Specificity of electrocardiographic stress test in women versus men

techniques, and by peak velocity (p <0.005). There were no differences in either heart rate (77 f 7 us 78 f 6 mm-t; p = not significant [NSJ) or rate-pressure product (10,364 f 1,033 us 10,292 f 923 mm Hg-beats/mitt; p = NS) for baseline versus hyperemia. There was a good correlation between the IWS Doppler technique and the peak velocity method for measuring coronary flow reserve (IWS Doppler coronary flow reserve = 1.227[peak velocity ratio] + 0.068; G = 0.87; p = O&M), although IWS Doppler was systematically higher than was the peak velocity ratio technique (Figure 3). Coronary flow reserve was 2.3 f 0.5 by CST (range 1.6 to 3.1), 2.8 f 1.0 by IWS Doppler (1.6 to 4.2), and 2.2 f 0.8 by peak velocity (range 1.3 to 3.1; p X0.02 for IWS Doppler us peak velocity; p = NS for CST us IWS/Doppler or peak velocity). With papaverme, coronary velocity increased severalfold, suggesting a hyperemic response in most patients. However, despite this increase in coronary flow, lefr main cross-sectional area did not change (0.23 f 0.05 us 0.23 i 0.05 cm2; p = NS). Thus, the combination of IVUS and Doppler velocimetry has the potential for measuring flow in peripheral and coronary arteries. Although CST is widely used to assesscoronary flow in both clinical and research settings, the IVUS Doppler method may have several advantages, including the possibility that it is more accurate in determining high flow rates. Furthermore, this new technique may have the advantage of beat-to-beat analysis. IVUS Doppler may also have the advantage of eventually examining individual arteries, although this has yet to be validated, and there may be significant limitations in more distal arteries. Finally, unlike CST, venous access and ability to cannulate the coronary sinus is not necessary with this technique. Further evaluation and validation of this technique needs to be performed, including use of a combined catheter to enable near simultaneous measurements of IVUS and Doppler. Because of a parabolic flow profile, it is possible to either sample a centerline velocity, which would overestimate the space average velocity across the lumen, or sample near the vesselwall, which would result in underestimation of the mean space average velocity.

Specificity of Electrocardiographic Morton

Thus, eventual use of a Doppler crystal with a dispersing signal may enable better space average velocity measurements. Finally, spectral analysis was not used, because it was not commercially available at the initiation of our study. However, we strongly believe that future IVUS software should have the ability to display and analyze (on- and off-line) spectral signals, because this study and otherslo suggest that absolute coronary flow may be measured with this technique. Despite using a zero-crossing detector, the IVUS Doppler technique showed a strong correlation with transonic flow probe measurements. Further work is necessary to validate and elucidate the use of this technology. Admowkdsmant: We gratefully extend our appreciation to Janie McCoulskey, CCRN, Willie Gary, Jenelle Durbin, RN, and Graciela Fields for expert help during the performance of the human studies, and to Dale Prince for help with the animal studies.

1. Zir LM, Miller SW, Dinsmore RE, Gilbert JP, Harthome JW. Interobserver variability in coronary angiography. Circularion 1976;53:627-632. 2. Ganz W, Tamura K, Marcus HS, Donoso R, Yoshida S, Swan HJC. Mcasurement of coronary sinus blood flow by continuous thormodilution in man. Circulation 1971;44:181-195. 3. Bagger JP. Coronary sinus blood flow determination by the thermodilution technique: influence of catheter position and respiration. Carcfixw Res 1985; 1927-31. 4. Niin SE, Gurley JC. Assessment of the functional significance of coronary stenosea: is digital angiography the answer? Circulation 1990;81:1431-1435. S. Engel HJ. &easment of regional myceardial blood flow by precordiil %enon clearance, technique. In: Schapcr W, ed. The Pathophysiology of Myocardial Perfusion. Amsterdam: Elsevier/North Holland Biomedical Press, 197958. 6. Graybum PA, Willard JE. Haagen DR. Brickner ME, Alvarez LG. Eichhom El. Measurement of coronary flow using high-frequency intravascular ultrasound imaging and pulsed Doppler velocimetry: in vitro feasibility studies. J Am Sot Echo 199255-12. 7. Hatle L, Angelsen B. Doppler Ultrasound in Cardiology: Physical Principles and Clinical Applications. Philadelphia: Lea & Febiier, 1985:40-63. 6. Win RF, i&hlin DE, Ackeg PH. Chilian WM, Holida MD, Hartley CJ, Armstrong ML, Marcus ML, White CW. Transluminal, suhselective measurement of coronary artery blood flow velocity and vasodilator reserve in man. Circulation 1985;72:82-92. 9. Drcet CJ, Thomas GG, Sellers AF. In-viva validation of the transit-time ultrasonic volume flowmeter. In: Proceedings of the 7th New England (Northeast) Bioengineering Conference. Troy, New York Center for Biomedical Engineering, 1979:22&223. 10. Yamagishi M, Hotta D, Tamai J, Nakatani S, Miyatake K. Validity of catheter-tip Doppler technique in assessment of coronary flow velocity and application of spectrum analysis method. Am J Cardiol 1991;67:758-762.

Stress Test in Women Versus Men

E. Tavel, MD

omen are generally believed to be more apt to have W false-positive electrocardiographic stress tests than men. Confusion exists, however, on whether the relatively high rate of false-positive results in women is a consequence of a low test specificity in this group, or a low positive predictive value of this test in a group with a relatively low prevalence of coronary disease. Several From the Department of Medicine, Indiana Heart Institute, St. Vimcent I-bxwital. Indianawlii. Indiana. Dr. Tavel is a Consulting Cardiolokst. No&side Gudioiogy,‘Inc., and Professor of Medicine, I&ma Un&er: sity, Indianapolis, Indiana. Mamtscript received February 24, 1992; revised manuscript received April 14,1992, and accepted April 19.

studies that purport to demonstrate low specificity of such testing in womerP4 are subject to “referral” or “workup” bias (i.e., stress tests were not excluded before definitive study), thus allowing these tests to influence selection for final confiition of the diagnosis. It is well known that this type of bias results in falsely low specificity values for any test.5*6Therefore, since the ECG stress test is currently used widely and often contributes to the selection of which patients will undergo coronary arteriography, confirmation of the diagnosis through arteriography will necessarily result in falsely low specificity values for stress testing. On the other hand, thallium-201 stress tests with BRIEF

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TABLE I Categories Reversible lschemia

by Diagnosis of Patients by Thallium Study

Having

False-Positive

Men Women

TABLE II Categorized

No

Tests

Total No.

Definite Positive

Borderline Positive

214 112

24 (11.2%)

21 (9.5%)

a (7.1%)

10 (8.9%)

Heart Rate Responses by Electrocardiographic

Within the Subgrops Response Men

Positive ECG Mean age (SD) Peak heart rate-mean Borderline ECG Mean age (SD) Peak heart rate-mean Negative ECG Mean age (SD) Peak heart rate-mean

n=24 (SD)

55 (9) 137 (101 n = 21

(SD)

(SD)

57 (IO) 145 (11) n = 169 57 (10) 143 (12)

Women

n=8 61 (11) 145 (13) n= 10 57 (10) 141 (12) n = 94 61 (9) 140 (11)

ECG = electrocardiogram

tomographic enhancement (single-photon emission computed tomography [SPECT]) are found to be highly accurate for detecting and quantitating coronary ischemia,7 can IX applied to populations in which referral bias is absent, and therefore, can provide an alternative means to study and compare the characteristics of the electrocardiographic stress test in both sexes. We have performed ECG and thallium-201 (SPECT) stress tests simultaneously in 674 consecutive patients whose average age was 60 f IO years (446 men, average age 59 f 10 years; 228 women, average age 62 f 9 years). Testing was performed for a variety of reasons, most often for assessment of coronary jlow after percutaneous coronary angioplasty, coronary bypass surgery and myocardial infarction. To minimize referral bias, patients referred because of prior positive or suspicious ECG stress tests were excluded. Patients with significant valvular or congenital heart disease were also excluded. Treadmill stress testing was performed through the use of a standard motorized treadmill (Quinton Instruments Corp.) using our own protocol: begin with a speed of 2 miles/hour and an incline of 3% and every 2 minutes increases by 0.5 miles/ hour and 3% incline. Thallium-201 was administered when the heart rate reached 85% of expected maximum according to age criteria, and the subjects then exercised for I additional minute at the peak work load before cessation of the exercise. Zf symptoms or signs of distress occurred before the target heart rate was achieved, this level was then used for thallium injection and termination. Bloodpressure was measured every 2 minutes during exercise and immediately after exercise. A baseline 12-lead electrocardiogram was obtained before exercise in both recumbent and standing positions. Leads ZZ, VI and VJwere monitored continuously durmg exercise and for 15 to 30 seconds after cessation. A 12-lead electrocardiogram was obtained every 2 minutes during exer546

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cise. An abnormal response was considered to be 1 mm or more of horizontal or downsloping ST-segment depression in 1 or more leads compared with those of the resting electrocardiogram. Upsloping ST-segment depression was considered positive if >I .5 mm below the baseline (PQ segment) at 0.08 second after the J point, and “borderline” if depressed between 1 and 1.5 mm at this time. Patients receiving digitalis glycosides, having left bundle branch block or resting ST-segment abnormalities were considered to have uninterpretable tracings. All B-blocking drugs and calcium antagonists with rate-limiting characteristics (diltiazem, verapamil) were withdrawn for a period of 24 to 72 hours before the test depending on each agent’s duration of action. Each patient received an intravenous dose of thallium-201 ranging from 2.0 to 3.5 mCi at the peak of exercise. Myocardial imaging (SPECT) was performed within 5 to 10 minutes of cessation of exercise and repeated 3 to 4 hours later. Group proportions were analyzed through the use of chi-square analysis. Confidence intervals were obtained with the binomial formula. Of the entire group, 449 patients had no evidence of reversible ischemia as demonstrated by thallium (279 men, mean age 58 f 11 years; 170 women, mean age 62 f 10 years), and 326 of these had interpretable ECG stress test results. Of this latter group, there was a total of 32 (9.8%) positive tests, yielding a specificity of 90.2%. An additional 31 patients (9.5%) had a borderline ECG test response. Tables Z and ZZsummarize the data derived from the 326 subjects without ischemia but with interpretable electrocardiograms. Although the average age of the women tested was slightly greater than that of men,peak heart rate responses and ages displayed no significant differences between the positive and negative stress test responders (Table ZZ). Zf only the definitely positive responders are included, the small difference of specificity between men (88.8%) and women (92.9%) equals -4.1%. The 95% confidence interval for this difference ranges from -10% to i-2.4%, meaning that it is extremely unlikely for women to have a specificity lower than men that exceeds 2.470, a clinically insignificant degree. Moreover, if one combines the positive and borderline test results, the 95% confidence interval for the combined differences ranges from -13.7% to +3.77%, again indicating it unlikely for women to have specificity values <3.77% than those of men. Thus, there appears to be no signi$cant difference in ECG test specificity between men and women, regardless whether one includes either positive or borderline responses. Previous studies have been divided concerning the relative specificity of ECG stress testing between the sexes. Early work (before 1975)8-11 in which testing was confined to asymptomatic women presumed free of coronary disease suggested that specificity was extremely low (range 34 to 75%), being especially low in older women. Criteria for a positive test were not as rigorous as those of today, however, and simultaneous comparisons with men were generally not performed. Moreover, no definitive tests were used to exclude occult coronary disease. More recently, Manta et al, I2 defining a positive response as horizontal or downsloping ST depression of 1 mm or AUGUST

15, 1992

more, found that the rate of positive responses (presumably falsepositive) was basically the same (6 to 8%) for both men and women who were young and middle-aged and who were asymptomatic, presumed healthy, and followed for up to 6 years to exclude coronary disease. Similar results (6% false-positive rate) were obtained in healthy women by Sheffield et al,13 and most of their positive responses were encountered in older women exceeding the age of 38. In contrast, data from Wu et ali4 suggested a relatively lower specificity in younger women than in men, although the rate of false-positive stress test responders was low in both groups (2.2% in women and 0.58% in men). Several studiesi-4+i5v*6in which coronary cineangiography was used as the definitive confirmatory standard for diagnosis have generally yielded low specificity values for women (range 33 to 86%). The inherent referral bias in this study design probably accounts for these low values. This type of bias occurs unless the results of prior stress tests are scrupulously avoided when selecting sub jects to undergo definitive study with coronary cineangiography. Despite this apparent shortcoming, however, 2 studiesi5*16demonstrated no significant specificity difference between the sexes, suggesting that selection bias may have been absent or equal for both sexes. Our results demonstrate that when one uses an objective test in which referral bias can be minimized (thallium stress test) to establish the absence of coronary ischemia, the ECG stress test is just as specific in women as in men. The use of thallium testing as the “gold standard” for comparison, while subject to debate, should be acceptable for this purpose, because it indicates the presence of physiologic ischemia and the results may be even more predictive of future coronary events than results derived from coronary cineangiography. la Thallium stress (SPECT) results are highly sensitive in detecting coronary ischemia, averaging as high as 94 to 96%,’ are more accurate than planar techniques,‘* and do not appear to be influenced significantly by sex.l9 Thus, in our series, negative responders to thallium have an extremely low probability of ischemia, thus providing an excellent group in which to assessspecificity of ECG testing. Our patient population, however, is composed primarily of older persons, and thus these results may not necessarily be extrapolated to younger persons, especially women, in whom hormonal or other factors may be operative. As mentioned previously, when current criteria for positive responses are applied, test specificity in younger women also is quite high. One shortcoming of this study is that, to obtain timely thallium images, ECG monitoring was necessarily stopped a few seconds after exercise was completed. Thus, delayed ECG changes could have been missed. We are unaware, of any greater propensity of either sex to manifest such delayed responses, and therefore believe it unlikely that the present results would have been modified significantly. In conclusion, these data suggest that the practical approach to diagnosis in women can be similar to that in

men. Even with identical specificity between the sexes, testing of women with few risk factors or in younger age ranges will generally yield a low predictive value for a positive test - generally lower than those of men. Conversely, a negative test under such circumstances would be highly predictive that disease is absent. Our data therefore suggest that the initial evaluation of the individual female patient need not generally involve costly nucle ar or cineangiographic techniques unless the standard ECG test is positive - a relatively uncommon occurrence. Adcnowkdgmant: We wish to thank John Woods, Phd, for aid in statistical analysis, and Mary Kerr for clerical assistance.

1. Sketch MH, Mohiuddin SM. Lynch JD, Zen&a AE, Runco V. Significant sex differences in the correlation of electrocardioaraobic exercise testina and coronarv arteriograms. Am J Cardiol 1975;36:169-173: 2. Linhart JW, Laws JG, Satinsky JD. Maximum treadmill exercise electrocardiography in female patients. Circulation 1974;50:1173-1178. 3. Hung J, Chaitman BR, Lam J, Lesperance J, Dupras G, Fines P, Bourassa MG. Noninvasive diagnostic test choices for the evaluation of coronaty artery disease in women: a multivariate comparison of cardiac fluoroscopy, exercise electrocardiography and exercise thallium myocardial perfusion scinitigraphy. J Am Coil Cardiol 1984;4:8-16. 4. Barolsky SM. Gilbert CA, Faruqui A, Nutter Do, Schlant RC. Differences in electrocardiographic response to exercise of women and men: a non-Baycsian factor. Circula?ion 1979;60:1021-1027. 5. Ransohoff DF, Feinstein AR. Problems of spectrum and bias in evaluating the efftcacy of diagnostic tests. N Engl J Med 1978;299:926-929. 6. Sox HC. Probability theory in the use of diagnostic tests. Ann Intern Med 1986;1046&66. 7. Belier GA. Diagnostic accuracy of thallium-201 myocardial perfusion imaging. Circulation 1991;84(suppl 1):1-1-I-6. 8. Lepeschkin E, Surawicz B. Characteristics of true-positive and false-positive results of electrocardiographic Master two-step exercise tests. N Engl J Med 1958;258:511-520. 9. Profant GR, Early RG, Nilson KL, Kusumi F, Hofer V, Bruce RA. Responses to maximal exercise in healthy middle-aged women. J Appl Physiol 197233: 595-599. 10. Cumming GR, Dufresne C, Kich L, Samm J. Exercise electrocardiogram patterns in normal women. Br Hearr J 1973;35:1054-1061. 11. Astrand I. Exercise electrocardiograms recorded twice with an a-year interval in a group of 204 women and men 48-63 years old. Acfa .&fed Stand 1965;178: 27-39. 12. Manca C, Dei Gas L, Bernardini B, Barilli AL, Tsialtas D, Vasini P, Visioli 0. Comparative evaluation of exercise ST response in healthy males and females. Cardiology 1984;71:341-347. 13. Sheffield TL, Maloof JA, Sawyer JA, Roitman D. Maximal heart rate and treadmill performance of healthy women in relation to age. Circulation 1978;57: 79-84. 14. Wu SC, Secchi MB, Radice M, Giagnoni G, Sachero A, Oltrona L, Morosini PL, Folli G. Sex differences in the prevalence of ischemic heart disease and in the response to a stress test in a working population. Eur Hear? J 198 1;2:461-465. 15. Hlatky MA, Pryor DB, Harrell FE, Califf RM, Mark DB, Rosati RA. Factors affecting sensitivity and specificity of exercise electrocardiography. Am J Med 1984;77:64-71.

16. Weiner DA, Ryan RJ, McCabe CH, Kennedy JW, Schloss M, Tristani F, Chaitman BR, Fisher LD. Exercise stress testing. N Engl J Med 1979301: 230-235. 17. Kaul S, Finkelstein DM, Homma S, Leavitt M, Okada RD. Boucher CA. Superiority of quantitative exercise variables in determining long-term prognosis in ambulatory patients with chest pain: a comparison with cardiac catheterization. J Am Co11 Cardiol

1988;12:25-34.

18. Fintel DJ, Links JM, Brinker JA, Frank TL, Parker M, Becker LC. Improved diagnostic performance of exercise thallium-201 single photon emmission computed tomography over planar imaging in the diagnosis of coronary artery disease: a receiver operating characteristic analysis. J Am Co11 Cardioll989;13:600-612. 19. Friedman TD, Greene AC, Iskandrian AS, Hakki A, Kane SA, Segal BL. Exercise thallium-201 myocardial scintigraphy in women: correlation with corenary arteriography. Am J Cardiol 1982;49:1632-1637.

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