CLINICAL DIABETES
VOL. 17 NO. 2 1999


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FEATURE ARTICLE


Coronary Artery Disease in People With Diabetes: Diagnostic and Risk Factor Evaluation

Stephanie Cooper, MD
James H. Caldwell, MD


IN BRIEF

People with diabetes are at high risk from coronary artery disease (CAD), tend to present late, and have silent ischemia. Early detection and intervention may improve survival. How to identify these patients is the topic of this review, which will discuss cardiac stress testing in diabetic patients with and without known CAD. The authors discuss who should be tested and review the modalities available for detection of CAD and for risk stratification.

CORONARY ARTERY DISEASE AND DIABETES
Cardiovascular disease is the leading cause of death among people with type 1 and type 2 diabetes. Coronary artery disease (CAD) is the cause of death in more than half of all diabetic patients, and many are debilitated by symptoms of congestive heart failure or angina. Patients with diabetes but without other conventional risk factors for atherosclerosis have a risk of death from CAD 2– 4 times that of age-matched controls.
1– 4 Those with type 2 diabetes commonly have other associated risk factors, such as hypertension or hyperlipidemia, thus further increasing their cardiovascular risk. Women with diabetes are at increased risk, with a risk of cardiovascular death up to 7.5 times that of women without diabetes. Diabetic women do not have the premenopausal benefit seen in the general female population.2,3,5

Individuals with diabetes and CAD fare worse than do other patients with CAD. Those who present with a myocardial infarction (MI) are at increased risk of dying from their event or of developing heart failure.5-7 They benefit less from thrombolysis in the setting of an acute MI.5,6,8 Coronary artery bypass surgery (CABG) and percutaneous transluminal coronary angioplasty (PTCA) are associated with greater long-term mortality in diabetic patients than in those without diabetes.7,9-12 Therefore, early detection of CAD is important to ensure that medical interventions to improve outcome are instituted.

Unfortunately, no studies to date specifically address early detection of, or risk stratification for, CAD in this very-high-risk population. Guidelines must therefore be empirical, based on the known epidemiology of cardiovascular disease in people with diabetes and on post hoc substudy analysis of diabetic patients in larger studies. People with type 1 and type 2 diabetes are grouped together in these recommendations because they have not been analyzed separately in existing trials.

SILENT ISCHEMIA
Silent ischemia is a particular concern in diabetic patients. Clinically, patients with diabetes are more likely to be without chest pain in the setting of unstable angina or MI, and thus late presentation contributes to a higher mortality in these patients.13 People with diabetes may also be less likely to experience exertional angina or chest pain with exercise testing, thus potentially increasing the difficulty of diagnosing significant CAD. In one small study, 58 diabetic men without symptoms and with normal electrocardiograms (ECGs) underwent cardiac stress testing. Seventeen percent were found to have significant CAD despite their absence of symptoms.14

Controversy exists about whether silent ischemia is associated with similar cardiac event (MI or death) rates or a similar amount of myocardium at risk as is symptomatic ischemia. Several studies of silent ischemia have demonstrated that MI and death rates and CAD disease severity are the same in patients with silent ischemia as they are in those with symptomatic ischemia.15 Conversely, several other studies have demonstrated increased severity of ischemic disease in patients whose exercise is limited due to anginal symptoms as compared to that in those with silent ischemia.16

However, there is evidence that in patients with CAD and silent ischemia, initial revascularization results in a better outcome than pharmacological therapy.17 In the Asymptomatic Cardiac Ischemia Pilot, 2-year follow-up revealed that of the 558 enrolled patients with silent ischemia, those who were randomized to revascularization had a 1.1% mortality compared to a 6.6% and 4.4% mortality in the two groups randomized to pharmacological therapy.17

The patients in these studies of silent ischemia usually have experienced symptoms of chest pain at some time in the course of their disease. Diabetic patients, on the other hand, are more likely to be truly "silent patients."  These are patients who never experience any chest pain despite demonstrable ischemia, rather than the more common phenomenon in patients with CAD of experiencing chest pain but also having episodes of silent ischemia. This may further increase diabetic patientsí risk in terms of late diagnosis and presentation.

There is a suggestion that early diagnosis and intervention in diabetic patients with silent ischemia is beneficial. In the Coronary Artery Surgery Study (CASS), diabetic patients with silent ischemia had a higher mortality than did nondiabetic patients with silent ischemia, and their outcome was better with revascularization than with pharmacological therapy.18 Unfortunately, there have been no other published studies directly addressing the outcome of diabetic patients with silent ischemia who are identified early versus those who are identified late (usually after their first event).

CARDIAC STRESS TESTING
Diagnosing CAD is useful in order to risk-stratify diabetic patients into a category demanding more aggressive lipid and blood pressure control. However, the goal of cardiac stress testing is not only to diagnose CAD, but also to assess risk for cardiovascular morbidity and mortality. The ability to assess risk of future events is helpful in determining management. Patients with diabetes have a higher rate of MI and repeat revascularization after PTCA than do nondiabetic patients, presumably due to increased rates of restenosis.9 At the time of CABG, they have higher rates of sternal wound infections and prolonged hospital stays.19 They also have a higher late cardiac mortality after both PTCA and CABG.10,12

Given the poorer long-term outcome with PTCA and CABG, it is not clear whether diabetic patients have an improved outcome with early revascularization. Currently, a proposal is being planned for a multicenter trial that will ask whether early revascularization is better than pharmacological therapy in diabetic patients found to have CAD. Unfortunately, there are no ongoing or planned trials to evaluate whether the high cardiovascular death rate among diabetic patients can be reduced with aggressive early identification of CAD and aggressive risk factor management.

At this time, there are no recommendations to perform early revascularization in diabetic patients. The indications for surgery are left-main disease or three-vessel disease, especially in the setting of reduced left ventricular (LV) function. In patients whose chest pain symptoms cannot be controlled medically, both PTCA and CABG are options. Not all patients with diabetes and CAD should undergo cardiac catheterization. Rather, coronary angiography should be performed in those in whom revascularization is being considered or in those who have evidence of being at high risk for death/MI in the near future. Cardiac stress testing can accurately assess this risk.

DIAGNOSING CAD IN DIABETIC PATIENTS
Risk Assessment
Given the prevalence of CAD in people with type 2 diabetes, all of these patients should be screened at the time of diagnosis of diabetes and frequently thereafter. The American Diabetes Association recommends annual risk factor assessment, including a history for possible anginal symptoms, a 12-lead ECG, and evaluation for hyperlipidemia and hypertension.20

Hypertension and hyperlipidemia are strong risk factors for CAD in the presence of diabetes. Current guidelines recommend maintaining a blood pressure of <130/85 mmHg and a low-density lipoprotein (LDL) cholesterol <130 mg/dl.21 ECG abnormalities are associated with increased risk of previously undetected CAD. Presence of significant Q waves suggests a history of a silent MI. In patients with type 1 diabetes, the duration of diabetes is an important risk factor, with onset of clinical CAD as early as the third and fourth decade, although usually after age 30.21

It has been reported that there is a 35% cardiovascular mortality by age 55 in patients with type 1 diabetes.22 Screening for CAD should therefore presumably begin around age 30–40.

Recent studies have also identified diabetic nephropathy and microalbuminuria as strong independent risk factors for cardiovascular morbidity and mortality in people with diabetes.23,24 Diabetic patients with proteinuria have an increase in cardiac mortality 8–15 times higher than diabetic patients without proteinuria and 37 times higher than the general population.24,25 A recent meta-analysis revealed that, in people with diabetes, microalbuminuria without overt nephropathy is associated with an odds ratio of 2:1 for cardiovascular mortality. This suggests that all diabetic patients should be screened for proteinuria, which is also recommended as a screening tool for those who may progress to nephropathy. Those with nephropathy or microalbuminuria should be considered for cardiac stress testing.

The role of diabetic autonomic neuropathy in increasing the risk from cardiovascular disease is controversial. Several studies have implicated autonomic neuropathy as a contributing factor in the mechanism of silent ischemia.14,26-28 Autonomic neuropathy is associated with an increased risk of sudden death, although the mechanism is unclear.19,27,29 Therefore, the presence of autonomic neuropathy may suggest a patient who is at increased risk but who may not experience symptoms in the presence of CAD. However, there are no current recommendations for cardiac stress testing in patients with autonomic neuropathy.

Peripheral vascular disease (PVD) in diabetic patients is associated with a particularly high rate of cardiovascular mortality.20,28 Lower-extremity PVD is an independent risk factor for mortality in diabetic patients with similar degrees of CAD.30 These patients are also at increased surgical risk.31 They are likely to be asymptomatic even in the presence of significant CAD due to limitation of activity by lower-extremity vascular disease. In one study that evaluated 30 patients with PVD but without known CAD, 57% had evidence of myocardial ischemia or infarct on radioisotope perfusion scanning.13 Patients with diabetes and PVD by history or on exam should be considered to be at high risk for CAD and should undergo stress testing.

Stress Testing to Diagnose CAD
The current American Heart Association and American College of Cardiology (AHA/ACC) exercise testing guidelines state that exercise testing is useful in patients with an intermediate pretest probability of CAD who can exercise to reach 85% of their maximum predicted heart rate for age [0.85
X (220 – age)].32 These patients are defined as men 30–39 years of age and women 30–59 years of age with typical anginal chest pain, or atypical chest pain that is probably angina in men over 29 years and women over 39 years. Similarly, the AHA/ACC committee states that symptomatic patients with a high risk of CAD may benefit from a cardiac stress imaging study in preparation for possible coronary arteriography.

Clearly, all diabetic patients with chest pain should undergo cardiac stress testing. However, as noted above, the absence of chest pain in people with diabetes and severe CAD is well recognized. Symptoms to consider as anginal equivalents in diabetic patients include dyspnea, lightheadedness, or severe fatigue with exertion. Unfortunately, there are no studies evaluating screening of diabetic patients with exertional symptoms that are not chest pain. However, diabetic patients with these symptoms should be screened for significant CAD.20

Several studies have demonstrated that asymptomatic patients with more than two risk factors for CAD are also at least at intermediate risk for CAD.33-35 Investigators with the Framingham Heart Study have developed a point system to assign risk of CAD based on the continuous variables of age, cholesterol level, and blood pressure and the noncontinuous variables of presence or absence of diabetes and smoking.35 They have demonstrated an accurate prediction of cardiovascular events based on this point system. The advantage of this system is that the risk of a particular individual can be determined based on risk factors, and deciding on whom to perform further testing can be based on what level of risk is considered unacceptable.

The AHA/ACC guidelines state that the diagnostic benefit of exercise testing for asymptomatic patients with multiple risk factors (defined as men over 40 who have hypercholesterolemia, hypertension, smoking, diabetes, or significant family history) is not well demonstrat-ed.32 However, based on the epidemiology of CAD in people with diabetes, the ADA, in conjunction with the ACC, recommend stress testing in diabetic patients with two or more other risk factors for CAD.21 Using the Framingham data, one could perhaps adjust this recommendation to include patients with diabetes and a single other severe risk factor, for example, very high cholesterol.

For women with diabetes, the protection seen in premenopausal women without diabetes is lost. Therefore, diabetic women should be risk-stratified similarly to men. Diabetic patients who are currently sedentary but are planning to begin an exercise program should also first be risk-stratified.

The frequency with which stress testing should be repeated in asymptomatic patients whose first test was negative is an unanswered question. Annual reassessment of risk should be performed. If a patient remains asymptomatic and has no new risk factors, repeat stress testing should be considered in 3–5 years. The frequency of testing should be increased to every 1–2 years if the patient has multiple or new risk factors on screening evaluation.21

RISK STRATIFYING PATIENTS WITH KNOWN CAD
Once the diagnosis of CAD is known, cardiac stress testing offers useful prognostic information. In patients who have symptoms associated with their CAD, their symptoms should guide testing. Exercise testing is warranted in any CAD patients with a change in clinical status.21,32 It is also useful in patients with nonspecific exertional symptoms or in those considering dramatically increasing their level of activity.

In diabetic patients who are to undergo surgical procedures, particularly vascular procedures, there should be a low threshold for risk stratification before surgery. Those with chest pain should be tested if their angina has been difficult to control or has recently changed in pattern. Patients with known silent ischemia should probably be tested within the year before surgery.

There is some evidence that the prognostic information gained from stress testing patients with known CAD is good for approximately 1–2 years. In a study published by Iskandrian and associates, the risk of death or MI in patients with known CAD but a normal or mildly abnormal radioisotope myocardial perfusion scan was very low for 24 months, at which time the event rate began to increase.36 Similar increases in event rates have been noted 2 years and more after initially normal stress echocardiograms.37 In patients with silent ischemia, stress testing should perhaps be repeated every 1–2 years.

STRESS TESTING METHODS
Exercise Treadmill Test
Diagnosing CAD. The reported sensitivity of exercise treadmill testing for diagnosing CAD in patients with an intermediate risk of CAD, those in whom the AHA/ACC guidelines state treadmill testing is warranted, ranges from 23 to 100%, depending on the study. In a meta-analysis of 147 studies (total of 24,074 patients) in which standard ECG criteria were used and where the diagnosis of CAD was defined as a 50% coronary artery stenosis at angiography, the mean sensitivity and specificity of exercise testing was reported as 68% (23–100%) and 77% (17–100%), respectively.38

However, a more accurate estimate of the diagnostic accuracy of the test was obtained by removing the studies in which patients with a prior MI were included and those in which the patients did not agree to undergo both coronary angiography and exercise testing. When this was done, the remaining studies revealed a mean sensitivity and specificity of 50% and 90%, respectively.32

In the meta-analysis, the sensitivity of the test was higher in patients with multivessel or left-main CAD, however, the specificity was lower. The reported sensitivity for triple-vessel and left-main disease was 86% and 81%, respectively. The specificity was 53% and 66%, respectively. Other studies have demonstrated the sensitivity of exercise ECG for single-vessel disease is lower, ranging from 25 to 71%.

Risk Assessment. Cardiac prognosis in asymptomatic patients cannot usually be predicted by an exercise tolerance test (ETT). Several large studies have demonstrated the inadequacy of the ETT at identifying individuals in a large, asymptomatic population who are at risk for future cardiac events. The exception to this is patients with multiple atherosclerotic risk factors with a markedly abnormal exercise test. In one study, the 6-year event-free survival was 67% in this group versus 98% in patients with risk factors but a normal or mildly abnormal ETT and 99% in those without risk factors regardless of the test result.33

In symptomatic patients or those with known CAD, risk is determined at exercise testing primarily by assessing exercise capacity. Patients who can exercise more than 9 minutes of a standard Bruce protocol are at low risk with a <1% per year mortality over 4 years. Those unable to complete 3 minutes are at high risk, with an annual mortality of >5% and up to 20%.39-41 The vast majority, unfortunately, lie between the two extremes.

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Figure 1.  Nomogram of the prognostic relations embodied in the treadmill score.  Determination of prognosis proceeds in five steps.  First, 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.  Second, the observed degree of angina during exercise is marked on the line for angina.  Third, 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.  Fourth, 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.  Fifth, the mark for ischemia is connected with that for exercise duration.  The point at which this line intersects the line for prognosis indicates the 5-year survival rate and average annual mortality for patients.  From reference 41.  Reprinted with permission of the New England Journal of Medicine.

The best-studied method of combining symptoms, ECG changes, and exercise time to predict prognosis is the Duke Treadmill Score (Figure 1), which was generated in 2,842 patients with known or suspected CAD without a history of MI or revascularization.42 The score is calculated as follows:

Treadmill score = exercise time – 5x [ amount of ST segment deviation in millimeters] –4x [exercise angina index], where 0 = no angina, 1 = angina , 2 = exercise stopped due to angina .

In the original study, the group with a score of <11 had an annual mortality of at least 5 %. Those with a score of >5 had an annual cardiovascular mortality of 0.5 %, and those in the moderate risk group with a score of –10 to +4 had a 10-year survival of about 82%. The score has been validated as a prognostic tool in several smaller studies at Duke University and other centers.32,41

Unfortunately, there are no studies evaluating the diagnostic or prognostic accuracy of the ETT in diabetic patients. Extrapolating from existing studies may be difficult given that diabetic patients should have a higher pretest likelihood, presumably increasing the sensitivity of the test; yet they are more likely to have angina without chest pain, thus probably decreasing the specificity of the test.

Exercise testing alone can be performed for screening purposes in diabetic patients who are expected to be able to exercise sufficiently to reach 85% of their maximal heart rate for age and who have a normal ECG. Not all patients with CAD will be identified, particularly those with single-vessel disease. However, those with good exercise capacity should have an acceptable prognosis even in the setting of a false-negative test for diagnosis of CAD. Those patients with poor exercise tolerance but a negative test by standard ECG criteria should be considered for an alternative method of stress testing to improve the diagnostic and prognostic accuracy of identifying significant CAD.

Exclusions. There are a number of situations in which exercise testing should not be used. Patients who are not expected to reach 85% of their heart rate with exercise need to be considered for a pharmacological stress test, which by necessity is performed with an imaging study to identify ischemic myocardium. Patients who have had a recent MI (<5 days) or have had medical stabilization of unstable angina, in whom a maximum test is requested, should be considered for pharmacological testing rather than exercise. Absolute contraindications to exercise testing include patients with severe symptomatic aortic stenosis, uncontrolled symptomatic cardiac arrhythmias, and acute cardiovascular or cardiopulmonary events. Relative contraindications include moderate aortic stenosis, severe arterial hypertension, electrolyte abnormalities, arrhythmias, and hypertrophic cardiomyopathy.32

ECG abnormalities that preclude exercise testing alone for diagnosis of CAD, due to the associated very low diagnostic accuracy, include resting ST depression of >1 mm, preexcitation (Wolff-Parkinson-White syndrome), left bundle branch block, and an electronic ventricular pacemaker.32 There is also reduced specificity of exercise ECG in patients on digoxin or with ECG criteria for LV hypertrophy with more than 1 mm of ST depression at baseline. These patients should be considered for a stress imaging test.

In the setting of left bundle branch block or a ventricular pacemaker and myocardial perfusion imaging, there is a high false-positive rate associated with the elevated heart rate generated with exercise or dobutamine. Therefore, these patients should undergo pharmacological testing with a coronary vasodilator. The other ECG abnormalities listed above do not preclude exercise, but the test must be done in association with myocardial imaging for diagnostic accuracy.

Women in general have a lower pretest likelihood of having CAD, and partly for this reason the ETT alone is less sensitive. Women also appear to be more likely to have nonspecific ECG changes during exercise testing, and exercise ECG in women has been reported to be less specific than that in men. Therefore, women with nondiagnostic ECG changes on the ETT often need to be referred for an ETT performed in conjunction with myocardial imaging, either nuclear scintigraphy or echocardiography.

There is some evidence that it is more cost-effective to refer women for an imaging modality up front.43 However, the ACC/AHA guidelines state that there is insufficient data to recommend routine use of stress imaging tests as first-line for diagnosing CAD in women. In our opinion, because of the prognostic information as well as the improved diagnostic information, women being evaluated for CAD should have a stress imaging test. Diabetic women have not been evaluated as a separate group, so it is not known whether there is also lower diagnostic accuracy of the ETT in this group.

Myocardial Imaging
In patients on whom a treadmill test cannot be performed, myocardial imaging is performed in conjunction with pharmacological stress testing. Other patients for whom an imaging modality may be chosen, in combination with either exercise testing or pharmacological testing, are those in whom a higher sensitivity or specificity of diagnosing CAD is desired or in those in whom a high degree of accuracy in prediction of cardiac risk is sought. These may include patients who are asymptomatic but at high risk for CAD. Imaging may also be useful in patients with known CAD in order to assess the physiological significance of known disease, to assess risk of cardiac events with known disease, or to time revascularization surgery.

Both available imaging modalities, echocardiography and nuclear myocardial perfusion imaging, have been extensively demonstrated to be more sensitive in diagnosing CAD compared with exercise treadmill testing alone, as discussed later. They also have been shown to be more accurate in predicting risk of cardiac events than the ETT alone, particularly in those who are in the intermediate area between very low and very high risk after their treadmill test.

Pharmacological Stress
In order to diagnose or risk-stratify patients with suspected CAD who have been excluded from exercise testing, pharmacological agents must be used to perform the stress test. All pharmacological testing is performed in association with a myocardial imaging modality. A description of the agents currently used follows.

Dipyridamole/adenosine. Dipyridamole (Persantine) and adenosine (Adenocard) are most often used in conjunction with myocardial perfusion imaging, although they have also been studied when used in association with echocardiography. Adenosine acts directly via specific receptors on smooth muscle in the coronary arteriolar wall to cause smooth muscle relaxation and vasodilation of the myocardial resistance vessels (10–100 mm), thus increasing coronary flow. Dipyridamole acts by inhibiting cellular re-uptake and break down of adenosine, thereby increasing adenosine concentration in the arteriolar vessels and causing vasodilation.

They both have minimal hemodynamic effects, in most cases resulting in only a slight increase in heart rate and decrease in blood pressure despite a two- to fourfold increase in coronary blood flow. Therefore, they do not increase cardiac stress. Rather, they create heterogeneity of myocardial blood flow with increased flow through epicardial vessels without obstruction compared to those with significant disease.

Dipyridamole and adenosine are associated with frequent, though generally transient and mild side effects. However, they have been used for many years with a demonstrated excellent overall safety profile.44,45 They are contraindicated in patients with severe asthma or chronic obstructive pulmonary disease with wheezing on exam.

Dobutamine. Dobutamine acts predominantly via myocardial beta-1 receptors to increase myocardial contractility and heart rate. Coronary blood flow is increased as myocardial workload and oxygen demands are increased. Peripheral vasodilatation may also occur due to a modest action of dobutamine on peripheral beta-2 receptors. Myocardial ischemia results from inadequate increases in blood flow relative to increased myocardial oxygen demand in territories perfused by significantly diseased coronary arteries. Two types of myocardial imaging modalities are frequently used with dobutamine. Echocardiography is used to detect regions of myocardial segmental wall motion abnormalities resulting from decreased contractility in regions of ischemia. Perfusion imaging is used to detect heterogeneous blood flow with regions of reduced coronary blood flow perfused by significantly diseased epicardial arteries compared with regions fed by normal arteries. Dobutamine has been proven to be an adequate stress when 85% of the maximal predictive heart rate for age is attained. It is currently the only pharmacological alternative in patients with significant reactive airway lung disease.

Assessment of LV Function
LV systolic function has a powerful impact on the outcome of patients with and without CAD. Determination of LV function at the time of stress testing is therefore useful for risk stratification. Resting LV function can be determined by a variety of techniques, all of which, when the information is pooled with the results of the stress test, lend prognostic value.

Change in overall LV function with stress is not a sensitive indicator of CAD. However, LV dilation and/or decreased global LV contractility is a poor prognostic sign that suggests left main or multivessel CAD.

Echocardiographic and nuclear medicine techniques have been developed that can evaluate LV function at rest, at peak exercise, and immediately after or later after exercise. When LV function is included, these modalities are not necessarily better in terms of diagnostic accuracy for CAD, but they do improve the prognostic accuracy for cardiac events.

Nuclear Cardiology
Diagnosing CAD.
In order to perform stress myocardial perfusion imaging, a radiolabeled compound such as thallium-201 (a potassium analogue) or technitium-99m, formulated to be delivered to and taken up by the myocardium in direct proportion to blood flow, is injected during maximum arteriolar vasodilatation during exercise or pharmacological stimulation. It is more likely to be delivered to and taken up by the myocardium fed by vessels without significant obstruction. In epicardial coronary vessels with significant fixed obstruction, the ability to increase blood flow due to arteriolar vasodilatation is reduced. Stenoses greater than about 50% begin to limit flow in the presence of vasodilation, and flow is increasingly limited with worsening stenosis.

Heterogeneity of myocardial radiotracer deposition is created as the normal vessels markedly increase blood flow and delivery of isotope compared to vessels that have significant fixed obstruction. The regions with less radioisotope uptake in comparison with other regions are referred to as ischemic. With exercise or dobutamine, this is probably accurate. However, using current vasodilator protocols, the myocardium is rarely (<30% of the time) truly ischemic during these pharmacological tests, because some degree of coronary flow is usually present even in significantly diseased vessels. Nevertheless, this region of myocardium is at risk for becoming ischemic when increased myocardial oxygen demand cannot be met during exertion or other forms of stress.

The original method described for performing myocardial perfusion imaging uses thallium-201 as the isotope, and planar imaging, which involves taking three images in different projections. Stress and rest images are typically taken approximately 4 hours apart or on separate days. Development of single-photon emission computed tomographic (SPECT) imaging has increased our ability to localize regions of ischemia and to detect high-risk, multivessel disease. With the SPECT method, a series of planar images are acquired at regular intervals as a gamma camera is rotated about the patient. These images are then reconstructed by a computer and displayed as "slices" of myocardium in three planes.

In addition to the SPECT methods, new technetium-99–labeled perfusion agents, sestamibi (Cardiolite) and tetrofosmin (Myoview), are thought to be useful in improving the diagnostic yield in very large patients because of the higher energy of these radiolabeled compounds compared with thallium-201. However, because of the 6-hour half-life of these agents, they require a 2-day imaging protocol for optimal results. To obviate this delay, dual isotope studies have been developed. For these studies, thallium is used for resting myocardial perfusion images, and one of the technetium-labeled compounds is used for stress images. This method has permitted testing to be completed in a single day, within about 2 hours, as long as the patient does not weigh more than about 250 lb for men and 180 lb for women.

The overall sensitivity and specificity of these various protocols, using different isotopes and imaging techniques, have been shown to be similar, as shown in Table 1.47-50 Most of these studies used 50% luminal diameter stenosis at coronary angiography as diagnostic criteria for CAD. The sensitivity increases with multivessel disease, from 83% for single-vessel, to 93% for two-vessel, and 95% for three-vessel disease.The sensitivity for single-vessel disease is notably higher than that with the ETT alone, in which single-vessel disease often results in false-negative results.46

Table 1. Myocardial Perfusion Imaging for CAD Diagnosis
Study Modality Sensitivity (%) Specificity (%)
Detrano et al. 198847
review of 55 studies
exercise planar
thallium
83 88
Maddahi et al. 199448
review of 7 studies
exercise SPECT
thallium
90 70
Mahmarian and Verani 199449
review of 8 studies
dipyridamole planar
thallium
82 75
Mahmarian and Verani 199449
review of 4 studies
dipyridamole
SPECT thallium
89 93
Mahmarian and Verani 199449
review of 4 studies
adenosine SPECT
thallium
90 91
Iskandrian and Verani 199846 exercise SPECT
sestamibi
90 74
Mahmarian and Verani 199449
review of 6 studies
dobutamine
scintigraphy
(isotope varied)
82 73
Berman et al. 199450 dual isotope 91 75
 

SPECT, single-photon emission computed tomographic imaging

A few studies have used myocardial perfusion imaging to diagnose CAD in diabetic patients. One prospective study found the sensitivity of dipyridamole thallium to be 80%, with a specificity of 87% in a diabetic population.51 An earlier prospective study found a sensitivity and specificity of 86% and 79%, respectively, in a population of patients with type 1 diabetes and end-stage renal disease.52 Finally, a recent group reported a retrospective review of their diabetic patients who underwent cardiac catheterization preceded by a myocardial perfusion study within the year.53 They reported a sensitivity of 97% and positive predictive value of 88%. Therefore, cardiac stress testing with myocardial perfusion imaging appears to be as accurate for diagnosing CAD in diabetic patients as it is in nondiabetic patients.

Risk Assessment. Possibly the greatest benefit of myocardial perfusion imaging over exercise treadmill testing alone is the ability to predict the risk of cardiovascular events. Assessing risk with nuclear cardiology has been extensively studied. Fourteen studies have been published in the past 4 years alone evaluating the prognostic value of SPECT imaging.

Myocardial perfusion imaging has been well demonstrated to be superior at assigning a probability of future major cardiac events, such as MI, cardiovascular death, and need for coronary revascularization. However, due to the small size of the studies, most have reported pooled events.

The value of radioisotope myocardial perfusion imaging for predicting cardiac events has been demonstrated in a wide range of patients, including those without known CAD but at intermediate to high risk for having disease, those with known CAD of varying degrees of severity, patients who have had a recent MI, and women. The diverse modalities of nuclear cardiology stress testing have been shown to have similar predictive value.

A normal myocardial perfusion scan at maximal exercise (>85% maximal predicted heart rate [MPHR]), or with pharmacological testing, has been shown in more than 20 clinical studies to be associated with a <1% per year risk of death or MI. This has held true in patients with chest pain and angiographically documented CAD or with an equivocal or positive exercise ECG.

In one study in which 281 patients with normal perfusion scans were followed, 75% of 89 patients who underwent coronary angiography were found to have CAD. However, the annual cardiac event rate was 0.7% after a 24-month follow-up.31 In a pooled analysis of studies involving a total of almost 3,600 patients with known CAD, the annual combined death and MI rate was 0.9% if the stress perfusion scan was normal for an average follow-up of 24 months.54

The clinical usefulness of this prognostic information is illustrated in a study by Berman and associates, which was designed to evaluate the incremental prognostic value of myocardial perfusion scanning in addition to clinical assessment and exercise treadmill testing in patients with interpretable exercise ECGs.55 The patients undergoing testing were clinically identified to be either at low or at intermediate-to-high risk both before and after their exercise treadmill stress test. Their myocardial perfusion scan was classified as normal or abnormal. The overall rate of death or MI in the 1,282 patients was 2.1% during a mean follow-up period of 20 months. The event rate in those classified as low risk after their treadmill test was 1.7%, but further risk-stratifying with perfusion scans revealed that those with a normal scan actually had no events. Patients classified as intermediate-to-high risk after their treadmill test had an overall event rate of 4%, but if their perfusion scan was normal, their event rate was only 0.7%. Thus, this study demonstrates that myocardial perfusion imaging gives useful prognostic information that is in addition to clinical assessment and exercise treadmill testing.

An abnormal scan, on the other hand, is associated with an increased risk for cardiac events. The risk increases with the severity, size, and/or number of perfusion defects, as well as with other abnormalities such as LV dilation with stress or increased lung uptake of thallium.

In the study by Berman and associates, patients thought to be at low risk after their treadmill test had an event rate as high as 6.2% if their perfusion scan was abnormal.55 If their treadmill and scan were read as intermediate-to-high risk, they had the highest event rate in the study at 7.9%. Again, this study thus demonstrates incremental prognostic benefit of perfusion imaging.

Other studies have shown that this benefit is similar to that of coronary angiography and that angiography does not add further prognostic benefit after cardiac stress testing with myocardial perfusion imaging.36,56

pg65f2.gif (22925 bytes)
Figure 2.  Prognostic benefit of radioisotope myocardial perfusion scan in predicting cardiac death rate in 5,534 patients followed for an average of 21 months.  Pre-scan risk was assigned by clinical assessment and exercise treadmill testing.  Event rate is for the entire follow-up period.  Data from reference 57.

In a recent study by Hachamovitch and associates, similar results were found in 5,534 patients who were followed prospectively after their nuclear cardiac stress test to assess incremental prognostic value of predicting MI or death, rather than combined endpoints as in all previous trials.57 All patients were followed for at least 1 year. The average follow-up was 21 ± 7 months. Again, stratification of patients by their myocardial perfusion scan results predicted better than other clinical factors and the ETT their risk for both MI and death, as shown in Figures 2 and 3.

pg66f3.gif (25308 bytes)
Figure 3.  Prognostic benefit of radioisotope myocardial perfusion scan in predicting rate of MI in 5,534 patients followed for an average of 21 months.   Pre-scan risk was assigned by clinical assessment and exercise treadmill testing.   Event rate is for the entire follow-up period.  Data from reference 57.

The authors further reported a statistically significant improved survival in those patients referred for revascularization compared with those who were not, based on nuclear scan results. Given the high accuracy of risk prediction, the authors suggested that perfusion imaging should be useful in guiding medical decision making. They suggested that only patients considered as intermediate-to-high risk for MI or death should be considered for cardiac catheterization and revascularization and that patients with a low risk scan should be treated medically.

These various studies demonstrate the powerful predictive accuracy of myocardial perfusion imaging. Further studies are needed to determine whether nuclear cardiology testing truly identifies which patients should be referred for early revascularization for a survival benefit.

Unfortunately, there have been no separate evaluations of diabetic patients in these studies to determine whether the predictive value of myocardial perfusion scanning in diabetic patients is better or worse than in the general population. Nevertheless, based on the available prognostic data and the small amount of data suggesting that myocardial perfusion imaging is as accurate for diagnosis of CAD in diabetic patients as it is in nondiabetic patients, the ADA currently recommends that diabetic patients at high risk for CAD or those with known CAD should undergo myocardial perfusion imaging in conjunction with a treadmill or pharmacological testing.21

Echocardiography
Diagnosing CAD. Exercise echocardiography can be performed with either a standard treadmill test or with upright or supine bicycling. In the former case, echo imaging is performed immediately after exercise. Images are quickly obtained after laying the patient down following exercise and hopefully before the heart rate has slowed. There is a possibility of normalization of a transient wall motion abnormality due to resolution of ischemia in the time between peak exercise and echo imaging. However, myocardial stunning due to severe ischemia usually persists for more than 2 minutes.

Echo images can be acquired throughout both upright and supine bicycling, particularly at peak exercise. Typically, images are digitized for later side-by-side review of cine loops of rest and stress images. The ability to obtain digital images also facilitates rapid acquisition. Useful hemodynamic information may be acquired during the bicycle test using Doppler methodology. For the detection of CAD, bicycle exercise appears to be more sensitive than treadmill exercise, largely because the chance of missing a transient wall motion abnormality is reduced.58

In multiple studies, the overall sensitivity of exercise echocardiography for detecting CAD, usually defined as an angiographically determined coronary stenosis of >50%, has been reported to be 71–97%, with a mean of 88%.58 As with other forms of stress testing, the sensitivity is reduced in single-vessel disease to 58–92% (mean 80%). Again, the sensitivity is significantly improved over that of ETT alone.

The overall specificity in these studies ranged from 64 to 100%, with a mean of 82%. Exercise echocardiography is therefore more sensitive and specific than ETT alone.

Dobutamine is the major pharmacological stress or used in conjunction with echocardiography. As mentioned above, it is an adequate stress or when >85% of  the maximum predicted heart rate is attained. It does not result in the same degree of  myocardial stress as symptom-limited exercise because it does not cause the same degree of elevation in blood pressure and in fact can result in slight lowering of blood pressure. Its usefulness in echocardiography is in part because it increases myocardial contractility directly, thus increasing myocardial workload in the absence of a high rate-pressure product.

The reported sensitivity and specificity of dobutamine echocardiography are 54–96% and 66–100%, respectively.58 The use of atropine in the dobutamine protocol increases the sensitivity of the test by ensuring a high maximal heart rate.

The vasodilators adenosine and dipyridamole have also been used at high doses in conjunction with echocardiography. However, dobutamine protocols appear to be more sensitive than vasodilator protocols, and the predictive value of dobutamine echo has been more extensively studied.58 Therefore, if an echocardiographic cardiac stress test is desired, and exercise is not feasible, dobutamine is currently the agent of choice for a pharmacological stress.

One study has evaluated dobutamine stress echo (DSE) in patients with diabetes. This study evaluated the predictive accuracy of DSE in detecting CAD, defined as >50% diameter stenosis on coronary angiography, in 52 patients with diabetes.59 The sensitivity and specificity were 82% and 50%, respectively. The reason for decreased specificity in the population in this study is not clear.

Risk Assessment. Stress echocardiography has been adequately demonstrated to accurately predict cardiac risk in patients with intermediate-to-high probability of cardiac disease, in those after recent MI, and preoperatively. Again, small studies have necessitated pooling of death, MI, and often revascularization in outcome assessment.

The prognostic value of exercise stress echocardiography has been evaluated in five published studies, although only two of these followed patients with both normal and abnormal results. They each demonstrated a low event rate in those with a negative test. In one study, Sawada and associates59a followed 148 patients with normal exercise echo for a mean of 28 months. There were two MIs and no deaths for an overall cardiac event rate of 0.85%. One of the two infarctions occurred at 41 months, possibly outside of the prognostic range of the test. A second study also demonstrated a low event rate in a cohort of 137 patients with a normal exercise echocardiogram. The most recent and largest study followed for a median of 23 months 1,325 patients who were referred for exercise echocardiogram and had normal results.37 There was a <1.0% incidence of MI, revascularization, or death at 1 year, and a 2.6% incidence of this combined endpoint at 3 years.

Two studies followed a cohort of patients with normal and abnormal exercise echocardiograms. Krivokapich and associates followed 360 patients who had a high pretest likelihood of a coronary event before their stress echo.60 Of the patients without evidence of ischemia on exercise echo, 2% had an MI at 1 year. On the other hand, 9% of those with a positive exercise echocardiogram had an MI. Finally, a recent study followed 500 patients with known or suspected CAD for up to 4.5 years after their exercise echocardiogram.61 The incidence of death, MI, or late revascularization was <2% in those with a normal stress test. In those with demonstrable ischemia, the 2-year event rate was about 22%.

Dobutamine stress echocardiography has been more extensively evaluated for prognostic benefit. Several studies involving patients with at least an intermediate probability of CAD have demonstrated a rate of MI and/or death of 0–4%, depending on the study. Follow-up in these studies ranged from 240 days to 3 years (Table 2).62-67 The largest study followed 860 patients for a mean of 52 months.67 The rate of death and MI per year were 1.1% and 0.5%, respectively, in those with a normal dobutamine echocardiogram. Half of the patients who had events in the setting of a normal study did not reach 85% of their maximum predicted heart rate.

Table 2. Dobutamine Stress Echocardiography for Risk Assessment
Study n Follow-up Events

Event Rate

        Abnormal DSE Normal DSE
Mazeika et al. 199366  51 24 ± 4 months MI +
unstable 
ischemia:* 8/25(32%) 2/26 (8%)
Afridi et al. 199463 77 10 months CHF + MI + death old infarct:# 7/27 (26%)
ischemia: 5/10 (50%)
2/40 (5%)
Poldermans et al. 199462 430 17 ± 5 months MI or cardiac death death:  7/183 (1.6%)
MI: 10/183 (2.4%)
(all showed ischemia)
death:   4/247 (0.9%)
MI: 8/247 (0.2%)
(all had previous MI)
Kamaran et al. 199565  210 median 240 days cardiac death ischemia: 16/63 (25%) 1/147 (0.7%)
Marcovitz et al. 199864 291 15 ± 4 months MI +
cardiac death
ischemia: 21/131 (16%)
old infarct: 7/68 (10%)
1/73 (1.4%)
Chuah et al. 199867    (14%)  860 3 years MI + cardiac death ischemia: 44/321
(7% at one year)
old infarct: 30/237 (13%)
12/302 (4%)
(2% at one year)
*Patients with evidence of ischemia only on their stress study

#Patients with evidence of prior MI only on their stress study

DSE, dobutamine stress echocardiogram; CHF, congestive heart failure; MI, myocardial infarction

The rate of hard cardiac events was significantly increased in all of these studies in those patients who had abnormal dobutamine stress echocardiograms. In one study of patients with a high pretest likelihood of disease, event-free survival was 78.5% and 23.5% at 30 months with abnormal and normal stress echocardiograms, respectively.62 In another study also of patients with a high pretest likelihood of disease, including some patients who were preoperative, the mortality in the group with a positive dobutamine stress echocardiogram was 25.4%.65 An incremental prognostic benefit of dobutamine stress echocardiography compared with pretest clinical factors alone is demonstrated in several of these studies.62,65,67

These studies demonstrate the prognostic value of performing stress echocardiography rather than exercise treadmill testing alone. Again, further studies are necessary to determine whether there is an outcome benefit in using stress echocardiography to identify patients who may benefit from early revascularization. As with myocardial perfusion scintigraphy, stress echocardiography has not been studied in the diabetic population. However, because the prognostic benefit of radioisotope perfusion scintigraphy has been more thoroughly studied, the ADA/ACC committee currently recommends this method over stress echocardiography in patients who warrant an imaging study and in centers where there is expertise in both fields.

SUMMARY
Diabetic patients are at very high risk for cardiovascular morbidity and mortality. Aggressive treatment of risk factors is essential to help limit their risk. Recent ADA guidelines highlight the importance of blood pressure and lipid control. Tight glycemic control may also be important to reduce cardiovascular complications and is actively being investigated.

Early identification of CAD is also very important so that pharmacological therapy, which may improve outcome, can be established. Diabetic patients at substantial risk for CAD, such as those with two or more other risk factors, an abnormal ECG, peripheral vascular disease, proteinuria or nephropathy, and possibly those with autonomic insufficiency, should undergo cardiac stress testing as part of their evaluation. All diabetic patients with typical or atypical chest pain or possible anginal equivalents, such as dyspnea on exertion, should be stress tested. Diabetic patients with known CAD should undergo stress testing to evaluate their risk if there is a change in their clinical status or if they are to undergo vascular surgery.

The type of stress test chosen depends on the clinical question. In many asymptomatic patients who can exercise to 85% of their MPHR and have a normal ECG, excerise treadmill testing alone should be sufficient. ETT will not identify all patients with CAD but should detect those at high risk and identify a low-risk population of those who can exercise for more than 9 minutes on a standard Bruce protocol.

Patients who are felt to be at high risk for CAD due to multiple risk factors or symptoms consistent with angina and patients with known CAD should be considered for a stress imaging study. This study will yield more accurate diagnostic and prognostic information to help guide medical decision making. Patients with identifiable CAD but a low-risk stress imaging study should be managed medically with aggressive risk-factor control. Those with a high-risk study should undergo coronary angiography for consideration of revascularization.

Future studies are clearly needed that investigate this very-high-risk diabetic population and the utility of early identification of CAD and risk stratification by cardiac stress testing. The management of those identified early also needs to be studied. Until then, our assumption must be that detecting and intervening early in CAD, the major cause of death in all diabetic populations, is of benefit.


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Stephanie Cooper, MD, is an acting clinical instructor and James H. Caldwell, MD, is a professor in the Department of Medicine, Division of Cardiology, at the University of Washington School of Medicine in Seattle. Dr. Caldwell is also an adjunct professor in the Department of Radiology and Bioengineering, Division of Nuclear Medicine, at the University of Washington and chief of cardiac services at the Veterans Administration Puget Sound Health Care System in Seattle


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