if their symptoms do not fulfill the criteria for a diagnosis of unstable angina. Stable angina patients who have survived sudden cardiac death or sustained ventricular tachycardia are generally referred for coronary angiography to identify coronary lesions that, if treated appropriately, could relieve the ischemic substrate for lethal arrhythmias (93).

From time to time, CCS class I to II patients, whose occupation or other circumstance constitutes a risk to themselves or others, should undergo coronary angiography even in the absence of high-risk markers for adverse outcome on noninvasive testing. Such “need-to-know” circumstances may exist for airplane pilots, train operators, firefighters, school bus drivers, serious athletes and others.

c Management approach for asymptomatic or mildly symptomatic patients with known or suspected CAD

A scheme for noninvasive evaluation of a mildly symptomatic or asymptomatic patient suspected or known to have significant CAD is shown in Figure 1. Exercise-induced ECG changes, abnormalities on radionuclide myocardial perfusion scans, and abnormalities on ventricular wall motion studies (Table 5)are established markers for high risk of adverse outcomes. Although these noninvasive stress test markers are neither 100% sensitive nor 100% specific, when properly used, they do have very acceptable predictive value for adverse outcome. Thus, they aid in the selection of appropriate candidates for coronary angiography when symptom severity alone does not support such a recommendation. A minority of patients undergoing noninvasive testing will have findings that suggest a high risk for adverse outcome, but in most of these high-risk cases, a recommendation for coronary angiography is warranted.

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Figure 1

Clinical context for noninvasive and invasive diagnostic testing of patients with suspected ischemic heart disease. ∗ECG interpretable unless preexcitation, electronically paced rhythm, left bundle-branch block or resting ST-segment depression >1 mm. See text for discussion of digoxin use, left ventricular hypertrophy, and ST depression <1 mm. ∗∗For example, high risk if Duke treadmill score predicts average annual mortality >3% (see Fig. 2for nomogram). Modified from Figure 1 of the “ACC/AHA Guidelines for Exercise Testing” (81).

The criteria (Fig. 2)cited for identifying patients at high risk for adverse outcome during exercise ECG testing have evolved from both the original and the revised joint ACC/AHA Task Force reports (81,95)and a special report on exercise standards from the AHA (96). These reports emphasize the difficulties in interpreting ECG changes in selected populations, such as premenopausal women with a low pretest likelihood of coronary disease. Also, it should be noted that most apparently healthy men who have a positive (i.e., 1-mm ST depression) exercise ECG test (without high-risk criteria) but who lack clinical risk factors do not have significant CAD (97).

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Figure 2

Nomogram of the prognostic relations in the treadmill score. Determination of prognosis proceeds in five steps: 1. The observed amount of exercise-induced ST-segment deviation (the largest elevation or depression after resting changes have been subtracted) is marked on the line for ST-segment deviation during exercise. 2. The observed degree of angina during exercise is marked on the line for angina. 3. The marks for ST-segment deviation and degree of angina are connected with a straight edge. The point where this line intersects the ischemia reading line is noted. 4. The total number of minutes of exercise in treadmill testing according to the Bruce protocol (or the equivalent in multiples of resting oxygen consumption [METs] from an alternative protocol) is marked on the exercise-duration line. 5. The mark for ischemia is connected with that for exercise duration. The point at which this line intersects the line for prognosis indicates the five-year survival rate and average annual mortality for patients with these characteristics.

Patients with <1 mm of exercise-induced ST-segment depression should be counted as having 0 mm. Angina during exercise refers to typical effort angina or an equivalent exercise-induced symptom that represents the patient’s presenting complaint. This nomogram applies to patients with known or suspected coronary artery disease, without prior revascularization or recent myocardial infarction, who undergo exercise testing prior to coronary angiography.

Modified from Mark et al. (94).

Copyright © 1991 Massachusetts Media Society. All rights reserved. Prognostic value of a treadmill exercise score in outpatients with suspected coronary artery disease. NEJM 1991;325:849–53. With permission Shaw L, Harrell FE Jr., et al.

Radionuclide perfusion imaging techniques generally have higher specificity for significant CAD than ECG-based tests used alone but are much more costly. The radionuclide techniques are most cost-effective in identifying severe multivessel CAD in patients with uninterpretable ECGs and in patients who have an abnormal exercise ECG that does not fulfill high-risk criteria (Table 5). These findings are summarized in the “ACC/AHA Guidelines for Clinical Use of Cardiac Radionuclide Imaging” (82,98). That committee concluded that use of exercise or pharmacologic myocardial perfusion imaging with thallium or rest and exercise radionuclide angiography was usually appropriate and considered useful for assessment of severity of ischemia and risk stratification of patients with known or suspected CAD. They thought that the use of gated sestamibi perfusion imaging was also acceptable for this purpose but that its usefulness was less well established. The most consistent predictor of cardiac death or nonfatal MI was the number of transient perfusion defects provoked by either exercise or pharmacologic stress. Patients with CAD and redistribution defects on stress thallium imaging in >1 coronary artery region or who have a combination of redistribution abnormalities and increased lung uptake are at increased risk for adverse outcome (98). Normal stress ²⁰¹Tl scans are highly predictive of a good outcome, even in patients with documented CAD. An analysis of 3,595 such patients, followed up for ≤29 months in 16 separate studies, revealed a 0.9% annual rate of cardiac death or MI (99), nearly as low as that seen in the general population (100).

Assessment of left ventricular function (radionuclide ventriculography or echocardiography) shows that mortality rates progressively increase as left ventricular ejection fraction at rest decreases. When ejection fraction decreases ≥10% with exercise or fails to exceed 0.50 during exercise, particularly in association with new or worsening regional wall motion abnormalities, prognosis is also impaired (98). Similarly, patients at increased risk for adverse outcome can be identified by a reduced ejection fraction with rest echocardiography or by stress echocardiography that shows multiple new or worsening regional wall motion abnormalities during stress (100–109).

Appropriate treatment of patients with ischemia but not severe symptoms was addressed in the Asymptomatic Cardiac Ischemia Pilot (ACIP) study (88,110,111). Clinically stable patients with CAD (a third were asymptomatic, and the majority had multivessel disease and normal ventricular function) and ischemia on both stress testing and ambulatory ECG monitoring were randomized to either initial medical or revascularization treatment strategies. Patients randomized to a medical strategy could cross over to revascularization at any time to relieve severe symptoms. Although there were only a small number of events, the results suggested that patients randomized to initial revascularization had better outcomes (fewer deaths and nonfatal MIs as well as hospitalizations) at one and two years than did those randomized to initial medical treatment (110,112). Although these findings require confirmation in a larger trial with mortality as the outcome, they do support overviews of nonrandomized (113,114)and randomized (115)trial data that concluded that asymptomatic or mildly symptomatic patients with severe ischemia on noninvasive testing do better with initial revascularization than with initial medical therapy.

There is varying opinion as to when coronary angiography should be performed in asymptomatic patients in whom noninvasive testing indicates ischemia (i.e., a high probability of CAD), but in whom test criteria do not indicate high risk for adverse outcomes. In part, this is attributable to the observation that the development of ischemia on these tests may not in itself indicate a poor prognosis (99). In this group with ischemia, but no test abnormalities to suggest high risk, the presence of multiple clinical risk factors such as increased age, diabetes, or occupational or lifestyle risks become increasingly important considerations when determining whether coronary angiography should be performed. However, it should be recognized that there are no controlled studies that show an advantage for angiography or revascularization over a conservative medical “wait and see” approach for any of these clinical subsets.

Because transplanted hearts often develop occlusive coronary arteriopathy, and because ischemia in patients with denervated hearts is generally asymptomatic, it has become common practice to perform periodic coronary angiography (and often intravascular coronary ultrasound), usually annually, after transplantation. The prognostic benefit of this practice has not been clearly established. It has also become a common part of the screening process to perform coronary angiography in candidates for liver, lung or kidney transplantation if they are ≥40 years of age, even in the absence of significant clinical risk factors for coronary disease. It would seem that noninvasive testing could be substituted for coronary angiography in many of these patients.

d Management approach for patients resuscitated from sudden cardiac death

Adult patients successfully resuscitated from cardiac arrest who do not have clinical findings that suggest other causes of the arrest generally have extensive CAD. In the absence of recognized precipitating factors, such as acute MI, these patients are at high risk for recurrent cardiac arrest, and coronary angiography is of value in determining the underlying cause and planning the most appropriate therapeutic approach. Observational data indicate that coronary bypass surgery may be associated with reduced adverse outcome in that subgroup with significant coronary disease (93). It has been reported that immediate coronary angiography in survivors of out-of-hospital cardiac arrest reveals acute coronary occlusion in ≈50% of patients and that successful emergency angioplasty of an acute occlusion is an independent predictor of survival (116). A recent AHA statement further addresses this issue (117).

Recommendations for Coronary Angiography in Patients With Known or Suspected CAD Who Are Currently Asymptomatic or Have Stable Angina

Class I

• 1. CCS class III and IV angina on medical treatment. (Level of Evidence: B)

• 2. High-risk criteria on noninvasive testing regardless of anginal severity (Table 5). (Level of Evidence: A)

• 3. Patients who have been successfully resuscitated from sudden cardiac death or have sustained (>30 s) monomorphic ventricular tachycardia or nonsustained (<30 s) polymorphic ventricular tachycardia. (Level of Evidence: B)

Class IIa

• 1. CCS class III or IV angina, which improves to class I or II with medical therapy. (Level of Evidence: C)

• 2. Serial noninvasive testing using identical testing protocols, at the same level of medical therapy, showing progressively worsening abnormalities. (Level of Evidence: C)

• 3. Patients with angina and suspected coronary disease who, due to disability, illness, or physical challenge, cannot be adequately risk stratified by other means. (Level of Evidence: C)

• 4. CCS class I or II angina with intolerance to adequate medical therapy or with failure to respond, or patients who have recurrence of symptoms during adequate medical therapy as defined above. (Level of Evidence: C)

• 5. Individuals whose occupation involves the safety of others (e.g., pilots, bus drivers, etc.) who have abnormal but not high-risk stress test results, or multiple clinical features that suggest high risk. (Level of Evidence: C)

Class IIb

• 1. CCS class I or II angina with demonstrable ischemia but no high-risk criteria on noninvasive testing. (Level of Evidence: C)

• 2. Asymptomatic man or postmenopausal woman with ≥2 major clinical risk factors and abnormal but not high-risk criteria on noninvasive testing (performed for indications stated in the ACC/AHA noninvasive testing guidelines) without known coronary heart disease. (Level of Evidence: C)

• 3. Asymptomatic patients with prior MI with normal resting left ventricular function and ischemia on noninvasive testing, but without high-risk criteria. (Level of Evidence: C)

• 4. Periodic evaluation after cardiac transplantation. (Level of Evidence: C)

• 5. Candidate for liver, lung or renal transplant ≥40 years old as part of evaluation for transplantation. (Level of Evidence: C)

Class III

• 1. Angina in patients who prefer to avoid revascularization even though it might be appropriate. (Level of Evidence: C)

• 2. Angina in patients who are not candidates for coronary revascularization or in whom revascularization is not likely to improve quality or duration of life. (Level of Evidence: C)

• 3. As a screening test for CAD in asymptomatic patients. (Level of Evidence: C)

• 4. After CABG or angioplasty when there is no evidence of ischemia on noninvasive testing, unless there is informed consent for research purposes. (Level of Evidence: C)

• 5. Coronary calcification on fluoroscopy, electron beam CT, or other screening tests without criteria listed above. (Level of Evidence: C)

e Management of patients with nonspecific chest pain

Chest pain syndromes that are not characteristic of angina have previously been called noncardiac, atypical, or angiographically negative chest pain, as well as chest pain of undetermined origin (37–39). These terms are generally used to describe chest pain syndromes that are not associated with myocardial ischemia and are not of a cardiac cause. However, “atypical angina” generally means that myocardial ischemia is the cause of the symptoms, but the clinical presentation is unusual and should not be confused with nonspecific chest pain. For the purpose of this document and for consistency with previous documents, chest pain or cardiac symptoms not thought to be consistent with definite or probable angina are classified as nonspecific chest pain.

Nonspecific chest pain is very infrequently due to myocardial ischemia secondary to significant CAD, with a prevalence of 14% in men and 6% in women in one study (85). Other causes of myocardial ischemia, such as variant angina due to coronary spasm, or cocaine abuse, or syndrome X due to microvascular dysfunction, can infrequently present as nonspecific chest pain as well. Other cardiac causes include mitral valve prolapse, myocarditis, pericarditis and aortic dissection. Mitral valve prolapse is often associated with nonspecific chest pain. Although the cause is poorly understood, one postulate is that traction of the papillary muscle, induced by abnormal mitral valve motion, causes ischemia (118).

Noncardiac causes of nonspecific chest pain include costochondritis and esophageal disorders. Several disorders of the esophagus cause retrosternal chest pressure that can mimic myocardial ischemic-type chest pain. These include gastroesophageal reflux, irritable esophagus with altered gastroesophageal motility and a hypertensive lower esophageal sphincter (119). Many patients with both ischemic cardiac and esophageal pain can distinguish the symptoms, but some cannot. Exertional symptoms resulting from an esophageal source may also occur (119–121). Gastroesophageal reflux is a common, treatable cause of chest discomfort in patients with CAD who have nonspecific chest pain symptoms and remain symptomatic despite aggressive antianginal therapy (122). In one study, esophageal manometry, pH, and Holter monitoring were performed in patients with refractory nonspecific chest pain on optimal medical therapy for CAD. Of the 88% with chest pain identical to their anginal syndrome, 23% had acid reflux, 4% had cardiac ischemia, and 73% had no demonstrable cause. Up to 30% of patients with nonspecific chest pain will have an esophageal motility disorder (123). In some cases, antianginal therapy may exacerbate esophageal reflux symptoms because many of the drugs used to reduce these symptoms also lower esophageal sphincter tone (124,125).

A generalized disorder of smooth muscle function involving the esophagus, airways, musculoskeletal vasculature, central nervous system, and coronary microvasculature has been proposed (121). Some data suggest that gastroesophageal reflux and esophageal motility abnormalities may elicit myocardial ischemia and chest pain, a phenomenon termed “linked” angina. Acid stimulation caused typical angina (associated with a reduction in coronary blood flow velocity) in about half of syndrome X patients, which suggests that linked angina may indeed occur (119). However, other studies refute this concept (125,126).

If noncardiac causes are excluded or unlikely, or if the patient has significant cardiovascular risk factors that raise the suspicion of coronary disease, a noninvasive evaluation is appropriate. A number of guidelines specifically address this issue in detail (81–83,95–99). If noninvasive testing indicates a high risk for adverse outcome, then referral for coronary angiography should be made. Patients with nonspecific chest pain and evidence of myocardial ischemia but without indicators of high risk may be started on medical therapy with careful follow-up to assess their clinical response (127). Those who are intolerant of medical therapy, who fail to respond adequately to medical therapy, or in whom chest pain limits their lifestyle significantly despite taking ≥2 antianginal medications should be considered for coronary angiography. Patients who repeatedly present to the hospital with nonspecific chest pain, but who fail to have high-risk markers for ischemia, may also benefit from coronary angiography. The findings of a normal coronary angiogram in such patients indicate a good long-term prognosis that is reassuring to both the patient and the physician. Studies have indicated that a normal angiogram in this setting significantly reduces symptoms and subsequent hospitalizations (128).

Recommendations for Coronary Angiography in Patients With Nonspecific Chest Pain

Class I

High-risk findings on noninvasive testing. (Level of Evidence: B)

Class IIa

None.

Class IIb

Patients with recurrent hospitalizations for chest pain who have abnormal (but not high-risk) or equivocal findings on noninvasive testing. (Level of Evidence: B)

Class III

All other patients with nonspecific chest pain. (Level of Evidence: C)

a Definitions

The acute coronary syndromes include unstable angina, non–Q-wave MI, and acute Q-wave MI. The diagnosis of unstable angina has been complicated by a broad range of presentations that can vary between atypical chest pain and acute MI. An expert panel of clinicians attempted to clarify the definition of unstable angina in the recently published “Clinical Practice Guideline for Unstable Angina” (129,130). Three possible presentations are described:

• • Symptoms of angina at rest (usually prolonged >20 min);

• • New-onset (<2 months) exertional angina of at least CCS class III in severity;

• • Recent (<2 months) acceleration of angina as reflected by an increase in severity of at least one CCS class to at least CCS class III.

Variant angina, non–Q-wave MI and recurrent angina >24 h after MI are considered part of the spectrum of unstable angina. However, in this document, non–Q-wave MI is discussed in the section on acute MI.

Our understanding of stable and unstable coronary syndromes continues to evolve along with our increased understanding of their pathophysiology. Locally produced vasoactive mediators and complex coronary morphologic characteristics may promote a dynamic process of thrombosis and fibrinolysis via platelet activation that can lead to acute coronary syndromes. Serum markers, such as creatine phosphokinase isoforms and cardiac troponin T and I, have led to an increased appreciation of the close relationship between unstable angina and MI.

b Pathophysiology

Unstable ischemic coronary syndromes are characterized by severe but often transient episodes of myocardial ischemia caused by a critical obstruction to coronary blood flow. These episodes are almost always caused by ≥1 of several pathophysiologic mechanisms that interfere with the balance of myocardial oxygen supply and demand. The spontaneous rupture of lipid-laden, macrophage-rich atherosclerotic plaques may initiate unstable angina, acute MI, or sudden death (131)through platelet aggregation and thrombus formation over the fissured plaque (132). Plaque rupture leads to total or subtotal occlusion, resulting in a silent progression of the occlusive process or an acute coronary syndrome. Coronary angiography cannot predict vulnerable plaques, but once thrombosis has occurred, a filling defect indicating thrombus may be detected by angiography (133). Patients with unstable angina have more complex coronary lesions and more intracoronary thrombus on angiography than patients with stable angina (134,135). The coronary angiographic findings in unstable angina are often indistinguishable from those of non–Q-wave MI (133). Unstable angina with a clinical duration of <2 months is characterized angiographically by a high incidence of complex lesions. In a blinded retrospective angiographic study of 52 patients with unstable angina <2 months in duration compared with 32 patients having “chronic” unstable angina for >6 months, those with chronic unstable angina had a greater number of diseased vessels, fewer eccentric lesions and a better collateral circulation (136).

c Risk stratification

Within the group of patients with unstable angina, variable clinical outcomes are seen. The Braunwald classification (137)was developed as a means to grade patients with unstable angina according to severity of expected outcome, on the basis of the clinical manifestations and circumstances of their presentation (137). In this classification, consideration is given to history, associated ECG changes, and concurrent medical therapy in evaluating symptomatology. Risk stratification based on the Braunwald classification system has recently been validated by two groups, confirming its prognostic utility (138,139). The Agency for Health Care Policy and Research (AHCPR) Clinical Practice Guideline for unstable angina is a refinement of the Braunwald classification. Categories of severity are different, but as with the original scheme, the AHCPR guideline uses clinical circumstances, ECG changes, and intensity of therapy to develop an algorithm for the diagnosis and management of patients with suspected unstable angina (140).

d Prognosis

Overall, the risk of a major adverse cardiac clinical event (death or nonfatal MI) in patients with unstable angina is less than that observed with acute MI but greater than in stable angina. This risk is highest at the time of presentation and declines to baseline within two months (141). One-year follow-up of the 1,473 Thrombolysis in Myocardial Infarction (TIMI) IIIB patients revealed a 4.3% mortality rate and an 8.8% incidence of nonfatal infarction at one year, but a substantial percentage of these cases had a non–Q-wave MI (142). In another study of 1,897 patients admitted to the coronary care unit in whom an infarction did not evolve and some of whom may not have had CAD, the 10-year cardiac mortality rate was 22% (143). Accordingly, identification of the high-risk patient is of paramount importance.

Silent ischemia has also been identified as a marker for unfavorable outcome in patients with unstable angina (144). In addition to the clinical history and ECG findings, certain serum markers have recently been shown to identify a high-risk subgroup (145–147). In these studies, elevations in creatine kinase (CK) isoforms, cardiac troponin T and I, and acute phase reactants appear to identify a subgroup of patients with unstable angina at high risk for adverse outcome (148–150).

e Management approach

A management approach to unstable angina is outlined in the AHCPR Clinical Practice Guideline that is based on an assessment of both the likelihood of CAD and the short- and long-term prognoses of such patients (129). For those judged in their initial evaluation and treatment phase to be at low risk for adverse outcomes (Table 6), the guidelines recommend outpatient management. Patients thought to be at intermediate or high risk for death or nonfatal MI should be admitted to the hospital for intensive medical management. For patients who do not respond after an hour of aggressive therapy or who have recurrence of symptoms after initial stabilization and are thus considered refractory, emergency or urgent coronary angiography should be performed and intraaortic counterpulsation considered. Emergency catheterization refers to a diagnostic catheterization study that is performed immediately or as soon as possible, i.e., within 6 h. Urgent coronary angiography refers to a study performed within 24 h of hospitalization.

For patients whose condition stabilizes after initial treatment, the AHCPR Unstable Angina Clinical Practice Guideline proposes either an “early invasive” or “early conservative” strategy. With the early invasive strategy, all hospitalized patients (intermediate and high risk) without contraindications, receive elective cardiac catheterization within 48 h. With the early conservative strategy, only patients with high-risk indicators (prior revascularization, congestive heart failure, left ventricular ejection fractions <0.50, malignant ventricular arrhythmia, persistent or recurrent ischemic pain and/or functional study indicating high risk) are referred for cardiac catheterization. In the TIMI IIIB trial, a low six-week mortality rate (2.4%) and occurrence of infarction or reinfarction (6.3%) were achieved with either an early conservative or early invasive strategy. However, the early invasive strategy resulted in a reduced length of stay and reduced number of readmissions as well as less use of antianginal drugs (151). In a further analysis of patients treated with PTCA in the TIMI IIIB study, PTCA within 24 h of admission was an independent predictor of the occurrence of a subsequent cardiovascular event, especially if these patients were being treated emergently (152). This committee believes that an early invasive strategy with early coronary angiography is useful and effective, although probably better done after 24 h of aggressive medical management, including aspirin, standard or low-molecular-weight heparin and a glycoprotein IIb/IIIa inhibitor, if the clinical situation allows.

As summarized earlier, coronary angiography is indicated in unstable angina when subsequent revascularization is likely to alter the natural history or when patients have continued symptoms. When symptoms are intractable, the guidelines recommend emergent or urgent coronary angiography. The incidence of truly refractory angina was evaluated in a group of 125 patients with unstable angina studied over a five-year period in the recent era of five-drug therapy (intravenous heparin, aspirin, nitrates, calcium channel blockers and beta-blockers). All patients had >20 min of angina at rest with reversible ECG changes. Of the 52% who were thought to be medically refractory by the referring practitioners, 83% could be rendered free of chest pain by a more aggressive medical regimen. The incidence of truly medically refractory unstable angina with this five-drug regimen was found to be infrequent at 8.8% (153)and would probably be even less frequent with the addition of low-molecular-weight heparin and/or glycoprotein IIb/IIIa inhibitors, as used today. Coronary angiography may be deferred for 48 h in these patients who have been thus stabilized.

Outpatient evaluation of low-risk patients (Table 6)should begin promptly and should include exercise stress testing for patients with normal rest ECGs who are not taking digoxin or exercise or pharmacologic stress testing with myocardial perfusion scanning or echocardiography for all others. Evaluation of left ventricular function is also important. In the low-risk patient with known coronary disease, the goal is to determine whether revascularization is indicated. In those not previously known to have CAD, the goal is to establish a diagnosis and further stratify the patients according to risk.

Many patients with recurrent chest discomfort not suggestive of angina have had normal coronary angiograms during the past five years. Even though many of these patients repeatedly seek cardiovascular care, repeat angiography is generally not considered to be indicated unless their clinical presentations convincingly suggest the presence of new CAD.

Patients with variant angina may present with chest pain and acute ECG changes. Cardiac catheterization is often performed in these patients to establish a diagnosis and to exclude fixed obstructive disease, which might require revascularization.

Recommendations for Coronary Angiography in Unstable Coronary Syndromes

Class I

• 1. High or intermediate risk for adverse outcome in patients with unstable angina (Table 6)refractory to initial adequate medical therapy, or recurrent symptoms after initial stabilization. Emergent catheterization is recommended. (Level of Evidence: B)

• 2. High risk for adverse outcome in patients with unstable angina (Table 6). Urgent catheterization is recommended. (Level of Evidence: B)

• 3. High- or intermediate-risk unstable angina that stabilizes after initial treatment. (Level of Evidence: A)

• 4. Initially low short-term-risk unstable angina (Table 6)that is subsequently high risk on noninvasive testing (Table 5). (Level of Evidence: B)

• 5. Suspected Prinzmetal variant angina. (Level of Evidence: C)

Class IIa

None.

Class IIb

Low short-term–risk unstable angina, without high-risk criteria on noninvasive testing. (Level of Evidence: C)

Class III

• 1. Recurrent chest discomfort suggestive of unstable angina, but without objective signs of ischemia and with a normal coronary angiogram during the past five years. (Level of Evidence: C)

• 2. Unstable angina in patients who are not candidates for coronary revascularization or in patients for whom coronary revascularization will not improve the quality or duration of life. (Level of Evidence: C)

a Definitions

Evidence of myocardial ischemia in the patient who has undergone a revascularization procedure (PTCA or CABG) may represent ischemic myocardium that was not revascularized by intention for either technical or clinical reasons, or was deferred for later treatment if the patient remained symptomatic. Alternatively, it may represent recurrent ischemia due to restenosis, graft occlusion or progression of atherosclerosis. Ischemia may present as a recurrence of the preprocedural symptoms. However, not uncommonly, especially after surgical revascularization, recurrent ischemia may present with atypical features. Indeed, there is an increased incidence of silent ischemia in postoperative patients (154,155).

b Recurrence of symptoms after catheter-based revascularization

c Recurrence of symptoms after coronary artery bypass surgery

Patients with prior bypass surgery who develop postoperative angina represent an important subset of patients who require thoughtful evaluation and therapy. Arterial conduits often provide long-term patency over at least 15 years. Saphenous vein grafts are more vulnerable to graft atherosclerosis and subsequent closure. Approximately 10% of patients will have vein graft closure within the first two months after surgery and another 10% within the first year (171). Vein graft patency is relatively stable from years 3 to 5, but after 10 years, 40% of vein grafts are occluded (172). In a study of 977 patients after bypass surgery, 30% had angina in the first year, 46% at 3 years and 50% at 8 years of follow-up (173). Postoperative angina occurs more frequently in women than men (174). Furthermore, many postoperative patients have asymptomatic myocardial ischemia (155). Postoperative angina is an increasing problem. For example, in the BARI registry (175), the percentage of patients presenting for revascularization who had prior surgical revascularization increased from 20% to 33% over the time period of enrollment. It is generally believed that patients with recurrent ischemia after coronary artery bypass surgery have an increased risk of adverse outcomes; treatment must balance the risk of reoperation with the risk of medical management or percutaneous revascularization. Reoperative risk is dependent on both age and the patient’s clinical presentation (176). In a study of 2,030 patients followed up for a mean of 7.8 years after surgery at a single site, there was a 5.7% mortality rate for patients undergoing elective reoperation, compared with a 10.9% mortality rate in patients having urgent reoperation, and a 16.4% mortality rate in those undergoing emergent reoperation (177). Five- and 10-year survival rates were 76% and 55%, respectively, for patients aged <50 years at reoperation and 63% and 40%, respectively, for those >70 years of age.

Catheter-based techniques are attractive as an alternative to the high risk of reoperation but are not without risk, especially when performed in an older vein graft. In a study of 89 saphenous vein graft lesions treated percutaneously in 75 patients with medically refractory angina, clinical success (angiographic success plus hospital discharge without major complication) was achieved in 70 (178). In this series, there was a 3% incidence of early mortality, 3% had nonfatal MI, and 1% required emergency reoperation. During late follow-up, 23% had a repeat PTCA, 3% needed reoperation, and 25% died. Long-term survival of this cohort was compared with a similar surgically treated group. At 30 days, survival was better in the graft angioplasty patients (97% vs. 92%), but there was no difference at six months, and by five years there was a trend toward better survival in the reoperative group.

Other percutaneous techniques such as transluminal extraction atherectomy, excimer laser, and directional coronary atherectomy do not appear to offer superior effectiveness in dealing with vein graft atherosclerosis compared with standard balloon angioplasty (179–183). The use of coronary artery stents for disease in saphenous vein grafts is becoming almost routine (184,185). One randomized controlled study has evaluated the role of stent placement in saphenous vein graft disease. In the SAVED trial, patients were randomized to stenting or balloon annuloplasty. In-hospital outcomes were similar, but there was a significant reduction in repeat revascularization six months after the procedure in the stent group (186).

Coronary angiography is reasonable in patients who are symptomatic within the first 12 months after bypass surgery, because relatively low-risk revascularization by percutaneous techniques can often be offered. Angiography should be avoided in postbypass patients who, by virtue of age or other comorbidity, are poor candidates for repeat revascularization by either reoperation or angioplasty. Postbypass patients who are suitable candidates for further revascularization and who have noninvasive evidence of high-risk disease are appropriate subjects for coronary angiography. Those who are symptomatic but deemed to be low risk by noninvasive testing, perhaps due to collateralization, can be treated medically before angiography is considered.

Recommendations for Coronary Angiography in Patients With Postrevascularization Ischemia

Class I

• 1. Suspected abrupt closure or subacute stent thrombosis after percutaneous revascularization. (Level of Evidence: B)

• 2. Recurrent angina or high-risk criteria on noninvasive evaluation (Table 5)within nine months of percutaneous revascularization. (Level of Evidence: C)

Class IIa

• 1. Recurrent symptomatic ischemia within 12 months of CABG. (Level of Evidence: B)

• 2. Noninvasive evidence of high-risk criteria occurring at any time postoperatively. (Level of Evidence: B)

• 3. Recurrent angina inadequately controlled by medical means after revascularization. (Level of Evidence: C)

Class IIb

• 1. Asymptomatic post-PTCA patient suspected of having restenosis within the first months after angioplasty because of an abnormal noninvasive test but without noninvasive high-risk criteria. (Level of Evidence: B)

• 2. Recurrent angina without high-risk criteria on noninvasive testing occurring >1 year postoperatively. (Level of Evidence: C)

• 3. Asymptomatic postbypass patient in whom a deterioration in serial noninvasive testing has been documented but who is not high risk on noninvasive testing. (Level of Evidence: C)

Class III

• 1. Symptoms in a postbypass patient who is not a candidate for repeat revascularization. (Level of Evidence: C)

• 2. Routine angiography in asymptomatic patients after PTCA or other surgery, unless as part of an approved research protocol. (Level of Evidence: C)

a Introduction

During the past 15 years, the treatment of Q-wave MI has shifted from a passive approach emphasizing supportive care and management of complications to a more active therapeutic approach. Coronary angiography is rarely performed during or after MI solely for diagnostic purposes. The vast majority of procedures are done to evaluate the patient for a percutaneous or surgical revascularization procedure. Therefore, the appropriateness of performing coronary angiography after MI is, by necessity, linked to the efficacy of these revascularization procedures as measured by an improved outcome for the patient. As discussed in section II, several recent studies have shown considerable variation in the use of coronary angiography after MI within regions of the U.S., between the U.S. and Canada, between health maintenance organizations and fee-for-service hospitals, between primary care physicians and cardiologists, and between invasive and noninvasive cardiologists (43–45,47,48,60,187). These data do not show a consistent relationship between the increased use of coronary angiography after MI and improvements in outcome.

Guidelines covering PTCA, CABG surgery and the treatment of patients with acute MI have been published by the ACC/AHA Task Force on the Assessment of Diagnostic and Therapeutic Procedures within the past five years and contain recommendations relevant to the use of coronary angiography (188–190).

b Definitions

According to World Health Organization criteria, the diagnosis of MI is based on the presence of at least two of the following: 1) a clinical history of ischemic-type chest discomfort, 2) changes on ECG tracings obtained serially and 3) a rise and fall in enzyme markers of myocardial cell necrosis (191,192). A convenient way to categorize patients who present with ischemic chest discomfort and suspicion of MI is by the presence or absence of ST-segment elevation, and this distinction will be used in these guidelines. The majority of patients presenting with ischemic chest pain and ST elevation will subsequently have some enzyme marker of myocardial necrosis with or without development of Q waves. Of those who present with ischemic chest pain and no ST-segment elevation, some will evolve serum markers of myocardial necrosis with or without Q waves while others, without an elevation in serum markers, will later be classified as having unstable angina (Fig. 3).

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Figure 3

Nomenclature of acute coronary syndromes. Patients with ischemic discomfort may present with or without ST-segment elevation on the ECG. The majority (large arrow)of patients with ST-segment elevation ultimately develop a Q-wave acute MI, whereas a minority (small arrow)develop a non–Q-wave acute MI. Of the patients who present without ST-segment elevation, the majority (large arrows) are ultimately diagnosed as having either unstable angina or non–Q-wave acute MI on the basis of the presence or absence of a cardiac marker such as CK-MB detected in the serum; a minority of such patients ultimately develop a Q-wave acute MI. The spectrum of clinical conditions ranging from unstable angina to non–Q-wave acute MI and Q-wave acute MI is referred to as the acute coronary syndromes. Reprinted with permission from Antman EM, Braunwald E. Acute myocardial infarction. In: Heart Disease. A Textbook of Cardiovascular Medicine. 5th ed. Philadelphia, PA: WB Saunders, 1996. ∗Positive serum cardiac marker.

These guidelines were developed following the general pattern used to organize the “ACC/AHA Guidelines for the Management of Patients With Acute Myocardial Infarction” (190). Accordingly, the use of coronary angiography was evaluated in three distinct time periods after infarction. It must be emphasized, however, that these time periods are somewhat arbitrary, because patients who present with MI may not be immediately identified, do not uniformly present at a common starting point in the event and may evolve through the infarction at different rates. It is also clinically useful to stratify patients with suspected MI by the presence or absence of ST-segment elevation on the ECG. Because clinical outcomes, especially after thrombolysis, are similar, we have included in the group with ST elevation patients with typical ischemic chest pain and a new (or presumed new) bundle-branch block obscuring the ECG diagnosis of MI. Patients with ongoing ischemic chest pain but without ST-segment elevation are a distinct group with different indications for coronary angiography compared with those who have ST-segment elevation.

The first time period discussed relates to the use of coronary angiography during the initial recognition and management of the patient in the emergency department. For the patient who presents acutely with ST-segment elevation or bundle-branch block obscuring the diagnosis of MI, coronary angiography is coupled with the intent to perform primary PTCA as an alternative to thrombolytic therapy. Other indications discussed are related to patients who present with similar ECG findings and are not treated by primary PTCA (i.e., who receive thrombolytic or no reperfusion therapy) or who have a strong suggestion of MI, but do not have ST-segment elevation.

The second general time period relates to the use of coronary angiography during the hospital-management phase of the patient with MI. During this phase, the need for coronary angiography is generally driven by the development of some complication of the infarction, such as spontaneous recurrent ischemia, heart failure related to ventricular septal defect, or papillary muscle dysfunction or persistent malignant arrhythmias occurring beyond the first 24 h after infarction.

The final general time period after MI during which coronary angiography may be necessary occurs when the patient is being prepared for hospital discharge and undergoes risk stratification. In practical terms, this is defined not by a specific time but rather by the evaluations performed to determine the risk of future morbid events and the need for additional therapies. The process of risk stratification occurs throughout the clinician’s entire encounter with the patient as information is gathered about the extent and consequences of the infarction.

c Coronary angiography during the initial management of patients in the emergency department

d Hospital-management phase of acute MI

The hospital-management phase of acute MI can encompass several clinical situations. Some patients with acute MI present too late in their course to be candidates for reperfusion therapy, and in others, the occurrence of infarction may not be appreciated at the time of presentation. These groups skip the acute-treatment phase of MI and enter the hospital-management phase directly. During the hospital-management phase, the actions of the clinician are driven by the consequences of the infarction, such as congestive heart failure, hemodynamic instability, recurrent ischemia or arrhythmias. Although it is still convenient to divide patients into those with Q-wave and non–Q-wave infarctions, some indications for coronary angiography are common to all patients with MI regardless of how they have been treated initially and whether or not Q waves ultimately develop.

e Risk stratification phase in preparation for discharge from the hospital after MI

The purpose of risk stratification is to assemble information that will help predict prognosis and the need for further therapies to improve prognosis (321). This process occurs throughout the entire encounter with the patient and is not strictly limited to the days before discharge. For example, rales, tachycardia, hypotension or congestion on the chest radiograph early in a patient’s course are all important predictors of increased risk and likely indicate depressed left ventricular performance (322). Many prior studies have shown that left ventricular ejection fraction is highly predictive of survival (323,324). In the prethrombolytic era, mortality one year after infarction was 2% to 5% when left ventricular ejection fraction was >0.40, 10% to 15% when it was between 0.20 and 0.39, and up to 50% when it was <0.20. One-year mortality is significantly lower now than it was in the past but is still related to left ventricular performance (293,294). The cause of the improvement in outcome is multifactorial and includes the use of thrombolytic agents, beta-blockers and angiotensin converting enzyme inhibitors and perhaps includes more aggressive invasive investigation and interventional treatment. Numerous factors have been related to prognosis after acute MI; these are summarized in Table 7(321–326). Of the deaths that occur within the first year after infarction, 50% happen within the first three weeks and 75% within the first three months (327). Therefore, patients at increased risk must be identified relatively early if they are to be considered for coronary angiography and possible revascularization.

Cardiac catheterization and coronary arteriography can identify major determinants of mortality after MI, such as left ventricular ejection fraction and the presence of multivessel CAD (325,328–332). Because of the skewed incidence of cardiac events and mortality early within the first year after infarction, some have proposed that coronary angiography be performed in all survivors even though it involves a small risk and is expensive (318). However, there are ample other data that suggest that evaluation by noninvasive methods such as standard exercise testing (Table 8), two-dimensional echocardiography, radionuclide ventriculography, thallium scintigraphy or these imaging techniques coupled with dynamic or pharmacologic stress can identify most high-risk patients who may benefit from revascularization (321,322,328,329,333–339). Moreover, coronary angiography demonstrates the anatomy and morphology of a stenosis at a discrete point in time. Progression of CAD is quite variable, but it is a major factor affecting prognosis (340,341). Although some angiographic predictors of future infarction have been identified (342,343), other studies have shown that 66% to 78% of infarctions are related to an artery with a ≤50% stenosis on a previous angiogram (344,345). Such lesions would not likely be the target of revascularization attempts.

Various strategies for the use of coronary angiography after MI have been discussed in the literature (291,318,321,337,346), but careful research in this area has been sparse. Ross et al. (347)developed a scheme in patients younger than 75 years of age that would avoid early coronary angiography in those at low risk (≤3%) for one-year mortality and recommends angiography in those at increased risk (average one-year mortality 16%). Indications for coronary angiography in this scheme included the following: severe resting ischemia at any time beyond the first 24 h after infarction (one-year mortality 18%); hospital survivors with a history of previous MI and clinical or radiographic signs of left ventricular failure in the hospital (one-year mortality 25%); an ischemic exercise response or poor workload achieved (one-year mortality 11%); and a resting left ventricular ejection fraction between 0.20 and 0.44 alone when exercise testing is not performed (one-year mortality 12%). With this approach, ≈55% of patients who survive to the fifth day after infarction would undergo coronary angiography. By comparison, data from the National Registry of Myocardial Infarction during 1990 through 1993 and the GUSTO trial show that ≈72% of patients treated by American participants undergo coronary angiography during their initial hospitalization after MI (47,259). This rate is considerably higher than the rate of 55% proposed by Ross et al. and the rate of 33% for coronary angiography used in the selective approach of the TIMI II trial (300). Although the frequent use of invasive evaluations and therapy in the United States is subject to debate, a recent subgroup analysis from the GUSTO trial shows that patients treated in the United States had a better quality of life, less angina and lower mortality during the first year after infarction than did their Canadian counterparts, of whom only 25% underwent coronary angiography (47). However, this approach has not been verified in other studies and is costly (44,45,346).

The most recent scheme for evaluation and risk stratification of patients early after MI was presented in the 1996 “ACC/AHA Guidelines for the Management of Patients With Acute Myocardial Infarction” (190). This approach is recommended by the committee and is outlined in Figure 4.

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Figure 4

Clinical indications of high risk at predischarge. Strategies for risk stratification soon after myocardial infarction. If patients are at high risk for ischemic events, on the basis of clinical criteria, they should undergo invasive evaluation to determine if they are candidates for coronary revascularization procedures (strategy I). For patients initially deemed to be at low risk at time of discharge after MI, two strategies for performing exercise testing can be used. One is a symptom-limited test at 14 to 21 days (strategy II). If the patient is taking digoxin or if baseline ECG precludes accurate interpretation of ST-segment changes (e.g., baseline left bundle-branch block or left ventricular hypertrophy), then an initial exercise imaging study can be performed. Results of exercise testing should be stratified to determine the need for additional invasive or exercise perfusion studies. A third strategy is to perform a submaximal exercise test five to seven days after MI or just before hospital discharge. The exercise test results could be stratified using the guidelines in strategy I. If exercise test studies are negative, a second symptom-limited exercise test could be repeated at three to six weeks for patients undergoing vigorous activity during leisure or at work. From Figure 10 of the ACC/AHA Guidelines for the Management of Patients with Acute Myocardial Infarction (190).

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Figure 5

The coronary artery map used by the BARI investigators. The map is derived from that used in CASS with the addition of branch segments for the diagonal, marginal and ramus vessels. Reprinted with permission from Alderman et al. (395). See Table 9for corresponding map location.

Recommendations for Coronary Angiography During the Risk-Stratification Phase (Patients With All Types of MI)

Class I

Ischemia at low levels of exercise with ECG changes (≥1-mm ST-segment depression or other predictors of adverse outcome) (Table 8)and/or imaging abnormalities. (Level of Evidence: B)

Class IIa

• 1. Clinically significant CHF during the hospital course. (Level of Evidence: C)

• 2. Inability to perform an exercise test with left ventricular EF ≤0.45. (Level of Evidence: C)

Class IIb

• 1. Ischemia occurring at high levels of exercise. (Level of Evidence: C)

• 2. Non–Q-wave MI in a patient who is an appropriate candidate for a revascularization procedure. (Level of Evidence: C)

• 3. Need to return to an unusually active form of employment. (Level of Evidence: C)

• 4. Remote history of MI without evidence of congestive heart failure during the current event and without evidence of inducible ischemia. (Level of Evidence: C)

• 5. Recurrent ventricular tachycardia, fibrillation, or both, despite antiarrhythmic therapy, without ongoing myocardial ischemia. (Level of Evidence: C)

Class III

Patients who are not candidates for or who refuse coronary revascularization. (Level of Evidence: C)