Is Noninvasive Testing for Coronary Artery Disease Accurate?
1997; Lippincott Williams & Wilkins; Volume: 95; Issue: 2 Linguagem: Inglês
10.1161/01.cir.95.2.299
ISSN1524-4539
Autores Tópico(s)Cardiovascular Function and Risk Factors
ResumoHomeCirculationVol. 95, No. 2Is Noninvasive Testing for Coronary Artery Disease Accurate? Free AccessResearch ArticleDownload EPUBAboutView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticleDownload EPUBIs Noninvasive Testing for Coronary Artery Disease Accurate? Pamela S. Douglas Pamela S. DouglasPamela S. Douglas the Cardiovascular Division, Beth Israel Hospital, Harvard Medical School, Harvard-Thorndike Laboratory, Boston, Mass. Originally published21 Jan 1997https://doi.org/10.1161/01.CIR.95.2.299Circulation. 1997;95:299–302Since the measuring device has been constructed by the observer . . . we have to remember that what we observe is not nature in itself but nature exposed to our method of questioning.Werner Karl HeisenbergPhysics and Philosophy, 1958Diagnostic testing forms an important component of cardiovascular medicine, such that optimal practice requires detailed knowledge of how to use and interpret tests. Methods of describing test performance, such as sensitivity and specificity, are widely used with the assumption that they are fairly constant descriptors of the ability of a given test result to detect the presence or absence of disease. Unfortunately, while such concepts are fundamental, accurate assessment of test performance is far more complex, and many factors significantly affect test performance.In the initial evaluation of a test, investigators often assess its performance by comparing results in populations with very low and very high likelihoods of disease—such as healthy volunteers and afflicted patients. The test in question appears to be an excellent discriminator, although the clinically relevant question of correctly classifying a patient with an intermediate probability of disease has not been addressed. Nevertheless, the published results will indicate very high sensitivity and specificity of the test. However, in subsequent test assessments based on wider use of the test in less clearly segregated populations, they appear to plummet.1 The accuracy of the test has not changed; rather, the population referred for testing has. Thus, apparent test performance can be altered by referral patterns or pretest selection bias. Related to this is the influence of disease prevalence in the population examined. This traditional bayesian consideration is well recognized and can dramatically affect the accuracy of a given test result so that the positive predictive value of a test declines as the disease prevalence decreases in the population under study while the negative predictive accuracy rises.2Verification or posttest bias is a third factor that has been examined only rarely. This bias results when a newly introduced technology is evaluated after physicians have begun to rely on its results and no longer require verification of them. Test results themselves become a factor in whether or not they are confirmed by some additional, definitive procedure. Thus, patients with positive tests (in this case, exercise echocardiography) are more likely to have their results verified (by undergoing angiography) while those with negative tests are rarely referred for subsequent studies. This practice will increase apparent sensitivity because false-negative results are unlikely to be discovered and decrease specificity and true-negative results will be less likely to be confirmed and therefore will be underrepresented. In this issue of Circulation, Roger and colleagues3 report the effects of such verification bias on the accuracy of exercise echocardiography for the detection of coronary artery disease. While this particular test was chosen because no similar analysis had yet been performed, its results are applicable to all forms of diagnostic testing.The effects of correcting for verification bias are striking. Using a large clinical series of patients undergoing exercise echocardiography in whom only a small minority (9%) were subsequently referred for coronary angiography Roger et al assessed test performance in two ways: (1) in the usual manner in the angiographic subgroup by the presence or absence of significant coronary artery narrowing and (2) in all patients by adding the angiographic results to those estimated in the nonangiographic majority by application of a clinically based logistic regression algorithm for disease presence derived from results in the angiographic subgroup.45 The first, or traditional, method resulted in fairly high sensitivity (78%), mediocre specificity (41%), and reasonable correct classification rate or overall predictive value (69%) in the angiographic group (Table 1). The second method, which incorporates a statistical correction for test verification bias,4 resulted in strikingly lower sensitivity (38%), higher specificity (85%), and modestly altered correct classification rate (60%) in the entire population. The decrease in sensitivity and increase in specificity both confirm that exercise echocardiography results were used to determine who would subsequently undergo catheterization and demonstrate the importance of verification bias (in an unbiased population neither would have changed substantially). The importance of test results to the process of verification is also supported by the independent association of a positive test with referral to catheterization (odds ratio 2.5 for exercise electrocardiography, 1.8 for exercise echocardiography).3On first examination, it appears that Roger et al have discovered a fatal flaw in exercise echocardiography. However, their results can be anticipated by recognition of the importance of the frequency of an abnormal test result on measures of test accuracy.5 Further, for every cardiovascular noninvasive test analyzed for the effects of verification bias (exercise ECG,6 exercise thallium,57 exercise radionuclide angiogram,5 and now exercise echocardiography), results are similar (see Table 8 in Roger et al). No type of test escapes this effect; all are similarly insensitive when assessed in an unbiased manner, assuming that validation studies are performed after the test was in clinical use, which is usually the case if large populations are studied. The degree to which verification bias affects test accuracy is related to the extent to which the diagnostic test results influence the decision to refer to angiography. These studies provide a clear illustration of the difference between test performance characteristics in a selected series and those obtained in general clinical practice.Why does cardiac diagnostic testing appear to perform so poorly? A cursory review of the data is deceiving because the impact of correction for verification bias is negative only if the sole desirable outcome of exercise echocardiography is the detection of coronary disease presence. Correction for verification bias actually improved both specificity (41% to 85%) and negative predictive accuracy (40% to 54%) (see Table 1), implying that disease can be excluded more reliably in a general population than data derived from a (selectively) angiographically validated series would suggest. However, this result is dependent on disease prevalence, which in Roger and colleagues' population was quite high, at 74% in the angiographic group. The result in an individual patient may differ, yet it is the relevant consideration. Consider a hypothetical patient with a 50% pretest probability of disease. (While arbitrarily selecting 50% makes calculations easier, it also represents a patient with an intermediate probability of disease in whom testing is most likely to be beneficial and in whom a clinician is least able to make a confident diagnosis.) For this patient, bayesian principles9 dictate that a positive test increases the likelihood of disease presence to 57% using biased test characteristics but to 72% using adjusted sensitivity and specificity, thereby tripling the incremental gain from test performance (Table 2). In contrast, adjustment for verification bias reduces the incremental gain from a negative test result by half. When analyzed in this manner, correction for verification bias actually improves the clinical value of a positive test while reducing that of a negative test.There are other factors that can influence the accuracy of diagnostic testing in general and exercise echocardiography in particular, but an exhaustive cataloging is not germane to this discussion. However, mention of at least one of these factors is appropriate in that it supports the value of diagnostic testing in suspected coronary artery disease, which can be questioned given the low sensitivities reported after adjustment for verification bias. Since all diagnostic tests detect the physiological consequences of ischemia (poor perfusion, decreased membrane function, decreased myocardial shortening, etc) while angiography detects only the anatomic stenosis, catheterization is a flawed gold standard that may detect "disease" in the absence of any physiological significance (thereby raising the apparent false-negative rate of noninvasive testing and reducing its sensitivity). This is especially true when a moderate degree of stenosis is used for the definition of angiographic disease (Roger et al used 50%), ensuring that many patients with anatomic "disease" will not have inducible ischemia. This also is particularly true for a diagnostic test such as exercise echocardiography, which relies on the development of systolic dysfunction for the diagnosis of ischemia, as this is a late event in the ischemic cascade. Use of a more appropriate standard might yield more favorable test characteristics.The second part of Roger and colleagues' work explores the effects of sex on the value of exercise echocardiography.3 Many prior investigators have noted differences in test performance between men and women for all forms of cardiac noninvasive testing. All of the types of bias discussed above may contribute to these differences: Women generally have a lesser prevalence of coronary disease than men, are less likely to be referred for testing even if symptomatic, and are less likely to be referred for angiography once they have a positive noninvasive test result.9 There are also sex-based differences in the pathophysiology of coronary disease10 : Women generally have less severe disease, risk factors are somewhat different, and even traditional ones convey different levels of risk, making clinical determinations of disease likelihood inaccurate if not done in a sex-specific manner.11 Finally, factors intrinsic to the testing procedure itself may differ: Estrogen may affect exercise performance and ischemic threshold, women are older and less likely to exercise adequately, they are more likely to have both hypertension and left ventricular hypertrophy, and are more likely to use medications that affect the results of exercise ECG.Given these possible influences on test results, it is perhaps surprising that Roger and colleagues' results were so similar in men and women. After adjustment for verification bias, they reported an 11 percentage point higher sensitivity of exercise echocardiography in men compared with women, a small but significant difference despite overlapping 95% confidence intervals. These results are consistent with those previously published in a similarly debiased population undergoing exercise ECG.6 However, a portion of the difference in sensitivity (3 percentage points) is explained by the greater extent of disease in the men. Further, there was a significant difference in the prevalence of disease in the angiographic subgroup (80% in men and 60% in women), which explains the observed sex differences in positive predictive value and in correct classification rate. Similarly, although the negative predictive value of exercise echocardiography was greater in women than in men in both the biased and adjusted groups, this may be related to lower disease prevalence in women. To aid interpretation of test results in an individual patient, let us turn again to the hypothetical patient with a 50% pretest probability of disease. Calculation of the influence of either a positive or negative test result on posttest probability of disease reveals similar incremental gains regardless of whether the patient is male or female (Table 2). Taken together, these results suggest little difference in the intrinsic test performance of exercise echo in individual men and women; apparent differences are due to variations in prevalence and extent of disease in the populations studied.Much has been written about sex bias in the referral of women to invasive cardiac testing and access to interventions, with investigators presenting both evidence of bias and of its absence. It is useful to examine Roger and colleagues' cohort with this question in mind, as comparison of the effects of correction for verification bias in men and women will shed light on the relative influences of exercise echocardiography results on the decision to refer to angiography.Overall, fewer women with a positive exercise echocardiogram were referred for angiography (19% versus 27%),3 but, since this decision incorporated clinical variables and was not solely based on test results, the numbers are difficult to interpret. More importantly, adjustment for verification bias resulted in a greater magnitude of correction for women, with sensitivity falling 47 percentage points in women compared with only 36 in men and specificity rising 49 percentage points in women and only 39 in men (Table 3). This suggests that physicians responded differently to a positive test result in women and relied more heavily on test results for the decision to proceed to catheterization in women than in men. Roger and colleagues3 data do not address the issue of sex differences in pretest bias or whether women are referred to diagnostic testing differently than men, nor do they address whether increased reliance on test results in women represents "good" or "bad" medical practice.How should Roger and colleagues3 results alter the way we use diagnostic testing? Certainly their data are strikingly different from those previously presented for exercise echocardiography and clearly demonstrate the dramatic effects of correction for verification bias. They indicate that such a correction should be included, when appropriate for the population under study, in evaluation of all forms of diagnostic testing. In addition to these general statements, two specific points arising from their findings can be made: First, in a clinical population, exercise echocardiography, like all cardiac diagnostic tests, is not a very sensitive test when compared with the anatomic gold standard of angiography. However, it is highly specific in a given population and provides incremental gain in estimating disease likelihood in individual patients, both important and valuable attributes. Second, in populations with sex-based differences in disease prevalence and extent, there will be sex-based differences in the accuracy of test results, which suggest that test results must be analyzed in a sex-specific fashion and that the decision to proceed to angiography must take into account sex-based differences in measures of test accuracy.11 What makes these results so important, however, it is that they are more likely to represent day-to-day test performance in a routine clinical setting, so that the adjusted measures of test value that Roger at al and others have derived provide the clinician with a more accurate basis for the interpretation of the results of exercise echocardiography.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. Table 1. Test Characteristics of Exercise Echocardiography Before and After Adjustment for Verification BiasBiased(Angiographic Subgroup)Adjusted(Entire Population)Sensitivity7838*Specificity4185*Positive predictive value7975*Negative predictive value4054*Correct classification rate69*60*All values are percentiles. All data are taken from Roger et al3 with the exception of those marked with an asterisk, which are calculated from data presented by Roger et al. Table 2. Posttest Probabilities of DiseaseEntire PopulationMenWomenBiasedAdjustedBiasedAdjustedBiasedAdjustedPositive test result577258715670 Incremental gain722821620Negative test result354233413644 Incremental gain158179146All calculations are performed on a patient with a 50% pretest probability of disease. All values are percentiles.Posttest probability of disease given a positive test result is calculated as the true-positive rate divided by the sum of the true-positive plus false-positive rates, or: sensitivity÷[sensitivity+(1−specificity)].Posttest probability of disease given a negative test result is calculated as the true-negative rate divided by the sum of the true-negative and false-negative rates, or: [1−sensitivity]÷[specificity+(1−sensitivity)].Incremental gain is the increase in certainly (probability) from pretest to posttest of a patient's having disease given a positive test, or not having disease (decrease in pretest to posttest probability) given a negative test. In the entire population, using biased test characteristics (first column), a positive test result increases the likelihood of disease from the pretest probability of 50% (assumed) to posttest probability of 57%, a "ruling in" gain of 7 percentage points. A negative test will decrease the likelihood of disease from 50% to 35%, a "ruling out" gain of 15 percentage points. Table 3. Test Characteristics in Men and Women Before and After Adjustment for Verification BiasMenWomenBiasedAdjustedBiasedAdjustedSensitivity78427932Specificity44833786Positive predictive value8483*6661*Negative predictive value34*43*54*65*Correct classification rate7156*6364*All values are percentiles. All data are taken from Roger et al3 with the exception of those marked with an asterisk, which are calculated from data presented by Roger et al.The author would like to thank George A. Diamond, MD, for his insightful critique.FootnotesCorrespondence to Pamela S. Douglas, MD, Cardiovascular Division, Beth Israel Hospital, 330 Brookline Ave, Boston, MA 02215. E-mail [email protected] References 1 Rozanski A, Diamond GA, Berman D, Forrester JS, Morris D, Swan HJC. The declining specificity of exercise radionuclide ventriculography. N Engl J Med..1983; 309:518-522.CrossrefMedlineGoogle Scholar2 Diamond GA, Forrester JS. Analysis of probability as an aid in the clinical diagnosis of coronary artery disease. N Engl J Med..1979; 300:1350-1358.CrossrefMedlineGoogle Scholar3 Roger VL, Pellikka PA, Bell MR, Chow CWH, Bailey KR, Seward JB. Sex and test verification bias: impact on the diagnostic value of exercise echocardiography. Circulation..1997; 95:405-410.CrossrefMedlineGoogle Scholar4 Begg CB, Greenes RA. Assessment of diagnostic tests when disease verification is subject to selection bias. Biometrics..1983; 39:207-215.CrossrefMedlineGoogle Scholar5 Diamond GA. Reverend Bayes' silent majority: an alternative factor affecting sensitivity and specificity of exercise electrocardiography. Am J Cardiol..1986; 57:1175-1180.CrossrefMedlineGoogle Scholar6 Morise AP, Diamond GA. Comparison of the sensitivity and specificity of exercise electrocardiography in biased and unbiased populations of men and women. Am Heart J..1995; 130:741-747.CrossrefMedlineGoogle Scholar7 Schwartz RS, Jackson WG, Celio PV, Richardson LA, Hickman JR. Accuracy of exercise 201T1 myocardial scintigraphy in asymptomatic young men. Circulation..1993; 87:165-172.CrossrefMedlineGoogle Scholar8 Griner PF, Mayewski RJ, Mushlin AI, Greenland P. Selection and interpretation of diagnostic tests and procedures: principles and applications. Ann Intern Med..1981; 94:453-600.Google Scholar9 Shaw LJ, Miller DD, Romeis JC, Kargl D, Younis LT, Chaitman BR. Gender differences in the noninvasive evaluation and management of patients with suspected coronary artery disease. Ann Intern Med..1994; 120:559-566.CrossrefMedlineGoogle Scholar10 Douglas PS. Coronary artery disease in women. In: Braunwald E, ed. Heart Disease. In press.Google Scholar11 Douglas PS, Ginsburg GS. The evaluation of chest pain in women. N Engl J Med..1996; 334:1311-1315.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Raso I, Passarelli I, Valenti G, Crimi G and de Servi S (2018) The diagnostic process of stable angina, Journal of Cardiovascular Medicine, 10.2459/JCM.0000000000000610, 19:2, (45-50), Online publication date: 1-Feb-2018. Polinsky R (2018) Age, Sex, and Gene Expression Score identifies a symptomatic, nondiabetic male patient as being at high risk of obstructive coronary artery disease, SAGE Open Medical Case Reports, 10.1177/2050313X17749081, 6, (2050313X1774908), Online publication date: 1-Jan-2018. Sara J, Widmer R, Matsuzawa Y, Lennon R, Lerman L and Lerman A (2015) Prevalence of Coronary Microvascular Dysfunction Among Patients With Chest Pain and Nonobstructive Coronary Artery Disease, JACC: Cardiovascular Interventions, 10.1016/j.jcin.2015.06.017, 8:11, (1445-1453), Online publication date: 1-Sep-2015. Warren J, Yu J, Grinfeld L and Mehran R (2015) Chest Pain in Women: Evaluation and Management Controversies in Cardiology, 10.1007/978-3-319-20415-4_9, (111-132), . Thomas G, Voros S, McPherson J, Lansky A, Winn M, Bateman T, Elashoff M, Lieu H, Johnson A, Daniels S, Ladapo J, Phelps C, Douglas P and Rosenberg S (2013) A Blood-Based Gene Expression Test for Obstructive Coronary Artery Disease Tested in Symptomatic Nondiabetic Patients Referred for Myocardial Perfusion Imaging The COMPASS Study, Circulation: Cardiovascular Genetics, 6:2, (154-162), Online publication date: 1-Apr-2013.Fihn S, Gardin J, Abrams J, Berra K, Blankenship J, Dallas A, Douglas P, Foody J, Gerber T, Hinderliter A, King S, Kligfield P, Krumholz H, Kwong R, Lim M, Linderbaum J, Mack M, Munger M, Prager R, Sabik J, Shaw L, Sikkema J, Smith C, Smith S, Spertus J and Williams S (2012) 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease, Circulation, 126:25, (e354-e471), Online publication date: 18-Dec-2012. Fihn S, Gardin J, Abrams J, Berra K, Blankenship J, Dallas A, Douglas P, Foody J, Gerber T, Hinderliter A, King S, Kligfield P, Krumholz H, Kwong R, Lim M, Linderbaum J, Mack M, Munger M, Prager R, Sabik J, Shaw L, Sikkema J, Smith C, Smith S, Spertus J and Williams S (2012) 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease, Journal of the American College of Cardiology, 10.1016/j.jacc.2012.07.013, 60:24, (e44-e164), Online publication date: 1-Dec-2012. Leuzzi C and Modena M (2010) Coronary artery disease: Clinical presentation, diagnosis and prognosis in women, Nutrition, Metabolism and Cardiovascular Diseases, 10.1016/j.numecd.2010.02.013, 20:6, (426-435), Online publication date: 1-Jul-2010. Rollini F, Mfeukeu L and Modena M (2009) Assessing coronary heart disease in women, Maturitas, 10.1016/j.maturitas.2008.12.013, 62:3, (243-247), Online publication date: 1-Mar-2009. Makaryus A, Mieres J and Shaw L (2009) Cardiovascular Imaging in Racial/Ethnic Populations: Implications for the Adequate Application of Cardiovascular Imaging Techniques Guided by Racial/Ethnic Risk Factor Variations Cardiovascular Disease in Racial and Ethnic Minorities, 10.1007/978-1-59745-410-0_12, (229-245), . Makaryus A (2008) Cardiovascular imaging for the assessment of atherosclerotic disease: Implications for cardiac risk stratification, Current Cardiovascular Risk Reports, 10.1007/s12170-008-0021-4, 2:2, (107-112), Online publication date: 1-Mar-2008. Biagini E, Elhendy A, Bax J, Schinkel A and Poldermans D (2005) The use of stress echocardiography for prognostication in coronary artery disease: an overview, Current Opinion in Cardiology, 10.1097/01.hco.0000175516.50181.c0, 20:5, (386-394), Online publication date: 1-Sep-2005. Redberg R and Shaw L (2003) Diagnosis of coronary artery disease in women, Progress in Cardiovascular Diseases, 10.1016/j.pcad.2003.09.002, 46:3, (239-258), Online publication date: 1-Nov-2003. Miller T, Hodge D, Christian T, Milavetz J, Bailey K and Gibbons R (2002) Effects of adjustment for referral bias on the sensitivity and specificity of single photon emission computed tomography for the diagnosis of coronary artery disease, The American Journal of Medicine, 10.1016/S0002-9343(01)01111-1, 112:4, (290-297), Online publication date: 1-Mar-2002. Finkelhor R, Pajouh M, Kett A, Stefanski R, Bosich G, Youssefi M and Bahler R (2000) Clinical impact of second harmonic imaging and left heart contrast in echocardiographic stress testing, The American Journal of Cardiology, 10.1016/S0002-9149(99)00851-6, 85:6, (740-743), Online publication date: 1-Mar-2000. Schroeder S, Enderle M, Ossen R, Meisner C, Baumbach A, Pfohl M, Herdeg C, Oberhoff M, Haering H and Karsch K (1999) Noninvasive determination of endothelium-mediated vasodilation as a screening test for coronary artery disease: Pilot study to assess the predictive value in comparison with angina pectoris, exercise electrocardiography, and myocardial perfusion imaging, American Heart Journal, 10.1016/S0002-8703(99)70189-4, 138:4, (731-739), Online publication date: 1-Oct-1999. Pfohl M, Koch M, Prescod S, Haase K, Häring H and Karsch K (1999) Angiotensin I-converting enzyme gene polymorphism, coronary artery disease and myocardial infarction. An angiographically controlled study, European Heart Journal, 10.1053/euhj.1999.1543, 20:18, (1318-1325), Online publication date: 1-Sep-1999., Online publication date: 1-Sep-1999. Gibbons R, Chatterjee K, Daley J, Douglas J, Fihn S, Gardin J, Grunwald M, Levy D, Lytle B, O'Rourke R, Schafer W, Williams S, Ritchie J, Gibbons R, Cheitlin M, Eagle K, Gardner T, Garson A, Russell R, Ryan T and Smith S (1999) ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina11This document was approved by the American College of Cardiology Board of Trustees in March 1999, the American Heart Association Science Advisory and Coordinating Committee in March 1999, and the American College of Physicians-American Society of Internal Medicine Board of Regents in February 1999.When citing this document, please use the following citation format: Gibbons RJ, Chatterjee K, Daley J, Douglas JS, Fihn SD, Gardin JM, Grunwald MA, Levy D, Lytle BW, O'Rourke RA, Schafer WP, Williams SV. ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). J Am Coll Cardiol 1999;33:2092–197.This document is available on the World Wide Web sites of the American College of Cardiology (www.acc.org) and the American Heart Association (www.americanheart.org). Reprints of this document are available by calling 1-800-253-4636 or writing the American College of Cardiology, Educational Services, at 9111 Old Georgetown Road, Bethesda, MD 20814-1699. Ask for reprint number 71-0166. To obtain a reprint of the Executive Summary and Recommendations published in the June 1, 1999 issue of Circulation, ask for reprint number 71-0167. To purchase bulk reprints (specify version and reprint number): Up to 999 copies call 1-800-611-6083 (US only) or fax 413-665-2671; 1000 or more copies call 214-706-1466, fax 214-691-6342, or e-mail [email protected], Journal of the American College of Cardiology, 10.1016/S0735-1097(99)00150-3, 33:7, (2092-2197), Online publication date: 1-Jun-1999. Alberto San Román J, Vilacosta I, Ramón Ortega J, Serrador A, Pastor G, Medina A, Fernández-Avilés F, Luis Bratos J and Jesús Rollán M (1999) Influencia del sexo en el rendimiento de la ecocardiografía con dobutamina para el diagnóstico de la cardiopatía isquémica, Revista Española de Cardiología, 10.1016/S0300-8932(99)75037-2, 52:12, (1.060-1.065), Online publication date: 1-Jan-1999. Hasdai D, Holmes D, Higano S, Burnett J and Lerman A (1998) Prevalence of Coronary Blood Flow Reserve Abnormalities Among Patients With Nonobstructive Coronary Artery Disease and Chest Pain, Mayo Clinic Proceedings, 10.4065/73.12.1133, 73:12, (1133-1140), Online publication date: 1-Dec-1998. Redberg R (1998) DIAGNOSTIC TESTING FOR CORONARY ARTERY DISEASE IN WOMEN AND GENDER DIFFERENCES IN REFERRAL FOR REVASCULARIZATION, Cardiology Clinics, 10.1016/S0733-8651(05)70385-4, 16:1, (67-77), Online publication date: 1-Feb-1998. January 21, 1997Vol 95, Issue 2 Advertisement Article InformationMetrics Copyright © 1997 by American Heart Associationhttps://doi.org/10.1161/01.CIR.95.2.299 Originally publishedJanuary 21, 1997 KeywordstestsdiagnosisEditorials Advertisement
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