SCREENING FOR CORONARY ARTERY DISEASE

~~~

0025-7125/99 $8.00

SCREENING

+ .OO

SCREENING FOR CORONARY ARTERY DISEASE Thomas H. Marwick, MB, PhD, and Peter Cain, MBBS

APPLICATION OF CORONARY SCREENING TO THE GENERAL POPULATION

Rationale

The purpose of screening tests is to prolong life or improve quality of life by the early diagnosis and treatment of disease, before complications occur. This desirable outcome, however, must be obtained at a reasonable cost in terms of both testing and treatment.l8With respect to the diagnosis of coronary artery disease (CAD) and asymptomatic patients, several questions need to be considered: (1) Can prognostically important coronary disease be identified? (2) Can clinicians do anything to change the outcome of patients at risk? (3) Is the change in outcome worth the cost? Despite advances in medical and interventional therapies, CAD remains among the principal causes of mortality and long-term morbidity in the Western world. In the United States, greater than half a million deaths per year occur as a result of coronary disease, and 1.5 million hospitalizations a year occur because of myocardial infarction. The American Heart Association3 estimates that the total cost to society of CAD approximates $100 billion per year. The concepts underlying the use of screening for coronary disease derive from pathologic data, which demonstrate that fatty streaks are present in the arteries of young patients in more than 90% of the population and that atherosclerosis is present in more than 75% of the population.126Thus, before the patient

From the Department of Medicine, University of Queensland, Queensland, Australia

MEDICAL CLINICS OF NORTH AMERICA

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VOLUME 83 NUMBER 6 * NOVEMBER 1999

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develops symptoms and signs of coronary disease, the atherosclerotic process has begun, and significant CAD may be found in more than 10% of young people. Therefore, the desire is to identify the presence of this atheromatous burden before the coronary plaque ruptures, causing myocardial infarction or sudden death, or before the artery progressively narrows, causing exercise limitation resulting from angina. Consideration of Pretest Risk-Bayes’

Theorem

Bayes’ theorem is important in the use of various investigations to identify disease in populations. According to this theorem, the posttest probability of CAD disease (as defined by angiography) is related to the likelihood of disease as well as the result of the test. The implication is that for the purposes of diagnosing coronary disease, in a population with a low pretest probability, the posttest probability would remain low regardless of the results of the test (Fig. 1). Table 1 summarizes various strategies that have been applied for the assessment of pretest probability of CAD on clinical grounds.22,30, 91, lo4, lo5, 11* These strategies should be distinguished from related efforts to identify the likelihood of subsequent cardiac events. The original work on clinical evaluation of pretest risk was undertaken by Diamond and Forrester?O who developed tables showing the anatomic prevalence of significant CAD according to age, gender, and

Pre-test Probability Figure 1. Relationship between pre- and post-test probability of coronary disease. At the extremes of pre-test probability, test accuracy has little impact on post-test probability, which corresponds closely to pre-test probability. Points A and B correspond to the results of a moderately accurate test. If the test is positive, this will increase the probability of disease being present (A), and if the test is negative, it will decrease the probability of the disease being present (B). A more accurate test substantially increases the probability of disease being present if the test is positive (C), and substantially decreases the probability of disease being present if the test is negative (D).

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Table 1. CLINICAL APPROACHES TO ASSESSMENT OF PRE-TEST RISK OF CORONARY ARTERY DISEASE Author

Stenosis Threshold

Variables

Method Developed

Validation

Diamond30

50%

X

1 vessel

Age, gender, symptoms

Tabulation

SaleP

75%

X

1 vessel

Complex statistical

ChaitmanZ2

70% X 1 vessel, 50% lms 75% X 1 vessel

Age, gender, smoking, diabetes, LVH, hypertension, hyperlipidemia Age, gender, symptoms

Tabulation

Yes

History IHD, gender, age, smoking, hyperlipidemia, resting ECG, diabetes Past history IHD, gender, age, smoking, hyperlipidemia, resting ECG, diabetes Age, gender, symptoms, estrogen status, diabetes, hypertension, smoking, hyperlipidemia, family history CAD, obesity

Nomogram

Yes

Complex statistical

Yes

Score

Yes

PryorlM

Morise9'

50%, 70% vessels

X 2

Validated postexercise test No

nature of symptoms in almost 24,000 patients. No subsequent validation of these data has been undertaken in any large prospective group. A similar approach was adopted by Chaitman et a12*using the Coronary Artery Surgery Study (CASS) database; tables assessing risk of CAD were based on symptom status, age, and gender in more than 8000 patients suspected of having CAD who had undergone coronary angiography. More complicated approaches have included assessment of standard CAD risk factors (hypertension, smoking status, diabetes, hyperlipidemia, family history of premature CAD) as well as addressing the role of other factors, such as estrogen status, homocysteine, and obesity. Pryor et allo4retrospectively analyzed 3627 patients from the Duke database on the basis of multiple variables. A statistical model was used to identify nine .clinical characteristics that reliably predicted the presence of CAD (defined as stenoses 270% in any vessel) in 1811 patients. A nomogram was derived to enhance the application of these findings clinically. Subsequently, Pryor et allo5adopted a similar approach to the assessment of possible CAD in outpatients undergoing coronary angiography, and a statistical model of CAD likelihood was developed and prospectively validated with 87% of patients being correctly

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grouped by this model with regards to angiographic severity of CAD. Pryor et allo5demonstrated in this study that initial clinical assessment of likelihood of CAD and estimation of long-term survival (3 years) was as predictive as electrocardiogram (ECG) treadmill testing. These statistical models do not readily lend themselves to routine practice. A more user-friendly method that deals with multiple clinical variables has been reported by Morise et al9I from a study of 915 patients with normal resting ECGs who underwent coronary angiography because of suspicion of CAD. A simple scoring method was derived and subsequently validated in 348 patients with prevalence of significant CAD in low-risk, medium-risk, and high-risk categories being l6%, 44%, and 69%. Several investigators have addressed the role of resting ECG changes in combination with clinical indices in the risk stratification of patients with CAD. In particular, both reports by Pryor et aPo4,lo5 demonstrated that resting ECG changes were of predictive value in combination with clinical factors. Most predictive data using the ECG, however, pertain to the stress setting. Certain aspects of these clinical risk systems have limited their widespread use. These include complex and time-consuming statistical methods, subjectivity of certain variables (e.g., atypical versus typical chest pain), and use of specific patient groups (precardiac surgery patients versus outpatients) to derive a statistical model, which may therefore impair applicability to the general population. Nonetheless, applied to similar populations to those from which they were derived, these approaches are of benefit in quantification of pretest risk. Use of Exercise Electrocardiogramfor Identification of Coronary Artery Disease and Coronary Artery Disease Risk Use of Exercise Testing for Diagnosis of Coronary Artery Disease Exercise testing is the cornerstone of diagnostic testing for CAD. Ischemia is identified by ST-segment depression, and although accuracy is less in the posterior wall and may be compromised by a number of factors, the accuracy of the test ranges from 70% to 75?'0.~The widespread availability and low cost of this approach are attractive for a screening test. There is little evidence, however, that use of exercise testing in asymptomatic patients is justified on the grounds of efficacy or cost.120Fundamentally, this problem reflects the statistical difficulties imposed by identification of disease in individuals at low risk. Application of Exercise Testing to Coronary Artery Disease Screening Table 2 summarizes large studies that have examined the use of exercise testing for the detection of coronary disease in asymptomatic

Y

1390 2365

4158

3260 6438

3168

Bruce15

LRCI6 MRFITI2

FraminghamI7

n

FroelicheP SeattleI4

Author

ST dep, ST/HR index

ST depression STslope

STdep CP, <6 min, HR
Criteria

15%

6% 12%

15%

14% 11%

Prevalence of ST Depression

Cardiac death Cardiac death Angina Myocardial infarction Composite

2 5

5

Composite

Composite Composite

Events

8

5 6

Event Rate (per 1000 Patient-Years)

Relative Risk

ST depression - 1.2 STindex - 2.2 Combined - 3.6

ST depression - 14.3 ST depression - 3.4 >2 criteria - 29 ST depression; men - 14.3, women - 6.7 Ex duration; men - 6.7, women - 3.6 Chest pain; men - 3.5, women - 3.3 Heart rate; men - 2.4, women - 1.8 HR-SBP product; men - 2.4, women - 1.3 ST depression - 4.6 ST slope - 3.8 ST slope - 1.6 ST slope - 1.2

Table 2. PREDICTION OF SUBSEQUENT CARDIAC EVENTS, BASED ON RESULTS OF STRESS ECG FOR SCREENING ASYMPTOMATIC PATIENTS

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patients.15,16, 41, 46, 96, lo7Various criteria have been employed, mainly focusing on the presence of ST-segment depression, and the prevalence of this finding has varied between 6% and 15% of asymptomatic populations. The presence of ST-segment change is associated with an increment of the relative risk of coronary disease; this risk is strongest when ST-segment depression is associated with chest pain or other abnormal hemodynamic responses to exercise. The absolute risk of cardiac events in these asymptomatic populations, however, has been low (2 to 8 per 1000 patients studied per year). Thus, the application of exercise stress testing to the diagnosis of coronary disease in asymptomatic patients offers the ability to identify unknown disease, but the benefit of this is small. It is balanced by cost considerations as well as a significant incidence of false-positive tests, which generate patient anxiety and may have financial implications for patients regarding their insurance status. Use of Stress Imaging Approaches for Coronary Artery Disease Screening Stress Nuclear Perfusion Imaging

Stress radionuclide techniques have been established for several decades as effective methods for the diagnosis of CAD, using various radionuclides (thallium-201 and various technetium-99m tracers) and stressors (exercise, dobutamine, dipyridamole, and adenosine). Metaanalyses have confirmed the high sensitivity (85% to 90%) and slightly lower specificity (75% to 80%) of these techniques for detecting hemodynamically significant CAD lesions in symptomatic patients.63,76 Moreover, despite the high prognostic power of a negative test,&, 75 even in patients with CAD, the event rate of patients with a positive test is not high, unless evidence of extensive CAD is identified.l" Asymptomatic healthy volunteers have been studied using thallium scintigraphy without stress. Perfusion defect rates of only 2% in the 40to 60-year age group and up to 15% in patients older than 80 years of age have been noted.37Prognostic data from this study showed a 48% event rate (death, myocardial infarction, or angina) over 4.6 years in those patients with silent ischemia detected by thallium perfusion and positive ECG changes. Other studies in young asymptomatic men have resulted in sensitivities and specificities of 45% and 78?'0"~-well below that observed in higher-risk symptomatic populations. Stress thallium imaging in the asymptomatic male population has revealed similar results to rest studies-with perfusion defect rates of only 109'0, associated with poor correlation of significant CAD on angiogr a ~ h y Application .~~ of stress perfusion imaging in higher-risk asymptomatic patients with discrete risk factors has been advocated, particularly in the asymptomatic hypertensive population. Perfusion defect rates as high as 50% may occur in this group, correlating closely with significant disease on coronary angiographyu Other higher-risk groups, such as siblings of CAD patients, have shown increased prevalence of

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ischemia on exercise thallium imaging, with one study reporting perfusion defect rates of 29% in men and 9% in women.7 After 5 years of follow-up, events (including the development of angina) were noted to be 13% in patients with perfusion defects alone (predictive value 20%) and 64% in patients with perfusion defects and a positive ECG treadmill test (predictive value 50%). Despite the accuracy of these techniques in intermediate-risk populations, the time required for imaging, the expense relative to other screening procedures, the limited availability, and the element of radiation exposure all make the widespread use of these techniques as screening tools unattractive. Their role, however, remains well justified in detecting CAD and stratifying prognosis in intermediate-risk and highrisk groups. Stress Echocardiography

Both exercise and dobutamine echocardiography have grown in popularity as methods of assessing CAD. The favorable features of relative low cost, portability, and capabilities of these techniques to detect unsuspected structural cardiac pathology are balanced by need for expert training in assessing regional wall motion although more objective scoring methods have been proposed. Although there are many indications for their respective use, their role in screening for CAD in lower risk asymptomatic patients remains unclear (Table 3). The accuracy of dobutamine echocardiography for detecting significant CAD ranges from 70% to 92?0'9' in symptomatic groups. The procedure involves echocardiographic imaging focusing on identification of wall motion performance during increasing levels of infused dobutamine (40 pg/kg/min with additional atropine as required). Pharmacologic stress differs from exercise stress in several aspects. First, the sensitivity of ECG changes during pharmacologic stress is poor, and therefore the accuracy of this test is mostly due to recognition of wall motion changes as the test progresses. Second, little correlation exists between exercise symptoms of myocardial ischemia and occurrence during pharmacologic stress. Moreover, the hemodynamic response during pharmacologic stress is not predictive of prognosis (compared to exercise stress). Nonetheless, dobutamine echocardiography may be effective for

Table 3. SELECTION BETWEEN EXERCISE AND NONEXERCISE (USUALLY DOBUTAMINE) STRESS ECHOCARDIOGRAPHY Exercise Echocardiography

Dobutamine Echocardiography

Diagnosis CAD Prognostic assessment of CAD Abnormal resting ECG

As for exercise echocardiography plus Unable to exercise Presurgical risk stratification Postmyocardial infarction Detection of viable myocardium

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screening certain high-risk subgroups for clinically silent CAD (notably the preoperative group). Exercise echocardiography is based on comparison of rest and postexercise or peak exercise images for the development of new or worsening wall motion abnormalities. Wall motion abnormalities are a more reliable predictor of CAD than are ECG changes during exercise stress. The test is accurate for the diagnosis of coronary disease and for symptom assessment. A meta-analysis of 44 exercise echocardiography and exercise single-photon emission computed tomography (SPECT) studies38revealed similar sensitivities (85% versus 87%) but more attractive specificity for exercise echocardiography (77% versus 64%), in both symptomatic and asymptomatic patients. In addition, the presence or 87 but as absence of ischemia carries important prognostic inf0rmation,8~* with standard stress ECG testing, adequate levels of exercise are required for both accurate diagnosis and prognostic assessment. The technique may be particularly valuable for the identification of CAD in women, in whom the stress ECG may be less specific than in men.81 Stress echocardiographic techniques are less costly and time-consuming than radionuclide perfusion techniques. Although their higher specificity may also make them more attractive for the assessment of low-risk groups, their predictive power is probably also less in the setting of low pretest probability. Coronary Artery Disease Screening Using ElectronBeam Computed Tomography

Standard x-ray computed tomography (CT) images are obtained by rotation of an x-ray source around the patient. In contrast, electronbeam computed tomography (EBCT) involves aiming electron beams at tungsten sources to produce avoiding a rotating x-ray source allows acquisition of images in an interval of 100 ms. In addition, ECG triggering of image acquisition (in late diastole) compensates for cardiac translation, allowing higher resolution. The prediction of CAD likelihood is based on detection and quantification of coronary artery calcification (Fig. 2). A threshold density of greater than 130 HU (twice the density of blood) has been used to define calcification, and the size and intensity of defects are taken into account to avoid false-positive results because of artifact. Varying protocols are used between centers; 8 adjacent pixels allow a reasonable combination of sensitivity and specifi~ity.~~ A given detected area is factor adjusted depending on the peak density of that region. The sum of such calculations allows an overall catcium score to be derived. The ability of EBCT to predict hemodynamically significant CAD is reported to be comparable to exercise testing with or without radionuclide perfusion imaging.58Limited data are available to define diagnostic accuracy for CAD in asymptomatic lower-risk individuals, but several investigators have demonstrated increasing calcium scores with age.56,

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Figure 2. Detection of coronary calcification using EBCT.

Others have shown correlation between the square root of the calcium score and the angiographic severity of coronary artery ~ t e n o s e s . ~ ~ The critical issue that defines the utility (or lack thereof) of EBCT is its prognostic value. In this respect, the data are limited, reflecting the short history of this technique as a clinical tool. The available prognostic information is summarized in Table 4.57 29, 115, lz3 Detrano et alZ9demonstrated higher event-free survival at nearly 4 years in symptomatic patients with coronary calcium scores less than 100. The absence of significant coronary calcification renders it unlikely that the patient will suffer a cardiac event (i.e., predictive value of a negative test approaches loo%), but EBCT has a poor (only 15%) positive predictive value.5 Moreover, Secci et a P 5 demonstrated that the events predicted by coronary calcium scoring in symptomatic patients were more commonly the need for revascularization rather than hard cardiac end points (e.g., cardiac death, myocardial infarction). EBCT is attractive as a screening tool for CAD in several respects. It is a noninvasive and fast technique (the scanning time may be as short Table 4. PREDICTION OF SUBSEQUENT CARDIAC EVENTS USING EBCT ~~~

Author

Patients

FOIIOW-UP

DetranoZ9

422. symptomatic

45 mo

Arad5

1173 asymptomatic

19 mo

Sec~i”~

326 asymptomatic

80 mo

Tang’23

146 symptomatic

20 mo

Result

Score
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as 10 minutes). No exercise is required to obtain the data, and the cost (separate from initial hardware outlay) is reported to be similar to standard exercise testing or nuclear stress imaging technique^.^^ Limitations of EBCT have also been recognized, however. Many lipid-rich lesions contain little or no calcium and may not be readily detected by EBCT; these lesions may be more likely to cause adverse events because of acute plaque rupture compared to chronic calcified lesions. Although extent of CAD correlates well with the calcium score, a high score cannot readily differentiate between diffuse disease and discrete hemodynamically significant lesions that might require intervention. There is little evidence as to the most appropriate method of progressing once a positive score has been obtained. Currently, some form of stress testing seems appropriate given that no functional data and ambiguous prognostic data are gained from EBCT. The economic aspects of such a stepped approach are undefined, however. Nonetheless, as further studies are performed and hardware costs are reduced, EBCT calcium scoring may become a feasible screening tool for CAD. Tests of Vascular Structure and Function as a Guide to Coronary Artery Disease Likelihood Intima-Medial Thickness

Intima-medial thickness (IMT) may be measured using a highresolution transducer and correlates with anatomic measurements of the same structures."Q lZ7 The rationale of this technique is to assess the atherosclerotic plaque burden from an accessible vessel that correlates with the process in the coronary arterial tree. Images acquired using B-mode ultrasound demonstrate echogenic boundaries that represent intimal-luminal and medial-adventitial borders, thus allowing IMT to be 59 and may be measured (Fig. 3). The measurement is repr~ducible~~, useful as a diagnostic and prognostic marker for generalized atherosclerosis, including CAD. The ability to obtain IMT images varies from site to site with reported success rates of 99%, 75% to 95%, and 67% in the common carotid, carotid bifurcation, and internal carotid arteries. In addition to the internal carotid being more difficult to visualize, greater intraobserver and interobserver variability has been noted with imaging the internal carotid compared with the common carotid.59Other errors can occur because of incorrect transducer orientation giving oblique views or from other technical concerns (e.g., gain settings). Because of the ambiguity of a bright/dark interface as compared with a dark/bright interface, posterior wall measurements are considered less dependent on gain settings and therefore more reliable and reproducible.loO Averaging of measurements from near and far walls at all three carotid levels has been reported as a more precise and reproducible method.'OO Because IMT measurements cannot separate intimal from medial

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Figure 3. Measurement of intima-medial thickness in the posterior wall of the common carotid artery.

thickness, the validity of increased IMT for representing atherosclerosis has been questioned. For instance, in the setting of prolonged systemic hypertension, IMT measurements may be partly elevated as a result of medial hyperplasia. In fact, correlation between left ventricular hypertrophy and IMT has been noted.lo6Moreover, although CAD correlates most closely with IMT at the internal carotid artery, the results are influenced by atherosclerotic risk factors and may be altered by risk factor intervention. The widespread implementation of IMT as a screening tool for CAD has been limited by the lack of large validated population reference ranges. Some have reported normal ranges of 0.4 to 1.0 mm, with a yearly progression rate of 0.01 to 0.3 mm per year.113Table 5 summarizes normal ranges of IMT values; values greater than 0.90 mm represent a high likelihood of the presence of CAD.', 8,42, 113 Brachial Artery Reactivity

Loss of the normal function of the vascular endothelium is considered to be an early event in atherogenesis,lo9with decreased nitric oxide activity thought to be central in this process.13oSeveral invasive studies have demonstrated decreased coronary artery reactivity to acetylcho74, 130 but the invasive nature of this test has restricted its use to investigations. Appreciation that vascular endothelial dysfunction may be generalized in nature, however, led to a relationship being sought

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Table 5. NORMAL RANGES OF CAROTID INTIMA-MEDIA THICKNESS Author

Patients

Bats*

8000 Dutch >55 y

Sa10nen"~ F~jii~~ Geroulakos5'

2600 Finnish >42 y hyperlipidemic 164 low-risk Japanese patients 89 random patients

Agewall'

25 patients

IMT Values

Low risk <0.60 mm, high risk >0.90 mm Mean 1.6 mm Mean 0.67 mm Low risk <0.75 mm, high risk >0.92 mm Low insulin sensitivity mean 0.85 mm High insulin sensitivity mean 0.90 mm

between reduced peripheral artery vasodilation and presence of CAD. Celermajer et alZ1first proposed noninvasive measurement of endothelial-dependent dilation (or flow-mediated dilation [FMD]) by measuring brachial artery diameter before and after cuff occlusion of the vessel for 4.5 minutes (reactive hyperemia) as well as endothelial-independent dilation after glyceryl trinitrate administration. This work established a relationship between atherosclerotic risk factors and reduced FMD of the peripheral vasculature (brachial and femoral arteries). Subsequent studies have confirmed these findings in both symptomatic and asymptomatic at-risk populations.zo* 24, 71 The interuser and intrauser variability of this technique has since been shown to be about 2%,119allowing reasonable reproducibility. Few investigators have examined the relationship between reduced FMD and the presence or extent of CAD. Neunteufl et a194demonstrated an association between FMD of the brachial artery and presence and extent of significant CAD (defined as >30% stenosis) in symptomatic patients compared with controls. ROC analysis in this study reported a FMD of less than 10% to detect significant CAD with 89% sensitivity and 77% specificity. Similar FMD values have been found in patients with so-called microvascular angina (typical anginal pain, positive exercise stress test, normal epicardial vessels on angiogram) and angiographically significant CAD (1.90/,versus 3.3%; P = not significant); both were less than FMD in normals (7.9%). The authors of the study" have suggested that a combination of IMT and FMD could be used to discriminate between microvascular and macrovascular angina. Quite different ranges of FMD in controls were described in this study compared with that of Neunteufl et a1 (7.9% versus 15.7%)despite similar .methods and similar populations. This situation raises the question of what constitutes normal population values for FMD when consideration is given to use in widespread screening. Thus, although BAR is attractive as a noninvasive method of assessing the integrity of vascular endothelial function, this does not necessarily translate into presence of macrovascular CAD requiring intervention. The data are concordant with CAD risk, however,

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and with more information, this cheap and easily performed test may prove to be of great value. SCREENING FOR CORONARY DISEASE IN SELECTED GROUPS Identification of High-Risk Groups

Because the major limitation to exercise testing for the diagnosis of asymptomatic coronary disease relates to low coronary disease prevalence, the technique may be made more feasible by selection of subgroups with a greater likelihood of having disease. In the Multiple Risk Factor Intervention Trial (MRFIT) study, such an enriched group was defined on the basis of mean age greater than 40 years old, with more than one of the following risk factors: hypercholesterolemia (>240 mg/ dL), hypertension (>140/90 mm Hg), smoking, diabetes, or a family history of premature coronary disease.'07 The Framingham model of using clinical and risk factor variables to predict risk of cardiac events has also been a ~ p l i e dOther .~ high-risk categories include patients with peripheral vascular disease, patients with chronic renal failure, patients after coronary bypass surgery, and patients after cardiac transplantation. All of these situations are associated with an increased prevalence of coronary disease and aggressive atherogenesis. With the exception of the aforementioned categories and attempts to identify asymptomatic coronary disease in special groups, such as pilots and firefighters (in whom it is justified on the basis of the risk of occult CAD), the use of exercise testing should probably not be applied to CAD screening.45 Screening for Coronary Disease in Peripheral Vascular Disease Justification

There is a close relationship between the presence of atherosclerotic peripheral vascular disease and the presence of disease in the coronary circulation. On anatomic grounds, most patients with vascular disease have coexistent coronary disease.50Because many patients with vascular disease are unable to exercise sufficiently to develop anginal symptoms, most of these patients with coronary disease are asymptomatic from the cardiac standpoint. In the absence of intervention, perioperative cardiac death can be expected in 2%, ischemic episodes in 8%, myocardial infarction in 3%, and congestive heart failure episodes in 8% of patients.78 Moreover, the presence of ischemic events or nonfatal infarction within 1 week of surgery significantly increases the risk of serious outcomes within 2 years. Therefore, this situation is more amenable to screening than an unselected population. The prevalence of coronary disease in

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this group is enriched. In the absence of diagnostic testing, unidentified coronary disease may translate into increased hospital stay as well as cardiac events, both of which may be saved by coronary screening and intervention. Selection of Patients for Screening

In general, it is most worthwhile screening patients who are undergoing major surgery. In addition to vascular operations, an evaluation of cardiac risk is justified before thoracic procedures, long and complex surgery, and some orthopedic and head and neck surgery.31As always, the initial evaluation should be based on clinical testing, and several clinical criteria have been described (see Table 2). The Eagle criteria are simplest and probably the most amenable to evaluation of vascular patients.33These criteria include age greater than 70 years, diabetes, angina, prior infarction, and congestive heart failure. The absence of any of these variables is associated with a low perioperative risk of events (55%), the presence of one to two of these clinical markers carries an intermediate risk (approximately 15%), and more than three of the clinical risk variables are associated with a high risk (>50%). It is important that patients are systematically evaluated regarding the nature of surgery and their clinical risk variables, rather than a general perception of risk being used. In the absence of a systematic approach, physicians tend to overestimate risk and therefore overinvestigate.llo Patients who are identified as at risk on the basis of their clinical evaluation and the nature of their surgery, together with those who have been unstable, warrant further investigation. Although Holter monitoring for ischemic ST-segment responses has been used to estimate cardiac risk, this technique is not widely used because its sensitivity and specificity are limited. Resting nuclear ventriculography was used for the assessment of risk about 10 years ago but is seldom used now. Although most events occur in patients with severe left ventricular function, the sensitivity of the test for predicting patients liable to have events is unacceptably low. Thus, the main useful approaches are stress perfusion scintigraphy and stress echocardiography, both usually performed with pharmacologic stressors because of the inability of these patients to exercise maximally. Screening With Myocardial Perfusion Imaging

Table 6 summarizes the results of dipyridamole and adenosine myocardial perfusion imaging, using thallium or technetium sestamibi for the prediction of coronary events? Although perfusion imaging has a high sensitivity, the specificity for the test is not so high-so that patients with positive test results do not necessarily proceed to have events. Although the predictive value of a negative test result is ex~~

'References 6, 9, 14, 17, 26, 32, 40, 49, 64, 73, 79, 88, 128

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Table 6. PREDICTION OF PERIOPERATIVE CORONARY EVENTS USING STRESS MYOCARDIAL PERFUSION SCINTIGRAPHY (STUDIES OF APPROXIMATELY 50 PATIENTS OR MORE).

Author

n

Boucher' 48 116 CutlerZ6 67 Fletcher40 200 Eagle3' 95 McEnroea8 111 YounislZ8 M a n g a n ~ ~ ~ 60 327 HendeP 355 Lette73 231 Brown8' 170 KresowikM 457 Baron6 Bry17 237

TI-Redistribution

MllDeath

PV Positive Scan

33% 47% 22% 41% 36% 36% 37% 51% 45% 33% 39% 35% 46%

6% 10% 4% 8% 7% 7% 5% 9% 8% 5 Yo 3% 5% 7%

19% 20% 20% 16% 9% 15% 5% 14% 17% 13% 4% 4% 11%

PV Negative Scan

100% 100% 100% 98% 96% 100% 95% 99% 99% 99% 98% 96% 100%

Data from Lazem F, et al: Coronary calcification detected by ultrafast computed tomography is a predictor of cardiac events in heart transplant recipients. Transplant Proc 29:572, 1997.

tremely high (>%YO),the predictive value of a positive test result ranges from 10% to 50%, with most being 20% to 30%. Thus, the use of nuclear perfusion imaging readily identifies patients to be at low risk, but a simple report of test positivity is of less value in stratifying the risk of an event. A more sophisticated approach to myocardial perfusion imaging, looking at the extent of ischemic myocardium as well as the presence of stress-induced left ventricular dysfunction (evidenced as transient left ventricular dilation or increased lung uptake of thallium) may be used to stratify levels of increasing risk.77 Screening With Stress Echocardiography Table 7 summarizes the results of dobutamine echocardiography for the prediction of events. Similar to perfusion imaging, this technique has been found to have a high sensitivity and negative predictive value Table 7. PREDICTION OF PERI-OPERATIVE CORONARY EVENTS USING STRESS ECHOCARDIOGRAPHY

Author

n

Ischemia

MllDeath

PV Positive Scan

Lanebh Lalka6s EichelbergeP Langad7 Poldermans'"' Divila RominZ7

38 60 75 74 131 88

50% 50% 36% 24% 27% 23%

8Yo 15% 3% 4% 4% 2%

16% 23% 7% 17% 14% 10%

PV Negative Scan

100% 93% 100% 100% 100% 100%

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MARWICK & CAIN

but a lower specificity and positive predictive value.27,34, 6547, Io3 A negative test confers a low probability of a cardiac event, whereas a positive test requires further stratification. In contrast to the results of thallium imaging, the extent or, severity of ischemia at dobutamine echocardiography is predictive of long-term but not short-term cardiac events,lo1,Io2 although ischemic threshold is predictive of the perioperative likelihood of an event. If a patient develops ischemia at a low heart rate (i.e., <120 beats/min), the likelihood of suffering an event is substantially greater than if ischemia develops only at peak stress, when the heart rate is substantially increased. The ischemic threshold is particularly predictive of adverse outcome when evaluated in the context of clinical variables. A meta-analysis of studies performed with dipyridamole thallium imaging and dobutamine echocardiography has shown the tests to be of comparable prognostic value, although the cost of dobutamine echocarA few indidiography is significantly less than the nuclear te~hnique."~ vidual studies have compared tests on a head-to-head basis, showing similar levels of sensitivity, but the stress echocardiography technique has the greatest specificity. Finally, both tests appear to have similar efficacy for the prediction of cardiac events over long-term follow-up in vascular patients.97 Responses to ldentification of Risk The preceding discussion has indicated that patients with vascular disease present an enriched group of individuals with coronary disease and that by initial clinical screening an intermediate-risk group can be directed toward stress-testing techniques, which are able to identify various levels of risk. The next step in the screening process is to use these data to change the risk status of the patient. Although the frequency of cardiac events in previously revascularized patients is substantially less than that of individuals with unrevascularized coronary disease, the efficacy of revascularization to avoid coronary events in vascular patients has never been proven. The first concern is that the benefits of myocardial revascularization need to be balanced against its risk. Various studies have used decision analytic models to balance risk and benefit, and generally the risk of coronary revascularization needs to be less than 2% to 4% to justify a protocol of screening vascular patients with the intent of revascularizing the myocardium if the test is positive. If the risk of cardiac surgery is greater than 47'0, the summation of coronary and vascular surgical risk is unacceptably high.39Similarly, it is difficult to justify investigation of patients with less than 10% to 20% probability of coronary disease, assuming that the mortality from vascular surgery is less than 8%. Even in the situations in which the patient is likely to profit prognostically from coronary surgery, it has not been established that a whole process of screening is worthwhile in financial terms. A simple analysis comparing the screening versus the nonscreening approach using thallium imaging suggested that thallium imaging costs $390,000 per life saved, or $180,000 per infarct averted.17These data were undoubtedly

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colored by the fact that many patients had positive thallium and negative coronary angiography, and a number of patients failed to undergo coronary angiography despite a positive thallium test. A more sophisticated decision analytic model presented by Mason et alX6suggested that by combining the mortality, infarct, and stroke risk of patients undergoing vascular surgery alone or surgery in combination with coronary bypass surgery, the cost of screening strategies almost doubled the overall cost of vascular surgery operations, without a major impact on outcome. From a cost standpoint, the problem with all of these approaches is that it is assumed that a positive test leads to myocardial revascularization, and this may be too simplistic. Instead the screening process should identify individuals at low risk, who can proceed directly to surgery; those at intermediate risk, who perhaps could be treated with intensive medical therapy and intensive operative monitoring; and those at high risk, in whom myocardial revascularization should be focused. Such an approach is more likely to be cost-effective. Screening Patients With Chronic Renal Failure

Cardiac disease is the commonest cause of serious morbidity and mortality in patients undergoing dialysis and renal transplantation. The number of patients with renal failure increases at the rate of about 10% per year in the United States, making this a significant group of patients with a high prevalence of coronary disease who warrant screening. Patients with chronic renal disease may represent a difficult group to evaluate using noninvasive testing. These patients are often debilitated, so that exercise testing approaches are not feasible. The almost uniform presence of left ventricular hypertrophy compromises the accuracy of the exercise ECG, and ST-segment interpretation is unreliable even in the absence of a left ventricular strain pattern on the resting ECG. Pharmacologic stress testing has been the norm in this patient group, usually involving a choice between dipyridamole stress myocardial perfusion imaging or dobutamine stress echocardiography. The value of nuclear perfusion imaging has been examined with varying results-concern has focused on the prevalence of left ventricular hypertrophy. Because perfusion techniques are based on measurement of relative flow distribution and left ventricular hypertrophy influences coronary flow reserve, this finding may affect the accuracy of perfusion imaging.”’ Dobutamine stress echocardiography is less influenced by 116 and initial studies have indicated that hypertrophy or hypertensi~n,~~. the test is accurate for the detection of coronary disease in renal patients5I,loxas well as having prognostic value.82The accuracy of dobutamine echocardiography and dipyridamole SPECT imaging in renal failure is summarized in Table 8.* Although the data presented indicate that the use of stress testing *References 10-13, 19, 28, 51, 52, 54, 70, 82, 84, 92, 108, 125.

h)

v,

Y W

Stress

Ex-TI Dip-T1 D&-T~ Dip-T1 Dip-T1 Ex-T1 Dip-T1 Ex-T1 Ex-TI Dip-T1 Dip-T1 DbEcho DbEcho DbEcho DbEcho

Study

Morrow92 Brown BoudreaulV Marwick Carnpl9 H01ley~~ Derfler2* Brown Le70 Vandenberg125 He~ton~~ Herzogsl Reis’v8 Brennan” Marwick

~~

85 Tx and HD pts 65 diab and non-diab Tx Dts 40 pts with DM and ESRb 45 Tx candidates 40 diab Tx candidates 141 diab Tx candidates 59 symplasymp ESRF (HD, Tx) 103 asymptomatic, ESRF 95 high risk Tx pts 41 Tx pts 95 Tx pts with T1 and neural net 50 pts with ESRF 97 pts with ESRF 47 pts with ESRF 193 uts with CRF

~

Group

72% 73%

73% 76% 86%

53% 75% 95%

Specificity

86% 37%

Sensitivity

T1 predictive-not more than Hx CAD/ECG Isc and EF predicted outcome (>30% prior MI) T1 did not predict outcome Only pts with T1 defects had events T1 did not predict periop risk T1 predicted events, not death Sens 88%, spec 70% for events T1-Isc/Scar predict outcome Outcome same with +- scan Sens 82%, spec 77% for events NO follow-~p NPV 97% over 12 months NPV 95% over 20 months Ischemia predicted outcome early, not late

Outcomes

Table 8. USE OF STRESS IMAGING TECHNIQUES TO PREDICT PRESENCE OF CAD AND OUTCOME IN PATIENTS WITH ESRF

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for the diagnosis of coronary disease is effective in renal patients, the second aspect of screening carries the proviso that these data can be used to improve patient outcome. This matter is much less well established, and several considerations are important. First, patients with chronic renal disease have an atherogenic milieu, to the extent that the favorable prognosis conferred by a normal scan in a normal patient is not witnessed for as long in a patient with renal disease. In fact, the warranty of a normal scan in a renal failure patient is approximately 2 years, after which time the number of cardiac events starts to increase.82 Second, the use of coronary angioplasty in patients with renal failure is associated with a relatively high incidence of restenosis, and although reservations have been expressed about the increased risk of bypass surgery in this patient gr0up,5~,lz9 this appears to be the most effective option at present. Limited data indicate that in diabetic end-stage renal failure patients with proven significant coronary disease, outcome after myocardial revascularization is more favorable than outcome after medical therapys0 Nonetheless, the justification of the cost of this approach requires further work. Preliminary data, presented from the group at St. Louis, indicate that screening may be expected to reduce mortality from cardiac death over follow-up from approximately 11%to 4%. The incremental cost for the avoidance of each death in this study was $52,000,122which is not excessive. In particular, the discussion of cost in this group needs to account for the wastage of scarce organ replacements if patients die prematurely from coronary disease.

Screening for Ischemia in Patients After Heart Transplantation

With the development of routine heart transplantation in many countries, allograft CAD has been appreciated as a major limiting factor of long-term outcome in these patientss9 Angiographically significant occurrence rates of CAD have been reported by some investigators to be 70% at 5 years. The cause of allograft CAD differs from native disease and is probably multifactorial-involving conventional CAD risk factors (especially hyperlipidemia) or other mechanisms, such as vascular and 89 By the time cellular rejection or peritransplant ischemic necrosis.25* focal stenotic lesions have developed, the pattern of CAD observed in this group is more diffuse and tends to involve the small vessels to a greater degree than in native CAD. The diffuse involvement of the vasculature, appreciated well by intravascular ultrasound,’jOhas important implications. First, although current screening strategies commonly involve a schedule of angiographic assessment, this technique is notoriously insensitive to the presence of diffuse narrowing. Second, if the angiogram is used to judge the accuracy of conventional screening techniques, these may appear to be nonspecific because of detection of flow limitation in diffusely diseased vessels that appear normal to the

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angiogram. A limited amount of data has compared the functional tests to intravascular ultrasound evidence of CAD.121 Standard ECG stress testing is not a feasible option in many transplant patients because many (59%) have an abnormal resting ECG.77 Moreover, the results of gated radionuclide wall motion assessment and oral dipyridamole thallium scintigraphy have demonstrated predictive values for hemodynamically significant stenoses well below those for the nontransplanted population.118Other screening tests have shown more promise. Resting echocardiographic left ventricular ejection fraction is an important determinant of outcome and may be as predictive as angiography for long-term event-free survival. Dobutamine stress echocardiography can predict both the presence of hemodynamically significant CAD and the long-term CAD outcome in recently transplanted patients.2 The role of exercise echocardiography is less clear; however, test specificities albeit in study groups of small numbers. of 97% have been The same author described a sensitivity of 92% for exercise perfusion scintigraphy in the same population. Finally, preliminary data suggest that EBCT coronary calcium scoring may predict cardiac events in heart transplant patients at 4 years.69 Although CAD may be detected in the transplant patient, the appropriate response to this finding is by no means clear-as such, the outcome value of screening is not established. Nonetheless, as the number of cardiac transplants increases and the age of both transplant donor and recipient increases, the need for accurate and cost-effective screening of early CAD in this high-risk population continues to pose special challenges. More work is likely to be forthcoming in this area.

Evaluation of Patients After Coronary Bypass Surgery

The number of patients undergoing coronary artery bypass surgery continues to increase, with more than 500,000 bypass procedures being performed in the United States in 1996.3 Although graft surgery is effective in the relief of angina and improvement of prognosis in subgroups of patients, it remains a palliative approach, and the atherosclerotic process continues in most patients. The consequence is that progressive native vessel disease and the development of graft stenosis limits the long-term efficacy of this approach. Because these patients already have established coronary disease, the use of screening in this setting relates more to the detection of progressive disease. Guidelines for the management of post-coronary bypass patients do not recommend routine screening procedures for the detection of ischemia. These decisions need to be based not only on the ability of stress testing or other procedures to identify individuals at risk, but also the ability to change outlook by intervention.

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Exercise Testing

The use of exercise alone in postbypass patients is problematic. Commonly, these patients have resting ST-segment changes because many have had previous myocardial infarction. Moreover, the inability of exercise testing to localize the site of ischemia is problematic because small areas of ischemia within nongrafted territories may cause STsegment abnormalities. Consequently, most work in this area has been in investigation of stress-imaging approaches. Nuclear Myocardial Perfusion Imaging

Several studies have now documented the accuracy of nuclear myocardial perfusion imaging for the detection of coronary disease in patients after bypass surgery.68,90,93 These tests are highly sensitive for the detection of recurrent ischemia, although the specificity of the tests is compromised somewhat by perfusion abnormalities resulting from presurgical myocardial infarctions or ischemia resulting from nonbypassed native vessel disease. Nonetheless, exercise thallium SPECT abnormalities have been found to be independently predictive of adverse and this is true even among asymptomatic patients. Based on the composite evaluation of clinical risk as well as scintigraphic results, patients may be allocated into various degrees of aggressiveness for intervention (Fig. 4). Stress Echocardiography

Other stress-imaging modalities, such as exercise echocardiography, have also shown promise in screening for CAD after coronary artery bypass grafts. Positive and negative predictive values of 85% and 81% have been emphasizing its diagnostic utility compared to exercise ECG alone. In contrast to thallium SPECT imaging, however, prognostic data are limited. cost

In a cost analysis, the use of thallium imaging rather than the exercise treadmill test increases the cost from $550 per high-risk patient identified to $1290 per high-risk patient identified, although it avoided unnecessary angiography in many patients who had a positive exercise test alone. Further study is required to balance the cost and benefit of screening for ischemia in this patient group, but these preliminary data indicate this is a worthwhile population for screening. CONCLUSIONS The success of screening for CAD, similar to many other screening programs, depends on the prevalence of disease in the population stud-

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Assess Risk Based on Clinical and Exercise Variables

(age,hypertension,time since CABG, no IMA, incomplete revascularization, and poor exercise capacity [<6 METs])

/

High

J

Thallium scintigraphy

/ \

Presence of reversible Derfusion defects

Absence of reversible Derfusion defects

\

Low

Thallium scintigraphy

/ \

Presence of reversible Derfusion defects

Absence of reversible Derfusion defects

J

I

Very high risk (13%)

Moderately high risk (13%)

Very high risk (13%)

Very high risk (13%)

Aggressive medical management Angiography

Aggressive medical management Consider viability assessment if extensive fixed defects

Aggressive medical management Consider angiography

Conservative management

J

I

Figure 4. Guidelines for management of asymptomatic patients after coronary bypass surgery. Percentages correspond to anticipated 1-year event rates. Aggressive medical management = aspirin, beta-blockers, angiotensin-converting-enzymeinhibitors, lipid-lowering drugs, aggressive dietary modifications, and tailored exercise programs.

ied. The tests for coronary disease are imperfect, and the simplest and least expensive test (treadmill ECG) is the least accurate. Most screening protocols use a more accurate, but also more expensive imaging approach. Once coronary disease is identified, the referring physician needs to consider the likelihood of changing outcome in high-risk patients. References 1. Agewall S, Fagerberg B, Attvall S, et al: Carotid artery wall intima-media thickness is associated with insulin-mediated glucose disposal in men at high and low coronary risk. Stroke 26:956-960, 1995 2. Akosah KO, McDaniel S, Hanrahan JS, et al: Dobutamine stress echocardiography early after heart transplantation predicts development of allograft coronary artery disease and outcome. J Am Coll Cardiol 31:1607-1614, 1998 3. American Heart Association: 1999 Heart and Stroke Statistical Update. http:// www.amhrt.org/statistics/ 1999 4. Anderson KM, Wilson PWF, Ode11 PM, et al: An updated coronary risk profile: A statement for health care professionals. Circulation 83:359-362, 1991 5. Arad Y, Spadaro LA, Goodman K, et al: Predictive value of electron beam computed tomography of the coronary arteries: 19-month follow-up of 1173 asymptomatic subjects. Circulation 93:1951-1953, 1996 6. Baron JF, Mundler 0, Bertrand M, et al: Dipyridamole-thallium scintigraphy and gated radionuclide angiography to assess cardiac risk before abdominal aortic surgery. N Engl J Med 330:663469, 1999 7. Blumenthal RS, Becker DM, Moy TF, et al: Exercise thallium tomography predicts

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future clinically manifest coronary heart disease in a high-risk asymptomatic population. Circulation 93:915-923, 1996 8. Bots ML, Hoes AW, Koudstaal PJ, et al: Association between the intima-media thickness of the common carotid and subsequent cardiovascular events in subjects, 55 years and older, in the Rotterdam study. Ned Tijdschr Geneeskd 1421100-1103, 1998 9. Boucher CA, Brewster DC, Darling RC, et al: Determination of cardiac risk by dipyridamole thallium imaging bef&e peripheral vascular surgery. N Engl J Med 312389-394, 1985 10. Boudreau RJ, Strony JT, duCret RP, et al: Perfusion thallium imaging of type I diabetes patients with end stage renal disease: Comparison of oral and intravenous dipyridamole administration. Radiology 175:103-105, 1990 11. Brennan DC, Vedala G, Miller SB, et al: Pretransplant dobutamine stress echocardiography is useful and cost-effective in renal transplant candidates. Transpl Proc 29233234, 1997 12. Brown JH, Vites NP, Testa HJ, et al: Value of thallium myocardial imaging in the prediction of future cardiovascular events in patients with end-stage renal failure. Nephrol Dial Transplant 8:433-437, 1993 13. Brown KA, Rimmer J, Haisch C: Noninvasive cardiac risk stratification of diabetic and non-diabetic uremic renal allograft candidates using dipyridamole thallium-201 imaging and radionuclide ventriculography. Am J Cardiol 64:1017-1021, 1989 14. Brown KA, Rowen M: Extent of jeopardized viable myocardium determined by myocardial perfusion imaging best predicts perioperative cardiac events in patients undergoing noncardiac surgery. J Am Coll Cardiol 21:325-330, 1993 15. Bruce RA, DeRouen TA, Hossack KF Value of maximal exercise tests in risk assessment of primary coronary heart disease events in healthy men: Five years’ experience of the Seattle Heart Watch study. Am J Cardiol 46:371-378, 1980 16. Bruce RA, Hossack KF, DeRouen TA, et al: Enhanced risk assessment for primary coronary heart disease events by maximal exercise testing: 10 years’ experience of Seattle Heart Watch. J Am Coll Cardiol 2:565-573, 1983 17. Bry JD, Belkin M, ODonnell TF Jr, et al: An assessment of the positive predictive value and cost-effectiveness of dipyridamole myocardial scintigraphy in patients undergoing vascular surgery. J Vasc Surg 19:112-121, 1994 18. Cairns J, Shackley P:Sometimes sensitive, seldom specific: A review of the economics of screening. Health Econ 243-53, 1993 19. Camp AD, Garvin PJ, Hoff J, et a1 Prognostic value of intravenous dipyridamole thallium imaging in patients with diabetes mellitus considered for renal transplantation. Am J Cardiol 65:1459-1463, 1990 20. Celermajer DS, Sorensen KE, Georgakopoulos D, et al: Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation 88:2149-2155, 1993 21. Celermajer DS, Sorensen KE, Gooch VM, et al: Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 340:1111-1115, 1992 22. Chaitman BR, Bourassa MG, Davis K, et al: Angiographic prevalence of high-risk coronary artery disease in patient subsets (CASS). Circulation 64:360-367, 1981 23. Chin WL, OKelly B, Tubau JF, et al: Diagnostic accuracy of exercise thallium-201 scintigraphy in men with asymptomatic essential hypertension. Am J Hypertens 5:465-472, 1992 24. Clarkson P, Celermajer DS, Powe AJ, et al: Endothelium-dependent dilatation is impaired in young healthy subjects with a family history of premature coronary disease. Circulation 96:3378-3383, 1997 25. Costanzo-Nordin MR Cardiac allograft vasculopathy: Relationship with acute cellular rejection and histocompatibility J Heart Lung Transplant 11:S90-103, 1992 26. Cutler BS, Leppo JA: Dipyridamole thallium 201 scintigraphy to detect coronary artery disease before abdominal aortic surgery. J Vasc Surg 5:91-100, 1987 27. Davila-Roman VG, Waggoner AD, Sicard GA, et al: Dobutamine stress echocardiography predicts surgical outcome in patients with an aortic aneurysm and peripheral vascular disease. J Am Coll Cardiol 21:957-963, 1993

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28. Derfler K, Kletter K, Balcke P, et al: Predictive value of thallium-201-dipyridamole myocardial stress scintigraphy in chronic hemodialysis patients and transplant recipients. Clin Nephrol36:192-202, 1991 29. Detrano R, Hsiai T, Wang S, et al: Prognostic value of coronary calcification and angiographic stenoses in patients undergoing coronary angiography. J Am Coll Cardiol 27285-290, 1996 30. Diamond GA, Forrester J S Analysis of probability as an aid in the clinical diagnosis of coronary artery disease. N Engl J Med 300:1350-1358, 1979 31. Eagle KA, Brundage BH, Chaitman BR, et al: Guidelines for perioperative cardiovascular evaluation for noncardiac surgery: Report of the ACC/AHA Task Force on Practice Guidelines. J Am Coll Cardiol 27910-948, 1996 32. Eagle KA, Coley CM, Newel1 JB, et al: Combining clinical and thallium data optimizes preoperative assessment of cardiac risk before major vascular surgery. Ann Intern Med 110:859-866, 1989 33. Eagle KA, Singer DE, Brewster DC, et al: Dipyridamole thallium scanning in patients undergoing vascular surgery: Optimizing preoperative evaluation of cardiac risk. JAMA 2572185-2189, 1987 34. Eichelberger JP, Schwarz KQ, Black ER, et al: Predictive value of dobutamine echocardiography just before noncardiac vascular surgery. Am J Cardiol 72:602-607, 1993 35. Espeland MA, Craven TE, Riley WA, et al: Reliability of longitudinal ultrasonographic measurements of carotid intimal-medial thicknesses. Asymptomatic Carotid Artery Progression Study Research Group. Stroke 274230485, 1996 36. Fiorino AS: Electron-beam computed tomography, coronary artery calcium, and evaluation of patients with coronary artery disease. Ann Intern Med 128:839-847, 1998 37. Fleg JL, Gerstenblith G, Zonderman AB, et al: Prevalence and prognostic significance of exercise-induced silent myocardial ischemia detected by thallium scintigraphy and electrocardiography in asymptomatic volunteers. Circulation 81:428436, 1990 38. Fleischmann KE, Hunink MG, Kuntz Kh4, et al: Exercise echocardiography or exercise SPECT imaging? A meta-analysis of diagnostic test performance. JAMA 280:913920, 1998 39. Fleisher LA, Skolnick ED, Holroyd KJ, et al: Coronary artery revascularization before abdominal aortic aneurysm suigery: A decision analytic -approach. Anesth Analg 791661-669, 1994 40. Fletcher JP, Antico VF, Gruenewald S, et al: Dipyridamole-thallium scan for screening of coronary artery disease prior to vascular surgery. J Cardiovasc Surg 29:666-669, 1988 41. Froelicher VF, Thomas MM, Pillow C, et al: Epidemiologic study of asymptomatic men screened by maximal treadmill testing for latent coronary artery disease. Am J Cardiol 34:770-776, 1974 42. Fujii K, Abe I, Ohya Y, et al: Association between hyperinsulinemia and intima-media thickness of the carotid artery in normotensive men. J Hypertens 15:167-172, 1997 43. Geroulakos G, OGorman D, Nicolaides A, et al: Carotid intima-media thickness: Correlation with the British Regional Heart Study risk score. J Intern Med 235:431433, 1994 44. Gianrossi R, Detrano R, Mulvihill D, et al: Exercise-induced ST depression in the diagnosis of coronary artery disease: A meta-analysis. Circulation 80:87-98, 1989 45. Gibbons RJ, Balady GJ, Beasley JW, et al: ACC/AHA Guidelines for Exercise Testing: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Exercise Testing). J Am Coll Cardiol 30:260-311, 1997 46. Gordon DJ, Ekelund LG, Karon JM, et al: Predictive value of the exercise tolerance test for mortality in North American men: The Lipid Research Clinics Mortality Follow-up Study. Circulation 74:252-261, 1986 47. Guerci AD, Spadaro LA, Popma JJ, et al: Relation of coronary calcium score by electron beam computed tomography to arteriographic findings in asymptomatic and symptomatic adults. Am J Cardiol 79:128-133, 1997 48. Hachamovitch R, Berman DS, Kiat H, et al: Exercise myocardial perfusion SPECT in

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patients without known coronary artery disease: Incremental prognostic value and use in risk stratification. Circulation 93:905-914, 1996 49. Hendel RC, Whitfield SS, Villegas BJ, et al: Prediction of late cardiac events by dipyridamole thallium imaging in patients undergoing elective vascular surgery. Am J Cardiol 70:1243-1249, 1992 50. Hertzer NR, Beven EG, Young JR, et al: Coronary artery disease in peripheral vascular patients: A classification of 1000 coronary angiograms and results of surgical management. Ann Surg 199:223-233,1984 51. Herzog CA, Marwick TH, Pheley AM, et al: Dobutamine stress echocardiography for the detection of significant coronary artery disease in renal transplant candidates. Am J Kidney Dis 33:1080-1090, 1999 52. Heston TF, Norman DJ, Barry JM, et al: Cardiac risk stratification in renal transplantation using a form of artificial intelligence. Am J Cardiol 79:415417, 1997 53. Hodgson JM, Marshall JJ: Direct vasoconstriction and endothelium-dependent vasodilation: Mechanisms of acetylcholine effects on coronary flow and arterial diameter in patients with nonstenotic coronary arteries. Circulation 79:1043-1051, 1989 54. Holley JL, Fenton RA, Arthur RS Thallium stress testing does not predict cardiovascular risk in diabetic patients with end-stage renal disease undergoing cadaveric renal transplantation. Am J Med 90:563-570, 1991 55. Jahangiri M, Wright J, Edmondson S, et al: Coronary artery bypass graft surgery in dialysis patients. Heart 78:343-345, 1997 56. Janowitz WR, Agatston AS, Kaplan G, et al: Differences in prevalence and extent of coronary artery calcium detected by ultrafast computed tomography in asymptomatic men and women. Am J Cardiol 72:247-254, 1993 57. Kafka H, Leach AJ, Fitzgibbon GM: Exercise echocardiography after coronary artery bypass surgery: Correlation with coronary angiography J Am Coll Cardiol 25:10191023, 1995 58. Kajinami K, Seki H, Takekoshi N, et al: Noninvasive prediction of coronary atherosclerosis by quantification of coronary artery calcification using electron beam computed tomography: Comparison with electrocardiographic and thallium exercise stress test results. J Am Coll Cardiol 26:1209-1221, 1995 59. Kanters SD, Algra A, van Leeuwen MS, et al: Reproducibility of in vivo carotid intima-media thickness measurements: A review. Stroke 28:665-671, 1997 60. Kapadia SR, Nissen SE, Ziada KM, et al: Development of transplantation vasculopathy and progression of donor-transmitted atherosclerosis: Comparison by serial intravascular ultrasound imaging. Circulation 98:2672-2678, 1998 61. Kaufmann RB, Sheedy PF, Maher JE, et al: Quantity of coronary artery calcium detected by electron beam computed tomography in asymptomatic subjects and angiographically studied patients. Mayo Clin Proc 70:223-232, 1995 62. Kaul S, Finkelstein DM, Homma S, et al: Superiority of quantitative exercise thallium201 variables in determining long-term prognosis in ambulatory patients with chest pain: A comparison with cardiac catheterization. J Am Coll Cardiol 12:25-34, 1988 63. Kotler TS, Diamond GA: Exercise thallium-201 scintigraphy in the diagnosis and prognosis of coronary artery disease. Ann Intern Med 113:684-702, 1990 64. Kresowik TF, Bower TR, Garner SA, et al: Dipyridamole thallium imaging in patients being considered for vascular procedures. Arch Surg 128:299-302, 1993 65. Lalka SG, Sawada SG, Dalsing MC, et al: Dobutamine stress echocardiography as a predictor of cardiac events associated with aortic surgery. J Vasc Surg 15:831-840,1992 66. Lane RT, Sawada SG, Segar DS, et al: Dobutamine stress echocardiography for assessment of cardiac risk before noncardiac surgery. Am J Cardiol 68:976-977, 1991 67. Langan EM, Youkey JR, Franklin DP, et al: Dobutamine stress echocardiography for cardiac risk assessment before aortic surgery. J Vasc Surg 18:905-911, 1993 68. Lauer MS, Lytle B, Pashkow F, et al: Prediction of death and myocardial infarction by screening with exercise-thallium testing after coronary-artery-bypass grafting. Lancet 351:615-622, 1998 69. Lazem F, Barbir M, Banner N, et al: Coronary calcification detected by ultrafast computed tomography is a predictor of cardiac events in heart transplant recipients. Transplant Proc 29:572-575, 1997

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70. Le A, Wilson R, Douek K, et al: Prospective risk stratification in renal transplant candidates for cardiac death. Am J Kidney Dis 24: 65-71, 1994 71. Lekakis J, Vassilopoulos N, Germanidis J, et a1 Detection of viable tissue in healed infarcted myocardium by dipyridamole thallium-201 reinjection and regional wall motion studies. Am J Cardiol 71:401-404, 1993 72. Lekakis JP, Papamichael CM, Vemmos CN, et al: Peripheral vascular endothelial dysfunction in patients with angina pectoris and normal coronary arteriograms. J Am Coll Cardiol 31:541-546, 1998 73. Lette J, Waters D, Champagne P, et al: Preoperative coronary artery disease risk stratification based on dipyridamole imaging and a simple three-step, three-segment model for patients undergoing noncardiac vascular surgery or major general surgery. Am J Cardiol 69:1553-1558, 1992 74. Ludmer PL, Selwyn AP, Shook TL, et al: Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med 315:1046-1051, 1986 75. Machecourt J, Longere P, Fagret D, et al: Prognostic value of thallium-201 single photon emission computed tomographic myocardial perfusion imaging according to extent of myocardial defect. J Am Coll Cardiol 23:1096-1106, 1994 76. Mahmarian JJ, Verani MS Myocardial perfusion imaging during pharmacologic stress testing. Cardiol Clin 12223-245, 1994 77. Mairesse GH, Marwick TH, Melin JA, et al: Use of exercise electrocardiography, technetium-99m-MIBIperfusion tomography, and two-dimensional echocardiography for coronary disease surveillance in a low-prevalence population of heart transplant recipients. J Heart Lung Transplant 14:222-229, 1995 78. Mangano D T Perioperative cardiac morbidity. Anesthesiology 72:153-184, 1990 79. Mangano DT, London MJ, Tubau JF, et al: SPI Research Group: Dipyridamole thallium-201 scintigraphy as a preoperative screening test: A reexamination of its predictive capacity. Circulation 84:493-502, 1991 80. Manske CL, Wang Y, Rector TS, et al: Coronary revascularization in insulin-dependent diabetic patients with chronic renal failure. Lancet 340:998-1004, 1992 81. Marwick TH, Anderson T, Williams MJ, et al: Exercise echocardiography is an accurate and cost-efficient technique for the detection of coronary artery disease in women. J Am Coll Cardiol 26:335-341, 1995 82. Marwick TH, Lauer MS, Lob0 A, et al: Use of dobutamine echocardiography for cardiac risk stratification of patients with chronic renal failure. J Intern Med 244:155161, 1998 83. Marwick TH, Mehta R, Arheart K, et al: Use of exercise echocardiography for prognostic evaluation of patients with known or suspected coronary artery disease. J Am Coll Cardiol 30:83-90, 1997 84. Marwick TH, Steinmuller DR, Underwood DA, et al: Ineffectiveness of dipyridamole SPECT thallium imaging as a screening technique for coronary artery disease in patients with end-stage renal failure. Transplantation 49:lOO-103, 1990 85. Marwick TH, Torelli J, Harjai K, et al: Influence of left ventricular hypertrophy on detection of coronary artery disease using exercise echocardiography. J Am Coll Cardiol 26:1180-1186, 1995 86. Mason JJ, Owens DK, Harris RA, et al: The role of coronary angiography and coronary revascularization before noncardiac vascular surgery. JAMA 273:1919-1925, 1995 87. McCully RB, Roger VL, Pellikka PA: Clinical outcome after normal exercise echocardiogram: Follow-up of 1421 patients. J Am Coll Cardiol 27403A, 1996 88. McEnroe CS, O’Donnell TF, Yeager A, et al: Comparison of ejection fraction and Goldman risk factor analysis to dipyridamole-thallium 201 studies in the evaluation of cardiac morbidity after aortic aneurysm surgery. J Vasc Surg 11:497-504, 1990 89. Miller LW, Schlant RC, Kobashigawa J, et al: 24th Bethesda conference: Cardiac transplantation. Task Force 5: Complications. J Am Coll Cardiol 22:41-54, 1993 90. Miller TD, Christian TF, Hodge DO, et al: Prognostic value of exercise thallium-201 imaging performed within 2 years of coronary artery bypass graft surgery. J Am Coll Cardiol 31:848-854, 1998 91. Morise AP, Haddad WJ, Beckner D: Development and validation of a clinical score

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Address reprint requests to Professor Thomas H. Marwick, MB, PhD University Department of Medicine Princess Alexandra Hospital Ipswich Road, Brisbane, Qld 4102 Australia e-mail: [email protected]