- Email: [email protected]
Carotid Ultrasound for Risk Clarification in Young to Middle-Aged Adults Undergoing Elective Coronary Angiography
AJH
2006; 19:1256 –1261
Heart
Carotid Ultrasound for Risk Clarification in Young to Middle-Aged Adults Undergoing Elective Coronary Angiography Kwame O. Akosah, Vicki L. McHugh, Sharon I. Barnhart, Ana M. Schaper, Michelle A. Mathiason, Pat A. Perlock, and Troy A. Haider Background: An important aspect of risk prediction is the apparent difference between calculated risk and true risk. Current risk predictor models are not sensitive enough to identify many subjects at risk for future events or to prevent overuse of expensive tests. The aim of this study was to determine the usefulness of carotid ultrasound for risk stratification in subjects undergoing elective coronary angiography. Methods: A total of 253 individuals (men ⱕ55 years of age and women ⱕ65 years of age) who were scheduled for elective coronary angiography underwent carotid ultrasonography. Noncoronary atherosclerosis was defined based on a maximal intima-media thickness of ⱖ1.0 mm or the presence of focal plaque. Results: Of the subjects, 236 completed all of the tests. The mean age was 51 ⫾ 8 years, and 58% were women and 42% men. Severe angiographic disease (ⱖ50%) was present in 72 subjects. Carotid atherosclerosis was present
in 141 subjects. Use of the Framingham risk score classified 172 subjects as low risk. Carotid atherosclerosis was diagnosed in 57% of the low-risk group compared with 70% of the high-risk group (P ⫽ .122). Carotid atherosclerosis was associated with severe coronary angiographic disease (OR ⫽ 2.2, CI ⫽ 1.2 to 4.0). Conclusion: Noncoronary atherosclerosis was associated with severe coronary disease as determined by angiography. Carotid atherosclerosis had a high negative predictive value in subjects with negative stress test results or risk-stratified as low risk. Noninvasive imaging by carotid ultrasonography for noncoronary atherosclerosis may be a good adjunct to clinical risk stratification for premature coronary heart disease. Am J Hypertens 2006; 19:1256 –1261 © 2006 American Journal of Hypertension, Ltd. Key Words: Ultrasound, carotid atherosclerosis, coronary angiography, Framingham risk score.
ardiovascular disease continues to remain a major cause of death.1 The effect on chronic disability and financial cost is unparalleled in the United States.2,3 Over the past few years there have been significant advances in the management of cardiovascular disease, but the improvement has been less evident in primary prevention.4 –7 For instance, there has been steady reductions in the age adjusted mortality rates after acute myocardial infarction, but preventing the first myocardial infarction has been a difficult challenge. Acute coronary syndrome results from pre-existing atherosclerotic plaques that remain silent over a long period.8,9 For many individuals the first clinical manifestation of atherosclerosis may be acute myocardial infarction or sudden death. Several risk assessment tools have been proposed, but there remains a substantial gap between subjects at potential risk
C
versus the actual number of subjects identified. This problem, termed “detection gap,” continues to be an important topic for both research interest and clinical concern. The Executive Summary of the 34th Bethesda Conference focused on various noninvasive imaging and other modalities for their potential in providing additive information to current guidelines.10 In part because of the inaccuracy of current risk predictor models, many individuals undergo invasive testing that is expensive and perhaps avoidable. Among the imaging modalities currently being evaluated to improve risk prediction, carotid ultrasound is unique in that it is widely accessible, relatively inexpensive, portable, and without risk. Because atherosclerosis is diffuse and systemic, it was reasoned that individuals with coronary artery disease would manifest carotid atherosclerosis. The objective of this prospective evaluation was to determine the utility of the
Received January 4, 2004. First decision May 15, 2006. Accepted May 21, 2006. From the Department of Cardiology Gundersen Lutheran Health System, La Crosse, Wisconsin.
Supported in part by The Gundersen Lutheran Medical Foundation. Address correspondence and reprint requests to Dr. Kwame O. Akosah, Gundersen Lutheran Health System, 1900 South Avenue, C03-001, La Crosse, WI 54601; e-mail: [email protected]
0895-7061/06/$32.00 doi:10.1016/j.amjhyper.2006.05.017
© 2006 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc.
AJH–December 2006 –VOL. 19, NO. 12
NONCORONARY ATHEROSCLEROSIS AND CORONARY ARTERY DISEASE
presence of noncoronary atherosclerosis for further risk clarification in patients undergoing elective coronary angiography. We hypothesized that young to middle-aged adults with noncoronary atherosclerosis are more likely to have concomitant coronary artery disease than were those without noncoronary atherosclerosis.
Methods Study Population A prospective evaluation comparing coronary angiography with carotid ultrasound imaging and clinical risk scores as defined by National Cholesterol Education Panel (NCEP) III guidelines was conducted. Subjects were recruited from among people scheduled for elective cardiac catheterization by their primary physicians. Our comprehensive regional health service is a not-for-profit system comprised of 50⫹ owned, managed, leased, or networked regional facilities, and also includes one insurance company/managed care organization. Although our delivery of cardiac care is concentrated in La Crosse, Wisconsin, we provide healthcare services in a 19-county region of southwestern Wisconsin, northeastern Iowa, and southeastern Minnesota. Our networked physicians routinely refer patients for diagnostic testing to the main campus. Approximately 800 individuals are scheduled for elective cardiac catheterization per year who meet our study specifications, with approximately 50% having normal coronary arteries on angiography. This provides a large pool for correlative studies. No subject underwent catheterization specifically for this study. Inclusion criteria were set to identify patients at low risk for premature coronary heart disease. Only young to middle-aged patients (men ⱕ55 years and women ⱕ65 years) were eligible. Subjects were excluded if they had any history of coronary heart disease or had been taking a 3-hydroxy-methyl-HmG-CoA reductase inhibitor (statin). Institutional review board approval was obtained and all patients provided informed consent before enrollment in the study. On the day of the angiographic procedure, subjects who agreed to participate completed a risk assessment survey, had fasting blood drawn for laboratory analysis, and underwent bilateral carotid ultrasound.
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Digitized images were transferred onto a digital reading station (Kinet DX; Acuson) for later review. Intima-media thickness (IMT) was defined as the distance from leading edge to leading edge of the intima and media (blood intima interface to the media adventitia interface). Measurements for IMT were obtained along a section of the common carotid artery 1 cm proximal to the bulb. IMT measurement was not obtained at the bulb. Both the near and far walls were equally well visualized. On each wall of both the right and left carotid artery, six measurements were performed and used for calculating the mean IMT. One experienced cardiologist, blinded to each subject’s clinical profile and angiographic data, reviewed all carotid ultrasound studies. In addition to IMT, the cardiologist noted focal plaques. Plaque was defined as distinct, focal areas of intima abnormality that protruded into the lumen. Calcific plaque was defined as an intraluminal density casting an acoustic shadow. For the purpose of this study, criteria for carotid atherosclerosis were met by the presence of plaque of any kind or by a maximal IMT reading of ⱖ1.0 mm. Angiographic Data No coronary angiography was performed specifically for this study. All angiography was performed by standard technique. Severe angiographic disease was defined as stenosis ⱖ50% in any major epicardial coronary artery. Coronary angiograms were graded by visual inspection. Statistical Analysis The data were analyzed with SAS software (SAS Institute, Cary, NC). Continuous variables were expressed as mean ⫾ standard deviation. Categorical variables were expressed as percentages. Accuracy values including sensitivity, specificity, positive predictive value, and negative predictive values were calculated for carotid ultrasound using coronary angiography as the gold standard. The unadjusted odds ratio (OR) as an estimate of relative risk and the 95% confidence intervals (95% CI) were calculated by logistic regression.
Results General Findings
Ultrasound Study All studies were performed using the SonoCT broadband probe, L12-5 interfaced with the HDI 5000 echocardiograph (Philips ATL at Bothel, WA). Two highly experienced echocardiography technicians performed all of the carotid ultrasound studies. Before initiating the study, carotid ultrasound testing was performed on 30 healthy individuals. Agreement between the two technicians for IMT mean measurement within a 0.1-mm difference occurred in 90% of the population. Vessels were imaged in the longitudinal plane, digitized online and recorded onto the hard drive of the echo machine.
A total of 253 subjects were enrolled, and 236 completed all tests. The analyses were computed for the 236 subjects with complete data. Of these, 58% were women (mean age 53 ⫾ 8 years) and 42% were men (mean age 47 ⫾ 6 years). Indications for cardiac catheterization were given by referring physicians and included 139 individuals with any mention of chest pain, of whom 52 had typical and 87 had atypical chest pain. Table 1 displays all indications for cardiac catheterization. The mean total cholesterol, LDL, and HDL for the group as a whole were 195 ⫾ 37 mg/dL, 122 ⫾ 30 mg/dL, and 51 ⫾ 14 mg/dL, respectively. Mean serum triglyceride levels were 147 ⫾ 76 mg/dL.
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Table 1. Indications for cardiac catheterization by referring physicians Indications for cardiac catheterization Symptom Typical chest pain Atypical chest pain Preoperative assessment Shortness of breath Other
No. (%) 52 87 35 19 43
(22%) (37%) (15%) (8%) (18%)
Stress testing results Test result Positive Negative Equivocal None
No. (%) 114 13 35 74
(48%) (6%) (15%) (31%)
Risk Factor Profiles by NCEP III Of the subjects, 43 had coronary heart disease equivalent defined as diabetes or symptomatic peripheral vascular disease per NCEP guidelines. A total of 172 subjects (73%) were stratified as having zero to one risk factor or ⬍10% risk for an event in 10 years, qualifying them as low risk according to the Framingham risk scores. Eighteen subjects (8%) had scores that placed them at a 10-year risk for an event as intermediate (10% to 20%). Only three subjects had risk scores of ⱖ20% for a 10-year event. Thus, including the 43 subjects with coronary heart disease equivalent, a total of 46 subjects met criteria for high risk. For this report, we use the term “high risk” to represent scores ⱖ20% or coronary heart disease equivalent.
Coronary Angiography Of the subjects, 72 (31%) had angiograms that met criteria for severe disease (stenosis ⱖ50%). Significant one-vessel disease was diagnosed in 29 subjects (40%), and 43 had multivessel disease (60%). A total of 43 additional patients were diagnosed as having insignificant coronary stenosis defined as lesion severity of 10% to 49%, or luminal irregularities. Carotid Ultrasound A total of 141 subjects were diagnosed as having carotid atherosclerosis, defined as maximal IMT (IMTmax) ⱖ1.0 mm, or the presence of focal plaque. Among these subjects meeting criteria for carotid atherosclerosis, 76 had IMTmax ⱖ1.0 mm within the main body of the artery. A total of 116 subjects had focal plaques in the main body of the artery, bulb, or proximal branches, with 39 subjects having calcium within the plaque. Only 25subjects met criteria by IMT alone. Thus, the majority of subjects with abnormal
AJH–December 2006 –VOL. 19, NO. 12
carotid ultrasound studies had multiple manifestations of atherosclerosis. Association of Carotid Ultrasonography and Coronary Angiography The sensitivity for carotid atherosclerosis in predicting angiographically apparent severe disease was 72%, with specificity of 46%. Negative predictive value was 79% with positive predictive value of 37%. Logistic regression revealed that carotid atherosclerosis was associated with an unadjusted OR of 2.2 (CI ⫽ 1.2 to 4.0; P ⫽ 0.010) in predicting coronary artery disease. Accuracy Values of Carotid Ultrasound Stratified per Subgroup We analyzed the data according to the results of the stress test. Among the 236 subjects, 74 individuals did not have a stress test performed before cardiac catheterization, 114 subjects had positive stress test results, and 48 subjects had negative or equivocal stress test results. The analysis limited to the subgroup with positive stress test results demonstrated that only 41 subjects (36%) had severe coronary artery disease, of whom 27 had a diagnosis of noncoronary atherosclerosis by ultrasonography. In this group, the sensitivity, specificity, positive, and negative predictive values were 66%, 41%, 39%, and 68%, respectively. Among the subgroup with negative or equivocal stress test results, as well as those for whom no stress test results were available, the corresponding values of sensitivity, specificity, positive and negative predictive values were 81%, 50%, 35%, and 88%, respectively. Table 2 shows coronary angiogram and carotid ultrasound data stratified by stress test results. Similarly, the results were also analyzed for Framingham risk groups. Because there were only 18 subjects stratified as intermediate risk, we limited the analysis to the high- and low-risk groups. Among the 46 subjects qualifying for coronary heart disease equivalent or high risk, only 25 had abnormal coronary angiograms (54%). In the low-risk group, 36 subjects also had severe coronary artery disease. Carotid atherosclerosis was present in 67% of subjects with severe coronary artery disease in the low-risk group. Among subjects with high-risk scores, carotid atherosclerosis was present in 80% of those with severe coronary artery disease. The results of coronary angiogram and carotid ultrasound data stratified by Framingham scores are detailed in Table 3.
Discussion A difficult task in prevention remains the inability to accurately predict an individual’s actual risk for an imminent event compared with relative risk. In our experience, we have found that many young to middle-aged adults presenting with their first myocardial infarction were risk
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Table 2. Coronary angiogram and carotid ultrasound results stratified according to stress test results (ⴙ) Stress test
(⫹) Carotid ultrasound (⫺) Carotid ultrasound Sensitivity Specificity Positive predictive value Negative predictive value
(ⴚ) Stress test
No stress test
(ⴙ) Cath
(ⴚ) Cath
(ⴙ) Cath
(ⴚ) Cath
(ⴙ) Cath
(ⴚ) Cath
27 14
43 30
5 3
19 21
20 3
27 24
66% 41% 39% 68%
63% 53% 21% 88%
87% 47% 43% 89%
Cath ⫽ catheterization. ⫺ ⫽ negative results throughout.
categorized as low risk according to the NCEP III guidelines.11–13 It is well known that currently available tools and risk predictor models do not accurately determine the true size of the population, or the actual individual, who eventually presents with cardiovascular events.14 –18 This problem, termed a “detection gap,” is important for both research and clinical medicine,19 as highlighted in the 34th Bethesda Conference.10 In fact, a paper from the Centers of Disease Control found that among individuals the United States population without coronary heart disease, only 3% risk stratify as high risk, whereas the majority (82%) qualify as low risk.20 The difficulty in achieving an accurate noninvasive diagnosis may explain in part the growth that has been seen of invasive cardiac catheterizations and expensive new technologies. A recent study demonstrated that despite increasing reliance on high-cost technology, there was a lack of any strong association between costs and patient outcomes or quality of care.21 Another study, by Lucas et al,22 reached similar conclusions, finding that increased cardiac testing and treatment were not explained by disease prevalence. This reliance on high technology and invasive procedures has major impact on cost of care. There is continued concern regarding the ever-increasing proportion of health care costs on the national budget. A recent report from the Centers of Medicare and Medicaid Services projects that over the next decade, accounting for population aging and changes in medical technology and use, national health expenditures are expected to double.
As a result, 20% of the gross domestic product will be accounted for by health care costs.23 This highlights the importance of developing relatively inexpensive strategies that could be used in further clarifying risks in the many individuals who undergo invasive evaluation who do not qualify as high risk. In this study, only 36% of patients with abnormal stress tests actually had severe coronary artery disease. When combined with the information obtained by ultrasonography, we found that an individual with abnormal stress test results and a diagnosis of noncoronary atherosclerosis had a greater chance of having severe coronary artery disease (66%). Similarly, as shown in Table 2, some individuals with negative stress test results did have severe coronary artery disease, of whom 63% had noncoronary atherosclerosis. In this group, a negative ultrasound– based evidence for noncoronary atherosclerosis had 88% negative predictive value. The information was similar in the subgroup who did not have stress tests performed, with a negative predictive value of 89% and a sensitivity of 87%. The carotid ultrasound results stratified per clinical risk group demonstrated that among individuals stratified as high risk, approximately half had severe coronary artery disease. Although the likelihood of having severe coronary artery disease was greater for the high-risk group compared with the low-risk group (54% v 21%), the absolute number of subjects having severe coronary artery disease was higher in the low-risk group. In the high-risk group, not surprisingly, the presence of noncoronary atheroscle-
Table 3. Results of carotid ultrasound and coronary angiogram stratified according to clinical risk profile All subjects
(⫹) Carotid ultrasound (⫺) Carotid ultrasound Sensitivity Specificity Positive predictive value Negative predictive value Cath ⫽ catheterization.
Low risk
High risk
(ⴙ) Cath
(ⴚ) Cath
(ⴙ) Cath
(ⴚ) Cath
(ⴙ) Cath
(ⴚ) Cath
52 20
89 75
24 12
74 62
20 5
12 9
72% 46% 37% 79%
67% 46% 25% 84%
80% 43% 63% 64%
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rosis was predictive of severe coronary artery disease (80%). In the low-risk group, 67% of the individuals who had severe coronary artery disease were identified by ultrasound, and indeed the negative predictive value for this group was comparable to that seen in the negative stress test group (84%). Identifying the individual at true risk for imminent heart attack is an important step in coronary heart disease prevention. Currently, many individuals undergo expensive new tests and invasive procedures for reasons including physician uneasiness and patient expectations. Our study demonstrates that the diagnosis of noncoronary atherosclerosis may be an important adjunct to clinical risk stratification or stress testing. Carotid ultrasound has been shown to detect early atherosclerosis. A recent report demonstrated that in young individuals with metabolic syndrome, subclinical atherosclerosis is already present and can be detected by carotid ultrasound.24 Other studies have correlated abnormal IMT with the presence and extent of cardiovascular risk factors25 and for predicting future events.26 –28 In the current study, identification of noncoronary atherosclerosis was associated with coronary angiographic disease. In young to middle-aged subjects undergoing evaluation for coronary artery disease, noncoronary atherosclerosis provided useful, supplemental information to stress testing and clinical risk stratification. Study Limitations Although the sample size is not necessarily small and included a high proportion of women, the investigators recognize that this is a single-center experience, and a larger, more inclusive study would be very helpful. The absence of minority group participation is regrettable, but it is a reflection of our geographical catchment area in which the population is predominantly of white ethnicity. Because we studied subjects referred for elective coronary catheterization by their respective physicians, the population may not be considered to be truly at low risk. It would have been ideal to study healthy volunteers from the general population, but it would be difficult (if not impractical or unethical) to subject such individuals to invasive cardiac catheterization. We remind the reader that clinical risk scores are not synonymous with coronary angiographic findings. Framingham risk appraisal provides probability estimates of risk for major coronary heart disease events over time. By contrast, coronary angiography provides a one-time snapshot of coronary disease and its severity. Although the disease is ultimately responsible for events over time, angiographic data and Framingham risk scores may not provide the same information at any one time. In conclusion, this study demonstrates that by combining carotid ultrasound imaging for noncoronary atherosclerosis with clinical risk stratification per the NCEP III guidelines, many more individuals with coronary artery disease can be identified. Individuals without noncoronary atherosclerosis stratified as low risk or having negative
AJH–December 2006 –VOL. 19, NO. 12
stress test results have excellent chances of not having severe coronary artery disease. Identification of noncoronary atherosclerosis by carotid ultrasound may serve as a good adjunct to the guidelines to improve risk stratification.
References 1.
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American Heart Association: AHA News. New stats show heart disease still America’s No. 1 killer, stroke No. 3. http://www. americanheart.org/presenter.jhtml?identifier⫽3018015. Accessed October 12, 2005. Wang G, Zheng ZJ, Heath G, Macera C, Pratt M, Buchner D: Economic burden of cardiovascular disease associated with excess body weight in U.S. adults. Am J Prev Med 2002;23:1– 6. Druss BG, Marcus SC, Olfson M, Pincus HA: The most expensive medical conditions in America. Health Aff 2002;21:105–111. Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V: Helsinki Heart Study: primary-prevention trial with gemfibrozil in middleaged men with dyslipidemia. N Engl J Med 1987;317:1237– 1245. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, Macfarlane PW, McKillop JH, Packard CJ: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301–1307. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr: Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/Tex/ CAPS. J Am Med Assoc 1998;279:1615–1622. Lloyd-Jones DM, O’Donnell CJ, D’Agostino RB, Massaro J, Silbershatz H, Wilson PWF: Applicability of cholesterol-lowering primary prevention trials to a general population. The Framingham Heart Study. Arch Intern Med 2001;161:949 –954. Yamagishi M, Terashima M, Awano K, Kijima M, Nakatani S, Daikoku S, Ito K, Yasumura Y, Miyatake K: Morphology of vulnerable coronary plaque: insights from follow-up of patients examined by intravascular ultrasound before an acute coronary syndrome. J Am Coll Cardiol 2000;35:106 –111. Libby P: Molecular bases of the acute coronary syndromes. From bench to bedside. Circulation 1995;91:2844 –2850. Taylor AJ, Bairey Merz CN, Udelson JE, 34th Bethesda Conference: Can atherosclerosis imaging techniques improve the detection of patients at risk for ischemic heart disease: presented at the 34th Bethesda conference, Bethesda, Maryland, October 7, 2002. J Am Coll Cardiol 2003;41:1855–1917. Akosah KO, Cerniglia RM, Havlik P, Schaper A: Myocardial infarction in young adults with low-density lipoprotein cholesterol levels less than or equal to 100 mg/dl: clinical profile and 1-year outcomes. Chest 2001;120:1953–1958. Akosah KO, Schaper A, Cogbill C, Schoenfeld P: Preventing myocardial infarction in the young adult in the first place: how do the National Cholesterol Education Panel III guidelines perform? J Am Coll Cardiol 2003;41:1475–1479. Akosah KA, Gower E, Groon L, Rooney BL, Schaper A: Mild hypercholesterolemia and premature heart disease: do the national criteria underestimate disease risk? J Am Coll Cardiol 2000;35: 1178 –1184. Taylor AJ, Feuerstein I, Wong H, Barko W, Brazaitis M, O’Malley PG: Do conventional risk factors predict subclinical coronary artery disease? Results from the Prospective Army Coronary Calcium Project. Am Heart J 2001;141:463– 468. Haq IU, Ramsay LE, Jackson PR, Wallis EJ: Prediction of coronary risk for primary prevention of coronary heart disease: a comparison of methods. Q J Med 1999;92:379 –385.
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16. Pashkow FJ: The prudent person’s paradox (editorial). J Am Coll Cardiol 2003;41:1480 –1481. 17. Reynolds TM, Twomey P, Wierzbicki AS: Accuracy of cardiovascular risk estimation for primary prevention in patients without diabetes. J Cardiovasc Risk 2002;9:183–190. 18. Michos ED, Vasamreddy CR, Becker MD, Yanek LR, Moy TF, Fishman EK, Becker LC, Blumenthal RS: Women with a low Framingham risk score and a family history of premature coronary heart disease have a high prevalence of subclinical coronary atherosclerosis. Am Heart J 2005;150:1276 –1281. 19. Greenland P, Smith SC, Grundy SM: Improving coronary heart disease risk assessment in asymptomatic people: role of traditional risk factors and noninvasive cardiovascular tests. Circulation 2001; 104:1863–1867. 20. Ford ES, Giles WH, Mokdad AH: The distribution of 10-year risk for coronary heart disease among U.S. adults. J Am Coll Cardiol 2004;43:1791–1796. 21. Skinner JS, Staiger DO, Fisher ES: Is technological change in medicine always worth it? The case of acute myocardial infarction. Health Affairs 25 (2006);w34 –w47 (published online 7 February 2006; 10.1377/hlthaff.25.w34). 22. Lucas FL, DeLorenzo MA, Siewers AE, Wennberg DE: Temporal trends in utilization of diagnostic testing and treatments for cardiovascular disease in the United States, 1993–2001. Circulation 2006; 113:374 –379.
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23. Centers for Medicare and Medicaid Services. Continued slowdown in health care cost growth projects in 2005 and 2006. http://www.cms. hhs.gov/apps/media/press/release.asp?Counter⫽1787. Accessed March 1, 2006. 24. Tzou WS, Douglas PS, Srinivasan SSR, Bond MG, Tang R, Chen W, Berenson GS, Stein JH: Increased subclinical atherosclerosis in young adults with metabolic syndrome. J Am Coll Cardiol 2005;46:457– 463. 25. van der Meer IM, Bots ML, Hofman A, del Sol AI, van der Kuip DAM, Witteman JCM: Predictive value of noninvasive measures of atherosclerosis for incident myocardial infarction. The Rotterdam Study. Circulation 2004;109:1089 –1094. 26. Wattanakit K, Folsom AR, Chambless LE, Nieto FJ: Risk factors for cardiovascular event recurrence in the Atherosclerosis Risk in Communities (AIRC) study. Am Heart J 2005;149:606 – 612. 27. Aboyans V, Lacroix P, Postil A, Guilloux J, Rolle F, Cornu E, Laskar M: Subclinical peripheral arterial disease and incompressible ankle arteries are both long-term prognostic factors in patients undergoing coronary artery bypass grafting. J Am Coll Cardiol 2005;46:815– 820. 28. Honda O, Sugiyama S, Kugiyama K, Fukushima H, Nakamura S, Koide S, Kojima S, Nirai N, Kowano H, Soejima J, Sakamoto T, Yoshimura M, Ogawa H: Echolucent carotid plaques predict future coronary events in patients with coronary artery disease. J Am Coll Cardiol 2004;43:1177–1184.
2006; 19:1256 –1261
Heart
Carotid Ultrasound for Risk Clarification in Young to Middle-Aged Adults Undergoing Elective Coronary Angiography Kwame O. Akosah, Vicki L. McHugh, Sharon I. Barnhart, Ana M. Schaper, Michelle A. Mathiason, Pat A. Perlock, and Troy A. Haider Background: An important aspect of risk prediction is the apparent difference between calculated risk and true risk. Current risk predictor models are not sensitive enough to identify many subjects at risk for future events or to prevent overuse of expensive tests. The aim of this study was to determine the usefulness of carotid ultrasound for risk stratification in subjects undergoing elective coronary angiography. Methods: A total of 253 individuals (men ⱕ55 years of age and women ⱕ65 years of age) who were scheduled for elective coronary angiography underwent carotid ultrasonography. Noncoronary atherosclerosis was defined based on a maximal intima-media thickness of ⱖ1.0 mm or the presence of focal plaque. Results: Of the subjects, 236 completed all of the tests. The mean age was 51 ⫾ 8 years, and 58% were women and 42% men. Severe angiographic disease (ⱖ50%) was present in 72 subjects. Carotid atherosclerosis was present
in 141 subjects. Use of the Framingham risk score classified 172 subjects as low risk. Carotid atherosclerosis was diagnosed in 57% of the low-risk group compared with 70% of the high-risk group (P ⫽ .122). Carotid atherosclerosis was associated with severe coronary angiographic disease (OR ⫽ 2.2, CI ⫽ 1.2 to 4.0). Conclusion: Noncoronary atherosclerosis was associated with severe coronary disease as determined by angiography. Carotid atherosclerosis had a high negative predictive value in subjects with negative stress test results or risk-stratified as low risk. Noninvasive imaging by carotid ultrasonography for noncoronary atherosclerosis may be a good adjunct to clinical risk stratification for premature coronary heart disease. Am J Hypertens 2006; 19:1256 –1261 © 2006 American Journal of Hypertension, Ltd. Key Words: Ultrasound, carotid atherosclerosis, coronary angiography, Framingham risk score.
ardiovascular disease continues to remain a major cause of death.1 The effect on chronic disability and financial cost is unparalleled in the United States.2,3 Over the past few years there have been significant advances in the management of cardiovascular disease, but the improvement has been less evident in primary prevention.4 –7 For instance, there has been steady reductions in the age adjusted mortality rates after acute myocardial infarction, but preventing the first myocardial infarction has been a difficult challenge. Acute coronary syndrome results from pre-existing atherosclerotic plaques that remain silent over a long period.8,9 For many individuals the first clinical manifestation of atherosclerosis may be acute myocardial infarction or sudden death. Several risk assessment tools have been proposed, but there remains a substantial gap between subjects at potential risk
C
versus the actual number of subjects identified. This problem, termed “detection gap,” continues to be an important topic for both research interest and clinical concern. The Executive Summary of the 34th Bethesda Conference focused on various noninvasive imaging and other modalities for their potential in providing additive information to current guidelines.10 In part because of the inaccuracy of current risk predictor models, many individuals undergo invasive testing that is expensive and perhaps avoidable. Among the imaging modalities currently being evaluated to improve risk prediction, carotid ultrasound is unique in that it is widely accessible, relatively inexpensive, portable, and without risk. Because atherosclerosis is diffuse and systemic, it was reasoned that individuals with coronary artery disease would manifest carotid atherosclerosis. The objective of this prospective evaluation was to determine the utility of the
Received January 4, 2004. First decision May 15, 2006. Accepted May 21, 2006. From the Department of Cardiology Gundersen Lutheran Health System, La Crosse, Wisconsin.
Supported in part by The Gundersen Lutheran Medical Foundation. Address correspondence and reprint requests to Dr. Kwame O. Akosah, Gundersen Lutheran Health System, 1900 South Avenue, C03-001, La Crosse, WI 54601; e-mail: [email protected]
0895-7061/06/$32.00 doi:10.1016/j.amjhyper.2006.05.017
© 2006 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc.
AJH–December 2006 –VOL. 19, NO. 12
NONCORONARY ATHEROSCLEROSIS AND CORONARY ARTERY DISEASE
presence of noncoronary atherosclerosis for further risk clarification in patients undergoing elective coronary angiography. We hypothesized that young to middle-aged adults with noncoronary atherosclerosis are more likely to have concomitant coronary artery disease than were those without noncoronary atherosclerosis.
Methods Study Population A prospective evaluation comparing coronary angiography with carotid ultrasound imaging and clinical risk scores as defined by National Cholesterol Education Panel (NCEP) III guidelines was conducted. Subjects were recruited from among people scheduled for elective cardiac catheterization by their primary physicians. Our comprehensive regional health service is a not-for-profit system comprised of 50⫹ owned, managed, leased, or networked regional facilities, and also includes one insurance company/managed care organization. Although our delivery of cardiac care is concentrated in La Crosse, Wisconsin, we provide healthcare services in a 19-county region of southwestern Wisconsin, northeastern Iowa, and southeastern Minnesota. Our networked physicians routinely refer patients for diagnostic testing to the main campus. Approximately 800 individuals are scheduled for elective cardiac catheterization per year who meet our study specifications, with approximately 50% having normal coronary arteries on angiography. This provides a large pool for correlative studies. No subject underwent catheterization specifically for this study. Inclusion criteria were set to identify patients at low risk for premature coronary heart disease. Only young to middle-aged patients (men ⱕ55 years and women ⱕ65 years) were eligible. Subjects were excluded if they had any history of coronary heart disease or had been taking a 3-hydroxy-methyl-HmG-CoA reductase inhibitor (statin). Institutional review board approval was obtained and all patients provided informed consent before enrollment in the study. On the day of the angiographic procedure, subjects who agreed to participate completed a risk assessment survey, had fasting blood drawn for laboratory analysis, and underwent bilateral carotid ultrasound.
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Digitized images were transferred onto a digital reading station (Kinet DX; Acuson) for later review. Intima-media thickness (IMT) was defined as the distance from leading edge to leading edge of the intima and media (blood intima interface to the media adventitia interface). Measurements for IMT were obtained along a section of the common carotid artery 1 cm proximal to the bulb. IMT measurement was not obtained at the bulb. Both the near and far walls were equally well visualized. On each wall of both the right and left carotid artery, six measurements were performed and used for calculating the mean IMT. One experienced cardiologist, blinded to each subject’s clinical profile and angiographic data, reviewed all carotid ultrasound studies. In addition to IMT, the cardiologist noted focal plaques. Plaque was defined as distinct, focal areas of intima abnormality that protruded into the lumen. Calcific plaque was defined as an intraluminal density casting an acoustic shadow. For the purpose of this study, criteria for carotid atherosclerosis were met by the presence of plaque of any kind or by a maximal IMT reading of ⱖ1.0 mm. Angiographic Data No coronary angiography was performed specifically for this study. All angiography was performed by standard technique. Severe angiographic disease was defined as stenosis ⱖ50% in any major epicardial coronary artery. Coronary angiograms were graded by visual inspection. Statistical Analysis The data were analyzed with SAS software (SAS Institute, Cary, NC). Continuous variables were expressed as mean ⫾ standard deviation. Categorical variables were expressed as percentages. Accuracy values including sensitivity, specificity, positive predictive value, and negative predictive values were calculated for carotid ultrasound using coronary angiography as the gold standard. The unadjusted odds ratio (OR) as an estimate of relative risk and the 95% confidence intervals (95% CI) were calculated by logistic regression.
Results General Findings
Ultrasound Study All studies were performed using the SonoCT broadband probe, L12-5 interfaced with the HDI 5000 echocardiograph (Philips ATL at Bothel, WA). Two highly experienced echocardiography technicians performed all of the carotid ultrasound studies. Before initiating the study, carotid ultrasound testing was performed on 30 healthy individuals. Agreement between the two technicians for IMT mean measurement within a 0.1-mm difference occurred in 90% of the population. Vessels were imaged in the longitudinal plane, digitized online and recorded onto the hard drive of the echo machine.
A total of 253 subjects were enrolled, and 236 completed all tests. The analyses were computed for the 236 subjects with complete data. Of these, 58% were women (mean age 53 ⫾ 8 years) and 42% were men (mean age 47 ⫾ 6 years). Indications for cardiac catheterization were given by referring physicians and included 139 individuals with any mention of chest pain, of whom 52 had typical and 87 had atypical chest pain. Table 1 displays all indications for cardiac catheterization. The mean total cholesterol, LDL, and HDL for the group as a whole were 195 ⫾ 37 mg/dL, 122 ⫾ 30 mg/dL, and 51 ⫾ 14 mg/dL, respectively. Mean serum triglyceride levels were 147 ⫾ 76 mg/dL.
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Table 1. Indications for cardiac catheterization by referring physicians Indications for cardiac catheterization Symptom Typical chest pain Atypical chest pain Preoperative assessment Shortness of breath Other
No. (%) 52 87 35 19 43
(22%) (37%) (15%) (8%) (18%)
Stress testing results Test result Positive Negative Equivocal None
No. (%) 114 13 35 74
(48%) (6%) (15%) (31%)
Risk Factor Profiles by NCEP III Of the subjects, 43 had coronary heart disease equivalent defined as diabetes or symptomatic peripheral vascular disease per NCEP guidelines. A total of 172 subjects (73%) were stratified as having zero to one risk factor or ⬍10% risk for an event in 10 years, qualifying them as low risk according to the Framingham risk scores. Eighteen subjects (8%) had scores that placed them at a 10-year risk for an event as intermediate (10% to 20%). Only three subjects had risk scores of ⱖ20% for a 10-year event. Thus, including the 43 subjects with coronary heart disease equivalent, a total of 46 subjects met criteria for high risk. For this report, we use the term “high risk” to represent scores ⱖ20% or coronary heart disease equivalent.
Coronary Angiography Of the subjects, 72 (31%) had angiograms that met criteria for severe disease (stenosis ⱖ50%). Significant one-vessel disease was diagnosed in 29 subjects (40%), and 43 had multivessel disease (60%). A total of 43 additional patients were diagnosed as having insignificant coronary stenosis defined as lesion severity of 10% to 49%, or luminal irregularities. Carotid Ultrasound A total of 141 subjects were diagnosed as having carotid atherosclerosis, defined as maximal IMT (IMTmax) ⱖ1.0 mm, or the presence of focal plaque. Among these subjects meeting criteria for carotid atherosclerosis, 76 had IMTmax ⱖ1.0 mm within the main body of the artery. A total of 116 subjects had focal plaques in the main body of the artery, bulb, or proximal branches, with 39 subjects having calcium within the plaque. Only 25subjects met criteria by IMT alone. Thus, the majority of subjects with abnormal
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carotid ultrasound studies had multiple manifestations of atherosclerosis. Association of Carotid Ultrasonography and Coronary Angiography The sensitivity for carotid atherosclerosis in predicting angiographically apparent severe disease was 72%, with specificity of 46%. Negative predictive value was 79% with positive predictive value of 37%. Logistic regression revealed that carotid atherosclerosis was associated with an unadjusted OR of 2.2 (CI ⫽ 1.2 to 4.0; P ⫽ 0.010) in predicting coronary artery disease. Accuracy Values of Carotid Ultrasound Stratified per Subgroup We analyzed the data according to the results of the stress test. Among the 236 subjects, 74 individuals did not have a stress test performed before cardiac catheterization, 114 subjects had positive stress test results, and 48 subjects had negative or equivocal stress test results. The analysis limited to the subgroup with positive stress test results demonstrated that only 41 subjects (36%) had severe coronary artery disease, of whom 27 had a diagnosis of noncoronary atherosclerosis by ultrasonography. In this group, the sensitivity, specificity, positive, and negative predictive values were 66%, 41%, 39%, and 68%, respectively. Among the subgroup with negative or equivocal stress test results, as well as those for whom no stress test results were available, the corresponding values of sensitivity, specificity, positive and negative predictive values were 81%, 50%, 35%, and 88%, respectively. Table 2 shows coronary angiogram and carotid ultrasound data stratified by stress test results. Similarly, the results were also analyzed for Framingham risk groups. Because there were only 18 subjects stratified as intermediate risk, we limited the analysis to the high- and low-risk groups. Among the 46 subjects qualifying for coronary heart disease equivalent or high risk, only 25 had abnormal coronary angiograms (54%). In the low-risk group, 36 subjects also had severe coronary artery disease. Carotid atherosclerosis was present in 67% of subjects with severe coronary artery disease in the low-risk group. Among subjects with high-risk scores, carotid atherosclerosis was present in 80% of those with severe coronary artery disease. The results of coronary angiogram and carotid ultrasound data stratified by Framingham scores are detailed in Table 3.
Discussion A difficult task in prevention remains the inability to accurately predict an individual’s actual risk for an imminent event compared with relative risk. In our experience, we have found that many young to middle-aged adults presenting with their first myocardial infarction were risk
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Table 2. Coronary angiogram and carotid ultrasound results stratified according to stress test results (ⴙ) Stress test
(⫹) Carotid ultrasound (⫺) Carotid ultrasound Sensitivity Specificity Positive predictive value Negative predictive value
(ⴚ) Stress test
No stress test
(ⴙ) Cath
(ⴚ) Cath
(ⴙ) Cath
(ⴚ) Cath
(ⴙ) Cath
(ⴚ) Cath
27 14
43 30
5 3
19 21
20 3
27 24
66% 41% 39% 68%
63% 53% 21% 88%
87% 47% 43% 89%
Cath ⫽ catheterization. ⫺ ⫽ negative results throughout.
categorized as low risk according to the NCEP III guidelines.11–13 It is well known that currently available tools and risk predictor models do not accurately determine the true size of the population, or the actual individual, who eventually presents with cardiovascular events.14 –18 This problem, termed a “detection gap,” is important for both research and clinical medicine,19 as highlighted in the 34th Bethesda Conference.10 In fact, a paper from the Centers of Disease Control found that among individuals the United States population without coronary heart disease, only 3% risk stratify as high risk, whereas the majority (82%) qualify as low risk.20 The difficulty in achieving an accurate noninvasive diagnosis may explain in part the growth that has been seen of invasive cardiac catheterizations and expensive new technologies. A recent study demonstrated that despite increasing reliance on high-cost technology, there was a lack of any strong association between costs and patient outcomes or quality of care.21 Another study, by Lucas et al,22 reached similar conclusions, finding that increased cardiac testing and treatment were not explained by disease prevalence. This reliance on high technology and invasive procedures has major impact on cost of care. There is continued concern regarding the ever-increasing proportion of health care costs on the national budget. A recent report from the Centers of Medicare and Medicaid Services projects that over the next decade, accounting for population aging and changes in medical technology and use, national health expenditures are expected to double.
As a result, 20% of the gross domestic product will be accounted for by health care costs.23 This highlights the importance of developing relatively inexpensive strategies that could be used in further clarifying risks in the many individuals who undergo invasive evaluation who do not qualify as high risk. In this study, only 36% of patients with abnormal stress tests actually had severe coronary artery disease. When combined with the information obtained by ultrasonography, we found that an individual with abnormal stress test results and a diagnosis of noncoronary atherosclerosis had a greater chance of having severe coronary artery disease (66%). Similarly, as shown in Table 2, some individuals with negative stress test results did have severe coronary artery disease, of whom 63% had noncoronary atherosclerosis. In this group, a negative ultrasound– based evidence for noncoronary atherosclerosis had 88% negative predictive value. The information was similar in the subgroup who did not have stress tests performed, with a negative predictive value of 89% and a sensitivity of 87%. The carotid ultrasound results stratified per clinical risk group demonstrated that among individuals stratified as high risk, approximately half had severe coronary artery disease. Although the likelihood of having severe coronary artery disease was greater for the high-risk group compared with the low-risk group (54% v 21%), the absolute number of subjects having severe coronary artery disease was higher in the low-risk group. In the high-risk group, not surprisingly, the presence of noncoronary atheroscle-
Table 3. Results of carotid ultrasound and coronary angiogram stratified according to clinical risk profile All subjects
(⫹) Carotid ultrasound (⫺) Carotid ultrasound Sensitivity Specificity Positive predictive value Negative predictive value Cath ⫽ catheterization.
Low risk
High risk
(ⴙ) Cath
(ⴚ) Cath
(ⴙ) Cath
(ⴚ) Cath
(ⴙ) Cath
(ⴚ) Cath
52 20
89 75
24 12
74 62
20 5
12 9
72% 46% 37% 79%
67% 46% 25% 84%
80% 43% 63% 64%
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rosis was predictive of severe coronary artery disease (80%). In the low-risk group, 67% of the individuals who had severe coronary artery disease were identified by ultrasound, and indeed the negative predictive value for this group was comparable to that seen in the negative stress test group (84%). Identifying the individual at true risk for imminent heart attack is an important step in coronary heart disease prevention. Currently, many individuals undergo expensive new tests and invasive procedures for reasons including physician uneasiness and patient expectations. Our study demonstrates that the diagnosis of noncoronary atherosclerosis may be an important adjunct to clinical risk stratification or stress testing. Carotid ultrasound has been shown to detect early atherosclerosis. A recent report demonstrated that in young individuals with metabolic syndrome, subclinical atherosclerosis is already present and can be detected by carotid ultrasound.24 Other studies have correlated abnormal IMT with the presence and extent of cardiovascular risk factors25 and for predicting future events.26 –28 In the current study, identification of noncoronary atherosclerosis was associated with coronary angiographic disease. In young to middle-aged subjects undergoing evaluation for coronary artery disease, noncoronary atherosclerosis provided useful, supplemental information to stress testing and clinical risk stratification. Study Limitations Although the sample size is not necessarily small and included a high proportion of women, the investigators recognize that this is a single-center experience, and a larger, more inclusive study would be very helpful. The absence of minority group participation is regrettable, but it is a reflection of our geographical catchment area in which the population is predominantly of white ethnicity. Because we studied subjects referred for elective coronary catheterization by their respective physicians, the population may not be considered to be truly at low risk. It would have been ideal to study healthy volunteers from the general population, but it would be difficult (if not impractical or unethical) to subject such individuals to invasive cardiac catheterization. We remind the reader that clinical risk scores are not synonymous with coronary angiographic findings. Framingham risk appraisal provides probability estimates of risk for major coronary heart disease events over time. By contrast, coronary angiography provides a one-time snapshot of coronary disease and its severity. Although the disease is ultimately responsible for events over time, angiographic data and Framingham risk scores may not provide the same information at any one time. In conclusion, this study demonstrates that by combining carotid ultrasound imaging for noncoronary atherosclerosis with clinical risk stratification per the NCEP III guidelines, many more individuals with coronary artery disease can be identified. Individuals without noncoronary atherosclerosis stratified as low risk or having negative
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stress test results have excellent chances of not having severe coronary artery disease. Identification of noncoronary atherosclerosis by carotid ultrasound may serve as a good adjunct to the guidelines to improve risk stratification.
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