 |
|
Utility of Stress Testing and Coronary Calcification Measurement for Detection of Coronary Artery Disease in Women
Khurram Nasir, MD, MPH;
Rita F. Redberg, MD, MSc;
Matthew J. Budoff, MD;
Elaine Hui, MBBS;
Wendy S. Post, MD, MS;
Roger S. Blumenthal, MD
Arch Intern Med. 2004;164:1610-1620.
ABSTRACT
| |
Accurate and safe diagnostic testing provides the crucial link between detection and optimal management of coronary artery disease (CAD). Noninvasive diagnostic testing for CAD may be less accurate in women than in men. Many noninvasive diagnostic modalities are available for this purpose. An exercise tolerance test provides an assessment of functional capacity and has the advantages of wide availability and low initial cost. However, exercise echocardiography may be the most cost-effective method for the initial assessment of coronary artery disease in intermediate-risk women owing to its higher sensitivity and specificity. Recent studies with electron-beam computed tomography reveal that women with no coronary calcification are very unlikely to have obstructive CAD. In symptomatic women with an intermediate likelihood of CAD, either an exercise treadmill test or exercise echocardiography is appropriate for initial screening and can provide useful prognostic information. Alternatively, an electron-beam computed tomographic scan with a 0 calcium score may spare many women with atypical chest pain or equivocal findings on an exercise tolerance test from undergoing more expensive stress imaging studies or coronary angiography. For high-risk symptomatic women, a more aggressive approach involving coronary angiography appears to be the preferred initial diagnostic strategy.
INTRODUCTION
Noninvasive detection of coronary artery disease (CAD) in women is challenging but important because approximately 40% of deaths in American women are due to cardiovascular disease. The detection of CAD is potentially problematic in women for a variety of reasons.1 Middle-aged women have a lower prevalence of manifest CAD than men and are more likely to have atypical symptoms. They are less likely to be promptly evaluated than men, which may also lead to delays in diagnostic testing.2 Since women are often older at the time of diagnosis, age-related comorbidities and reduced exercise capacity contribute to a lower accuracy of exercise tests in women than in men. Hormonal and anatomic differences in women may alter the electrocardiography (ECG) or imaging results compared with those obtained in men. Therefore, optimal diagnostic tests for women may differ from those used for men.
When reviewing the literature on stress testing, one must note that sensitivity and specificity may vary from one study to another owing to different pretest probabilities of significant CAD or different reference standards (>50% vs >70% coronary obstruction in 1 or  2 vessels vs simply a positive radionuclide finding). In the present review, we discuss the efficacy of various noninvasive tests currently available for the diagnosis of CAD as well as methods to determine the risk of future cardiovascular events in women. Most of the women included in the following studies of stress testing were evaluated for the presence of obstructive CAD because they had a history of chest pain or dyspnea.
EXERCISE ECG
Exercise treadmill testing (ETT) is often used as the initial method for noninvasive assessment of CAD owing to its wide availability and relatively low cost. The 2002 joint report from the American College of Cardiology and the American Heart Association Task Force on exercise testing (ACC/AHA)3 indicates that an exercise ECG is most useful as a diagnostic test in patients with an intermediate (25%-75%) pretest probability of CAD. Abnormal exercise stress test results in these patients are more likely to be true positives than in patients with lower pretest probabilities. The 2001 ACC/AHA guidelines for management of chronic stable angina also recommend that a standard ETT be used for diagnosis and risk stratification in patients who have not undergone revascularization if they have chest pain and an intermediate probability of CAD, provided that they (1) are able to exercise; (2) have a normal resting ECG; and (3) have no unstable symptoms that warrant urgent angiography. The guidelines acknowledge that the accuracy of ETT is lower in women.4
DUKE TREADMILL SCORE
A number of investigators have proposed methods to improve the accuracy of the standard ETT. Shaw et al5 studied 2758 symptomatic patients (30% women) who underwent ETT and cardiac catheterization to evaluate the efficacy of using the Duke Treadmill Score (DTS) for risk stratification. The DTS was calculated as follows: DTS = exercise time – (5 x exercise-induced ST-segment deviation) – (4 x exercise angina index), where exercise time is measured in minutes of Bruce protocol; ST-segment depression is the largest stress-induced downward displacement; and angina index is assigned as follows: 0 = none, 1 = nonlimiting, and 2 = exercise-limiting. When compared with angiographic findings, DTS was found to be a reliable method of stratifying patients. In the study population, the odds of severe CAD (3-vessel coronary disease or 75% left main disease) was 4-fold and 26-fold higher for individuals with moderate-risk and high-risk DTSs, respectively, compared with those with low DTSs. The authors conclude that low-risk patients (DTS +5) might be managed without further testing, whereas high-risk patients (DTS  –11) should be considered for cardiac catheterization, possible revascularization, and more aggressive risk-factor modification. Of the remaining moderate-risk patients (DTS between –10 and +4), use of an imaging modality is proposed for further risk stratification.5
In a study of 976 symptomatic women (mean age, 51 years), Alexander et al6 demonstrated that the DTS could effectively stratify women into diagnostic and prognostic risk categories. In another study by Shaw et al,7 3620 symptomatic patients, stratified by DTS (42% women; mean age, 63 years), underwent exercise myocardial perfusion imaging (MPI) and were observed for 2.5 years for the development of subsequent cardiovascular events. The cardiac mortality rate was very low (0.3%-0.4% per year) among patients with a low DTS. The authors recommended that patients with a normal baseline ECG could undergo an exercise test initially without imaging and that further testing could be reserved for those patients with intermediate-risk or high-risk test results, consistent with the clinical guidelines published by the AHA and ACC.3-4
Although the DTS has been recommended by the AHA/ACC task force, its prognostic value in elderly persons is not as well established. Kwok et al8 describe the results of a 7-year follow-up study of 247 elderly persons (mean age, 77 years; 44% women) and 2304 younger persons (mean age, 60 years; 42% women). These researchers found that although the DTS predicted cardiac outcomes in younger patients, it had a limited prognostic power in patients 75 years or older, which suggests that it has less of a role in the assessment of elderly patients. Clearly, however, more sex-specific studies are needed to confirm the role of the DTS in elderly women.
SEX DIFFERENCES IN ETT ACCURACY
The presence of greater than 2 mm of ST-segment depression has been shown in some studies to be equally predictive of cardiac death in women and men.9 However, several older studies suggest that exercise-induced ST-segment changes are less accurate in women than in men and have a higher false-positive rate or lower positive predictive value.10 Bayesian theory may explain some but not all of the higher false-positive rate in women because of a lower prevalence rate of CAD in the populations undergoing testing. In studies in which the prevalence of CAD was similar in men and women, there was still a lower specificity of ETT in women (64%-68%) than in men (74%-89%).11-12 Other studies in women have also reported specificities in the same range (55%-75%).13-15 However, in a follow-up of 3094 patients (men and women) who had ETT and coronary angiography for the evaluation of suspected CAD from 1969 to 1984, 1930 of them (20% women) were found to have CAD defined as stenosis of 75% or more.16 In this study, there was no sex difference in the specificity (86% for women vs 83% for men),16 while the sensitivity was different (57% for women vs 72% for men) (P = .05). Nevertheless, meta-analyses have shown that the overall sensitivity and specificity of ST-segment depression on ETTs is lower in women.17
IMPACT OF REFERRAL BIAS
By definition, true specificity should represent the percentage of negative responders in a population known to be free of disease confirmed by coronary angiography as the reference standard.18 Unfortunately, such a design is difficult to achieve because it is rare for an individual with a negative stress test result to undergo a coronary angiogram. Thus, in stress testing, the test sensitivity and specificity are affected by referral bias (ie, the preferential selection of patients with positive exercise ECG results to undergo the confirmatory tests such as coronary angiography),16 which results in an overestimation of the sensitivity and underestimation of the specificity with the ETT.19
A retrospective analysis of clinical and exercise ECG test data in 4467 patients (27% women) referred for the evaluation of the presence of obstructive CAD in the exercise laboratories compared the accuracy of exercise ECG in biased and unbiased populations with possible coronary heart disease.20 Within the cohort of women, the biased group represented a subset of patients who underwent coronary angiography (284 women), and the unbiased group was the entire cohort of 1643 women. In the unbiased group the accuracy of a positive ETT result was assessed with a method that used disease probability (derived with a logistic algorithm) rather than angiography results. Patients with a history of cardiovascular disease, those taking digitalis, and those with a noninterpretable ECG were excluded. The unbiased group had a higher mean ± SD specificity (89% ± 2% vs 73% ± 3%) and a lower mean ± SD sensitivity (33% ± 4% vs 47% ± 5%) than the biased group. These differences reflect the effect of posttest referral bias. Of note, the sensitivity and specificity were still significantly greater in men than in women in both groups.20 In contrast, a single large angiographic study, the Coronary Artery Surgery Study,21 matched subjects for age, prevalence, and severity of coronary disease and showed no significant difference in sensitivity between women and men (76% vs 78%).
Two studies using MPI as the reference point have reported better-than-expected specificities in women. Tavel22 found no difference in stress ECG specificity between men (89%) and women (93%); of note, most of the study participants had a history of CAD. A Mayo Clinic study23 reported that women had a higher specificity (78% vs 52%; P<.001) and a lower sensitivity (30% vs 42% P<.001) than men. However, interpretation of these studies is limited by the fact that they used MPI as the reference standard rather than the usual clinical and angiographic evaluation. Myocardial perfusion imaging may not always be accurate or reproducible enough to be an optimal reference standard.
POSSIBLE REASONS FOR THE APPARENT SEX DIFFERENCE
The vasodilator effect and the digitalislike structure of estrogen have been proposed as explanations for the lower accuracy of traditional ST-segment depression criteria in women than in men.24 Other proposed mechanisms of the sex difference in stress test results include inappropriate catecholamine response to exercise, a higher incidence of mitral valve prolapse in women, a lower prevalence of obstructive multivessel disease, a higher incidence of underlying repolarization abnormalities, and the difference in the chest wall anatomy of women.7, 25-26
ADDITIONAL CRITERIA TO IMPROVE THE INTERPRETATION OF ECG IN WOMEN
Integrating information from hemodynamic and functional parameters and ST-segment changes can improve the diagnostic and prognostic predictive accuracy of exercise ECG testing in women with suspected CAD. For instance, the degree of ST-segment displacement in relation to the increase in heart rate (HR) during exercise ( ST/HR index),27 a ST-segment depression of 0.5 mm or more and R-wave amplitude depression of 1 mm or more in the same lead of any of the 12 leads,28 QT dispersion,29 and abnormal HR recovery30 appear to enhance the accuracy for detecting the presence and severity of CAD in women. In a population involving 9454 patients who were specifically referred for stress ECG without imaging, Nishime et al31 reported that HR recovery predicted risk above and beyond that estimated by the DTS. These studies indicate that additional criteria that can be obtained from the standard ETT support the ACC/AHA recommendation for exercise ECG to be the initial evaluation for women with low to intermediate likelihood for CAD and normal resting ECG (Table 1).32
|
|
|
|
Table 1. Characteristics of Selected Major Studies Using Exercise Electrocardiography for Diagnosis of Coronary Artery Disease in Women
|
|
|
STRESS MPI
Stress MPI with thallium Tl 201 (hereinafter "Tl 201") or technetium Tc 99m (hereinafter "Tc 99m") can provide incremental diagnostic and prognostic value in women above that provided by standard ETT.33 A recent study of 7163 consecutive adults (mean age, 60 years; 25% women) demonstrated that myocardial perfusion defects detected by Tl 201 single-photon emission computed tomography (SPECT) is predictive of long-term all-cause mortality.34 Pancholy et al33 showed that SPECT added independent and incremental prognostic information to clinical, exercise, and coronary angiographic results in 212 women (using angiography as a reference) observed for 40 months, and the women with a large thallium abnormality (15% of the myocardium) had significantly worse event-free survival rates than women with no or small abnormalities.
Planar imaging and SPECT with Tl 201 have been associated with higher false-positive rates in some studies of women. This may be attributable to image attenuation artifacts predominantly caused by overlying breast tissue, to the smaller left ventricular chamber size in women, and to obesity.35-37 Although breast attenuation with Tl 201 affects 8% to 30% of the images,38 experienced readers usually can distinguish these artifacts from perfusion abnormalities secondary to inducible ischemia or myocardial scar.37 In the meta-analysis by Kwok et al,17 the exercise thallium test had a weighted mean sensitivity and specificity of 78% and 64%, respectively, lower than ETT alone in women. Nevertheless, the specificity was only 68% despite attempts at breast attenuation correction. Another meta-analysis, by Fleischmann et al,39 reported similar diagnostic ability of stress MPI in identifying obstructive CAD (sensitivity, 87%; specificity, 64%), but the results were not sex-specific.
Newer radiotracers of Tc 99m compounds such as Tc 99m sestamibi and Tc 99m tetrofosmin have higher photon energy, which leads to less photon scatter and attenuation than with Tl 201 and may overcome some of the problems with soft tissue artifacts and obesity.38, 40 The diagnostic accuracy of Tc 99m MIBI SPECT appears similar in men and women when posttest selection bias is corrected.41 There was no significant difference in sensitivity (87% vs 88%) or in specificity (91% vs 96%) in men and women, respectively. Taillefer et al,42 in a prospective study of 115 women, compared the ability of Tl 201 and Tc 99m MIBI SPECT to detect CAD. They found that Tc 99m sestamibi SPECT perfusion and Tl 201 SPECT had a similar sensitivity (80% vs 84%, P = .48); however, Tc 99m sestamibi SPECT perfusions had a higher specificity (82% vs 59%, P = .01) for detecting stenosis of 70% or more.42
Exercise Tc 99m sestamibi perfusion imaging may provide greater prognostic value in women than in men.43-45 The Economics of Noninvasive Diagnosis (END) Study Group43 observed for a mean of 2.4 years 3402 symptomatic women who underwent MPI (mean ± SD age, 66 ± 11years). The investigators found that the number of abnormal territories in the 3 main coronary arteries remained the strongest correlate of mortality after adjustment for exercise variables. Boyne et al46 showed that patients with abnormal scans have an approximately 7-fold increase in combined cardiac death and nonfatal infarction (5.4% per year in abnormal scans vs 0.8% per year in normal scans). Giri et al,47 in a large cohort of diabetic (n = 929) and nondiabetic women (n = 3826) observed prospectively for a mean ± SD of 2.5 ± 1.5 years, found that SPECT MPI independently predicted cardiac death alone (P = .007). Hachamovitch et al44-45 analyzed 3008 consecutive patients (35% women) who underwent exercise dual-isotope SPECT and found that this technique yielded incremental prognostic value and enhanced risk stratification in a cost-effective manner in both women and men with intermediate to high risk of prescan likelihood of CAD as determined by normal resting ECGs. However, the use of MPI as a routine first-line test in all women may not be practical owing to availability and cost. Women at low to moderate risk with a normal baseline ECG can probably undergo an exercise stress ECG alone as the initial diagnostic test.
In a recent study,48 2408 patients (48% women; mean age, 53 years) were randomly assigned to receive either the usual emergency department evaluation (n = 1260) or the usual evaluation supplemented with results from acute resting MPI using SPECT. The results were interpreted in real time by local staff physicians and were provided to the emergency department physician for incorporation into clinical decision-making. Among patients with acute myocardial infarction and unstable angina, there were no differences in the hospitalization by the above strategies. However, among patients without acute cardiac ischemia (n = 2146), hospitalization was 52% with usual care vs 42% with SPECT-enhanced care (relative risk [RR], 0.84; 95% confidence interval [CI], 0.77-0.92). In other words, the use of SPECT reduced unnecessary hospitalizations among patients without acute ischemia and did not reduce appropriate admission for patients with acute ischemia.48 Recently, the American Society of Nuclear Cardiology,49 in their consensus paper, stated that exercise stress radionuclide testing has higher diagnostic accuracy than exercise ECG in the diagnosis of CAD in women and is recommended for the diagnosis of CAD in women with an intermediate to high pretest likelihood of CAD.
EXERCISE STRESS ECHOCARDIOGRAPHY
Exercise stress echocardiography can also provide incremental prognostic and diagnostic information in the noninvasive assessment of CAD risk.17 Echocardiography combined with exercise or pharmacologic (dobutamine, dipyridamole, or adenosine) stress testing is widely used in the noninvasive assessment of CAD. Its capability to assess multiple parameters including global and regional ventricular function, chamber size, wall thickness, and valvular function renders echocardiography valuable for diagnosing CAD and other types of cardiovascular disease in women. A recent study50 assessed 5798 consecutive patients (42% women; mean ± SD age, 62 ± 12 years) who underwent exercise echocardiography for evaluation of known or suspected CAD. Major cardiac events, including cardiac death and nonfatal myocardial infarction, occurred in 3% of women. The echocardiographic data provided incremental information in predicting cardiac events for women (P = .046). By multivariate analysis, exercise ECG and exercise echocardiographic predictors of cardiac events in men and women were workload and exercise wall motion score index. There was no significant interaction effect of rest echocardiography (P = .79), exercise ECG (P = .38), or exercise echocardiography (P = .67) with sex. Although cardiac events occurred more frequently in men, the incremental prognostic value of exercise echocardiography was comparable in both sexes.50
In studies of exercise echocardiography involving 384 women, the reported overall sensitivities ranged from 79% to 88%, while the specificities ranged from 81% to 86%.19, 51-53 The sensitivity was maintained for the subsets of women with single-vessel disease (88%) and with atypical chest pain (84%). The summarized positive predictive value, negative predictive value, and overall accuracy, weighted for sample size, were 72%, 84%, and 72%, respectively.54 Studies using angiography as an end point have shown that stress echocardiography is superior in the detection of CAD and is somewhat better at stratifying women with intermediate pretest probability than standard ECG stress testing.52-53 In a meta-analysis of 21 studies (N = 4113 women) published between 1966 and 1995, Kwok et al17 looked at the ability to detect CAD in women using exercise ECG (19 studies, 3721 women), exercise Tl 201 imaging (5 studies, 842 women) and exercise echocardiography (3 studies, 296 women). Exercise ECG had a weighted mean sensitivity of 61% and a specificity of 70%. Exercise echocardiography had the highest sensitivity and specificity of 86% and 79%, respectively (Table 2). However, the available data are still limited owing to relatively small sample sizes and referral bias. In fact, the true unbiased sensitivity of stress echocardiography may be as low as 42%, while the specificity is reasonably good at 83%.55
|
|
|
|
Table 2. Weighted Mean Sensitivities and Specificities for Exercise Tests in Women*
|
|
|
In summary, exercise stress echocardiography is often helpful in providing diagnostic information in women presenting with chest pain and in those who have a baseline ECG abnormalities other than left bundle branch block. However, in women with a normal baseline ECG, an exercise ECG is a reasonable initial noninvasive test in women at low to intermediate risk because it has a high negative predictive value and lower cost vs stress MPI studies.56 Nevertheless, many cardiologists prefer exercise stress echocardiography as the initial diagnostic test in women (even in the presence of a normal baseline ECG), because it allows evaluation of ventricular function at rest and stress, and it also provides an estimate of the severity, extent, and location of myocardial ischemia.
PHARMACOLOGIC STRESS TESTING
|
