Glenn Gandelman, MD, MPH; Monty M. Bodenheimer, MD

Heart Dis 5(5):335-344, 2003. © 2003 Lippincott Williams & Wilkins

Posted 01/26/2004

Abstract

Recent studies indicate an expansion of the population eligible for primary prevention of coronary artery disease with lipid-lowering therapy. This change has led to the unnecessary treatment of many individuals and an overall decreased effectiveness of medication with potentially significant side effects. If instead, the asymptomatic population is screened for the presence of early coronary artery disease (CAD), lipid lowering can be targeted to those who can truly benefit. The prevalence of asymptomatic CAD in men older than 50 years of age approaches 20% and arteriography is currently the best available test to identify these men. The approximate complication rate of arteriography in such a population (1 or 2 per 10,000) approaches that of other screening tests. Although insufficient data exists for formal cost analysis, approximations indicate significant savings for arteriographically targeted treatment of at-risk asymptomatic individuals. The authors show that coronary arteriography is a potentially safe and cost-effective method of screening an asymptomatic adult population for presence of early CAD, allowing for the targeting of lipid lowering to those who can benefit most from this therapy.

Introduction

Nearly 30 years ago, Dr. Sones^[1] realized the potential use of coronary arteriography in screening asymptomatic individuals to optimize treatment. Without the anatomic information offered by arteriography, primary prevention of coronary artery disease (CAD) has focused on pharmacologic therapy in an ever-expanding population despite significant debate regarding its value.^[2-5] The National Health and Nutrition Evaluation Survey (NHANES) III indicates that between 5.5 and 21.1 million asymptomatic individuals in the United States are eligible for lipid-lowering medication.^[2,6] Even the more stringent European guidelines for drug eligibility indicate that over 80% of the asymptomatic low-to-moderate risk Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) population stands to benefit from statins.^[7] Such expansion of the drug-eligible population has resulted in an overall decreased effectiveness of lipid-lowering therapy. The West of Scotland Coronary Prevention Study (WOSCOPS) indicated that only 1 in 40 high-risk asymptomatic men benefit from lipid-lowering therapy, while even fewer (1 in 80) low-to moderate-risk individuals benefited in the AFCAPS/TexCAPS group.^[5,8,9] We propose that such poor outcomes are due to the unnecessary treatment of many individuals. Assuming that CAD is a strong independent predictor of morbidity and mortality, the targeting of pharmacologic therapy to those asymptomatic adults with significant CAD could improve its effectiveness.

Unfortunately, current screening for asymptomatic CAD is limited by a lack of both sensitivity and specificity. Although noninvasive tests adequately detect the physiologic consequences of obstructive coronary artery disease, they usually fail to identify earlier anatomic changes and are thus not recommended for asymptomatic individuals.^[10-12] Newer, noninvasive anatomic imaging of the coronary arteries remains controversial. Independent analyses of the role of electron beam tomography (EBT) have not recommended its use for screening in the asymptomatic population.^[12] A recent large population-based study of asymptomatic adults evaluated by EBT supports this negative recommendation. They found that a coronary artery calcium score indicating high risk for obstructive CAD is very rare in men younger than 60 years old and almost nonexistent in women younger than 65 years.^[13] Yet, other data indicate that about 15% would be expected to have significant CAD (discussed later). Noninvasive screening with contrast-enhanced computed axial tomography scanning and magnetic resonance imaging remain limited to the proximal coronary tree and unproven in their ability to detect preclinical disease.^[14] Neither EBT nor computed axial tomography modalities are recommended by the American College of Cardiology/American Heart Association for use in asymptomatic individuals. In summary, significantly more data are needed before these modalities are ready for screening use.

At present, coronary arteriography is the only technique able to assess the entire coronary anatomy with both high sensitivity and specificity. However, the routine use of coronary arteriography without previous noninvasive testing is currently not advocated because of perceived high risk and relatively high cost.^[15] This analysis will present coronary arteriography as an accurate, safe, and cost-effective method to detect CAD in the asymptomatic population. While limitations in data make any formal calculation of cost impossible, we will show that focusing aggressive treatment on those patients with arteriographically proven preclinical disease has the potential to improve clinical outcomes and reduce costs.

In order for cardiac catheterization to be a cost-effective screening modality, the prevalence of asymptomatic CAD must be sufficiently high such that screening of relatively few people would identify a significant number of individuals with treatable CAD. Unfortunately, there have been no prospective studies randomizing asymptomatic individuals to have coronary arteriography. Estimates of prevalence therefore depend on autopsy data of people who died of noncardiac causes and from patients undergoing cardiac catheterization despite having no or negligible symptoms suggesting CAD.

Diamond and Forrester reviewed results of nearly 24,000 autopsies of individuals who died of noncoronary causes.^[16] Although the definition of CAD varied widely in these studies, the average prevalence of CAD in this population was 4.5%. Men in their 50s had a prevalence of 10%, contrasted with a prevalence of 3% in women in the same age group. Additional autopsy studies (Table 1) of patients who were asymptomatic in life indicate single-vessel narrowing of over 50% in approximately 10% to 15% of patients.^[17,18] Recent pathologic studies have examined the prevalence of arterial lesions according to age. In the Pathologic Determinants of Atherosclerosis in Youth (PDAY) study, raised plaque was seen in as many as 50% and complicated lesions in 1% of men in their 30s with noncardiac cause of death.^[19] In the Bogalusa study the percent of the intimal surface involved with fibrous plaque ranged from less than 1% to 7%, depending on patients' risk factors.^[20]

Coronary arteriographic data from the Coronary Artery Surgery Study show that in men aged 40 to 49 years who underwent cardiac catheterization for nonspecific chest pain and no history of myocardial infarction or unstable angina, 61% had normal coronaries and 20% had stenosis of <50%. In women, the rates were 81% and 13%, respectively.^[21] A recent study examined the role of coronary arteriography in patients being evaluated for acute coronary syndromes with negative electrocardiograms and cardiac enzymes.^[22] Over 80% of these patients had normal coronary arteries. Arteriographic studies in patients who are asymptomatic are limited (Table 2). Among patients with noncoronary cardiac conditions who underwent coronary arteriography as part of their evaluation 5% to 15% had coronary stenosis of 50% or more.^[23-25] Similarly, in small series of patients studied for noncardiac reasons, the prevalence was 10% to 15%.^[26,27]

These studies suggest that the prevalence of CAD in asymptomatic 50-year-old men is between 15% and 20%; the few studies including women suggest a prevalence of about 5%. Although autopsy data suggest a much higher prevalence, the definitions used are different and the implications for prognosis may not be the same. Screening with coronary arteriography can thus be expected to detect a significant number of patients with CAD while excluding most of asymptomatic individuals from pharmacologic treatment.

If coronary arteriography is to be considered as a screening tool for asymptomatic patients, the arteriographic results must correlate strongly with both the actual presence of disease and with future morbidity and mortality. In other words, a finding of normal coronary arteries must offer a significant survival advantage irrespective of other variables and risk factors. Support for arteriographic validity comes from both pathologic and intravascular ultrasound (IVUS) studies and morbidity and mortality data.

Pathological Correlation

Direct correlation of coronary arteriography with pathology is limited to patients with CAD who underwent in vivo coronary arteriography and postmortem examinations. These studies (Table 3) generally show good agreement between arteriographic and pathologic diagnosis, especially in coronaries with lesser degrees of luminal narrowing.^[28-32] However, it is difficult to extrapolate from these data to the pathology in patients with arteriographically normal vessels.

Intravascular Ultrasound

Coronary arteriography, though still the most sensitive and specific test used to diagnose CAD, can only define the inner arterial contour. Such anatomic descriptions may not accurately reflect true vascular disease. Additionally, a reading of normal on coronary arteriography may be misleading because defining a normal range of lumen size for the coronary artery has proven difficult.^[33] Of even greater concern is the phenomenon of compensatory coronary artery dilatation. The resulting preservation of lumen size despite vessel-wall damage can result in failure to identify significant plaque development.^[34] Thus, an essential question is the extent to which a visually normal coronary arteriogram actually defines the absence of CAD.

IVUS provides cross-sectional information on the coronary artery and thus can aide in determining the true anatomic meaning of an arteriographically normal coronary artery lumen. IVUS was used in 1 series to study the transplanted hearts of 25 patients with an average age of 28 years.^[35] Five patients had localized eccentric plaque despite arteriographically normal coronaries. Another IVUS study of 55 patients with suspected CAD (average age 54 years), with arteriographically normal coronary artery anatomy, found 25 patients with localized plaque.^[36] Erbel et al correlated IVUS findings with the standard pathologic classification of lesions in 49 patients undergoing arteriography for chest pain and found to have normal or near normal coronary arteries.^[37] Of the 822 segments studied, higher grades of lesion including atheroma and fibroatheroma were present in 38%. Of note, in patients aged 41 to 50 years, less than 20% of sites showed such lesions. Unfortunately, the data do not allow for a determination of what percentage of patients this represents. Calcium deposits were rare, consistent with the clinical study by Hoff et al^[13]

In summary, both pathologic and IVUS data indicate that a significant percentage of patients with arteriographically normal arteries have disease. However, the prognostic significance of IVUS-detected disease is unknown.^[38] In contrast, as indicated below, a normal coronary arteriogram in a 50-year-old man confers an excellent prognosis with low morbidity and mortality.

Prognostic Value of a Normal Finding of Coronary Arteriography

The long-term prognostic significance of a normal coronary arteriography finding has been studied extensively (Table 4).^[39-44] Most of patients included in these studies were referred for a chest pain syndrome and risk factors for CAD were common. Both Kemp et al and Papanicolaou et al reported that over 50% of the patients were smokers and between one third to one half had hypertension. No data on lipid levels were provided. Lichtlen et al found that over 40% of their patients had at least 2 risk factors. Irrespective of the presentation and risk factor profile in these studies, arteriographically normal coronary arteries predicted a coronary cause of death from 0 to 0.18% per year and nonfatal myocardial infarction (MI) rate of 0.01 to 0.24% per year.

Despite better average risk-factor profiles, patients in the placebo groups of AFCAPS/TexCAPS and WOSCPOS had significantly higher coronary event rates. These asymptomatic individuals approximate the general population. Among the AFCAPS/TexCAPS patients, 12% smoked and 22% had hypertension, whereas in WOSCOPS all had hyperlipidemia, 44% smoked, and 16% had hypertension. Of note, diabetes was uncommon in both studies. The coronary event rates in these 2 groups were 0.6% and 1.9% per year, respectively.^[5,9] Additionally, analysis of Framingham data indicates an expected annual rate of fatal and nonfatal MI of about 1% in the general population.^[45] Thus, as Dr. Sones predicted in 1972, arteriographically normal coronary anatomy or minimal luminal disease offers a significant survival advantage despite similar or worse risk-factor profiles.^[1]

The annual mortality and nonfatal MI rates among patients with normal and minimally diseased coronaries appear to remain constant throughout study duration.^[39-41,43] Survival curves remain flat, with the first-year rates maintained through the final study year. Had progression of disease occurred, the incidence would have increased and survival curves would indicate an increased rate of events with time. As expected, in patients with significant CAD, progression does occur, as does a progressive decline in survival curves.^[39,40] Kemp et al attempted to identify causes for the rare progression in patients with normal and near-normal coronary arteries.^[42] Smokers had a significantly sharper decline in survival at the end of a 7-year interval compared with those who had never smoked. Studies using serial arteriography are more limited and generally performed for a change in symptoms, with average interarteriography time of 33 to 58 months. Patients with initially normal vessels rarely showed progression.^[46-51] Unfortunately, few studies with longer intervals are available. These studies and the data presented in Table 4 suggest that patients with normal and minimally diseased coronary vessels are unlikely to have significant disease progression for a period of approximately 10 years.

The definition of a normal arteriogram remains qualitative despite available quantitative techniques,^[33] and the potential for different definitions of normal thus exists. However, it is striking that in all the papers quoted the definition of normal is given as a fact. Also, the prognosis associated with a normal finding of coronary arteriography is excellent and remarkably similar despite the large number of centers reporting their data. Thus, we would submit that similar to Justice Stewart's famous quote regarding pornography, the arteriographer may correctly be defining normal as, I know it when I see it.^[52]

Recent data^[53,54] seemingly contradict the above conclusions regarding progression in normal or near normal vessels. Such retrospective arteriographic studies of patients with an acute myocardial infarction indicate that progression to acute occlusive disease often occurs at sites with minimal luminal disease on an earlier arteriogram. However, on closer analysis, nearly all patients who developed a coronary event in these series had at least 1 other coronary artery segment with a greater than 50% stenosis. Thus, although coronary events do occur in areas with arteriographically insignificant disease, the presence of significant lesions in other portions of the coronary tree in most of these patients would have clearly identified them as having CAD and therefore requiring treatment.

An often-cited reason against the use of coronary arteriography in asymptomatic patients is its significant risk. Because no study has ever randomized asymptomatic patients to undergo coronary arteriography, we rely on studies of symptomatic individuals with normal coronary anatomy to approximate the complication rate. It is even more difficult to extrapolate risk in individuals without comorbid conditions.

As Table 5 indicates, mortality ranges between 0 to 2 per 10,000 in those with normal coronary anatomy who undergo diagnostic cardiac catheterization.^[55-57] The nonfatal MI rate in this group ranges between 0 to 2 per 10,000 and the rate of embolic phenomena (usually cerebral vascular accidents) is approximately 7 per 10,000. Among those with minimal coronary disease (usually no more than 50% narrowing in any vessel) the mortality and morbidity are similar to those with normal coronary anatomy, whereas both mortality and nonfatal MI are significantly higher in those with greater CAD.

Any screening test must have a complication rate sufficiently low such that the risk from not identifying the disease outweighs the risk of the diagnostic test. For example, colonoscopy is currently being considered the optimal method to screen patients for colon cancer^[58,59] despite a procedure-related mortality of approximately 1 to 3 per 10,000 and significant morbidity in 1 to 3 per 1000,^[60] which is similar to that for cardiac catheterization in patients with normal coronary anatomy. Yet, CAD causes many more deaths and greater morbidity than colorectal cancer. In a large cohort of 350,000 men screened in the Multiple Risk Factor Intervention Trial study and followed up for 12 years, mortality from coronary heart disease was 4 times greater than from colon cancer.^[61] Thus, arguably, coronary arteriography to detect CAD in the asymptomatic population may be an acceptable diagnostic test despite the finite rate of complications.

Determining what cost is acceptable for managing any particular medical condition is a societal decision. The number is subject to the willingness of society to add resources via increased taxes, higher premiums, or diverting resources to a particular area of health care. Models used to determine the costs of diagnosing CAD in symptomatic patients suggest that noninvasive testing is optimal in patients with an intermediate likelihood of disease whereas direct angiography is appropriate when disease is likely.^[62,63] This conclusion is supported by Shaw et al in an observational study of over 11,000 symptomatic patients with about a 50% prevalence of disease.^[64] The comparable cost of these 2 strategies in a population with a low prevalence of disease in asymptomatic individuals is unknown. It is estimated that noninvasive testing can detect about 70% to 80% of patients with physiologically significant disease and is generally ineffective in detecting nonobstructive disease. Hunink et al analyzed the cost of testing in relation to capability of the technology to detect CAD and found that the cost-effectiveness depended to a large degree on the sensitivity and specificity of the test..^[65] For example, if one assumes that society is willing to pay $50,000 per quality-adjusted life year, a test costing $500 would need a sensitivity and specificity of more than 95%. No noninvasive test, including EBT or magnetic resonance imaging, currently meets these standards or is projected to meet these standards in the near future. Indeed, only coronary arteriography can attain this level of sensitivity and specificity.

Any analysis of costs must further consider that CAD is a chronic disease with no cure. Thus, while both medical and revascularization therapies improve morbidity and mortality, the disease progresses. The overall cost of treating CAD may thus actually increase if the time course of treatment is extended by earlier diagnosis. However, accurately determining the status of the coronary arteries should result in savings accrued by avoiding unnecessary tests and therapy. Indeed, Keavney et al showed that in symptomatic patients found to have normal coronary arteries the costs associated with their care decreased to the point that the cost of angiography was recouped within 18 months.^[66]

A recent report based on the AFCAPS/TexCAPS study is helpful in formulating a cost analysis.^[67] Although a lower event rate in the statin-treated group resulted in an average saving of $523 compared with the placebo group, this was completely offset with an actual excess cost in the statin-treated group of $4416 over the same period because of the cost of the drug and related testing. This is a direct result of the need to treat large numbers of individuals who will not benefit to aid the few who will benefit.

One approach to cost analysis is to determine the cost of treating all asymptomatic individuals considered at risk^[6,7,68] compared with costs of screening coronary arteriography and treatment only of those individuals with significant luminal disease. The 3 major variables in this approach are prevalence of CAD, cost of coronary arteriography, and cost of treatment with a statin. Additional cost results from uncovering and treating coronary artery disease, which would otherwise be unknown. However, this ignores the cost of not providing care to these individuals at an early stage. If, on the other hand, society decides they do not want to invest in treating CAD, than clearly all screening is moot.

Published data provide a guide to the costs of cardiac catheterization^[69] and treatment with statins.^[67] Cohen et al examined the costs related to coronary arteriography from 70 different institutions involving over 44,000 patients.^[69] They found that the direct variable costs to the facility averaged $306 ± 146, which included the costs associated with complications. Even after adding professional costs estimated at $300, based on Medicare reimbursement, the direct cost is below $1000. Because, as already discussed, the actual prevalence of CAD is unknown, one can estimate the effect on cost by varying the prevalence from 10% to 20%. As seen in Figure 1, even if the cost of diagnostic catheterization is doubled to $2000 and the cost of statin discounted to $3000 over 5 years with a prevalence of 20%, arteriography and targeted treatment over 5 years offers a significant cost saving. If, as discussed previously, the finding of a normal coronary arteriogram is valid for at least 10 years, the cost saving will be even larger.

Figure 1. Cost analysis of 1000 patients for 5 years.

The above analysis shows that with relatively few assumptions, a strategy of screening for CAD with coronary arteriography can result in substantial savings. A recent study evaluated return emergency department visits in patients who presented with chest pain but ruled-out for acute MI and had normal coronary artery anatomy during diagnostic arteriography.^[22] These individuals had fewer emergency department visits (10% versus 30%, P = 0.0008) and hospital admission (3% versus 16%, P = 0.003) compared with patients with negative/nondiagnostic exercise treadmill testing. Added savings from elimination of routine, often annual cardiac testing including ECGs, stress tests and, more recently, EBT, despite guidelines advising strongly against this approach, have not been included.

A last caveat regarding cost. When projecting over 10 years, it is difficult if not impossible to predict future costs of treatments. One need only think back less than 10 years ago when the use of statins in almost any setting was still arguable and only came into vogue as secondary prevention with the 4S study published in 1994.^[70] Such unforeseen additional therapies could undoubtedly increase treatment costs. This being said, that does not obviate the need to act on available data while remaining cognizant of changes in approach with advances in diagnosis and treatment.

A policy of elective screening for CAD using coronary arteriography would effectively divide patients into those identified as normal and those with varying degrees of coronary artery narrowing (Fig. 2). As already discussed, current estimates indicate that about 15% of asymptomatic 50-year-old men have arteriographic CAD. In those without luminal disease, risk-factor modification (eg, smoking cessation, control of hypertension) is clearly appropriate. However, treatment of hypercholesterolemia, particularly with drugs, is unlikely to yield substantial clinical benefit in these individuals.^[2,4,5]

Figure 2. Treatment algorithm based on results of coronary arteriography in asymptomatic patients.

A more complex issue is the need and timing of repeat coronary arteriography in those with arteriographically normal coronary anatomy. As already noted, prognostic studies suggest that those with normal coronaries are highly unlikely to show new lesions within a 10-year interval. Specific subgroups, dependent on age, timing of angiography, and lack of comorbid conditions, may conceivably not require any future diagnostic testing or treatment. However, this is an area of significant uncertainty and in need of study.

In patients found to have asymptomatic coronary artery disease, there is little doubt that aggressive treatment of high cholesterol in addition to treatment of other risk factors is warranted. Recent studies document the beneficial effect of risk factor modification and lower LDL and total cholesterol levels in those with angiographically identified CAD.^[9,71-75] It is thus reasonable to assume that the observed decreases in morbidity and mortality in recent large lipid-lowering primary prevention studies occur primarily if not completely in patients with arteriographically detectable CAD.^[5,8,9]

In asymptomatic individuals found to have obstructive disease, the appropriate role of medical therapy and/or revascularization remains a source of controversy.^[10] In patients with symptoms and 1 or 2 vessel disease including a lesion in the proximal left anterior descending artery, a recent review of randomized studies suggests that medical therapy is equivalent to revascularization with regard to the endpoints of death and myocardial infarction although symptoms are reduced with revascularization.^[76] Management of the small percentage of asymptomatic patients found to have 3-vessel or left main coronary artery disease is unclear. Extrapolating from data obtained in patients with symptoms is difficult. Upcoming developments such as drug eluting stents could further complicate the question. It is conceivable that this group may very well benefit from revascularization combined with aggressive medical management. However, this is an area where a randomized study will be needed to determine the optimal approach.

The ability to modify the course of CAD has raced ahead of our ability to detect its presence. Treating everyone at risk would subject over 50% of the adult population to medication with the associated significant costs and potentially unknown complications, while achieving a relatively small benefit. While coronary arteriography is a more aggressive approach, it does identify the truly high-risk preclinical patient with CAD and thus, as shown, may actually lower overall cost. Even more importantly, from the patients' standpoint, it directs treatment to those who will benefit. At least until other techniques reach the stage where they can provide coronary anatomic data in sufficient detail to supplant coronary arteriography, it is time to reconsider our approach to screening for CAD. At a minimum, a study to determine the true prevalence in the asymptomatic population would be of immense value in guiding any approach to treatment and prevention of coronary events.

Although Dr. Sones's forecasted use of coronary arteriography, as a screening tool in asymptomatic patients, has not yet come true, the lack of human and physical resources that stood in the way has improved. Nevertheless, systems to deal with the large incremental volume of procedures would be needed. In our view, the time has arrived to test Dr. Sones's hypothesis.^[1] The favorable analysis of prevalence and cost data outlined in this study strongly suggest the necessity for a prospective trial of screening coronary arteriography in the asymptomatic population.

1. Sones FM Jr. Indications and value of coronary arteriography. Circulation. 1972;46:1155-1160.
2. Jacobson TA, Griffith GG, Varas C, Gause D, Sung JCY, Ballantyne CM. Impact of evidence-based clinical judgment on the number of American adults requiring lipid-lowering therapy based on updated NHANES III Data. National Health and Nutrition Examination Survey. Arch Intern Med. 2000;160:1361-1369.
3. LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA. 1999;282:2340-2346.
4. Pignone M, Phillips C, Mulrow C. Use of lipid lowering drugs for primary prevention of coronary heart disease: meta-analysis of randomized trials. BMJ. 2000;321:983-986.
5. Kumana CR, Cheung BM, Lauder IJ. Gauging the impact of statins using number needed to treat. JAMA. 1999;282:1899-1901.
6. Gotto AM Jr. Lipid management in patients at moderate risk for coronary heart disease: insights from the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Am J Med. 1999;107(2A):36S-39S.
7. Gotto AM Jr, Ehitney E, Stein EA, et al. Application of the National Cholesterol education Program and joint European treatment criteria and clinical benefit in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Eur Heart J. 2000;21:1627-1633.
8. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279:1615-1622.
9. Shepherd J, Bobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333:1301-1307.
10. Gibbons RJ, Chaterjee K, Daley J, et al. ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina: executive summary and recommendations. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients With Chronic Stable Angina). Circulation. 1999;99:2829-2848.
11. Pitt B, Rubenfire M. Risk stratification for the detection of preclinical coronary artery disease. Circulation. 1999;99:2610-2612.
12. Shaw LJ, O'Rourke RA. The challenge of improving risk assessment in asymptomatic individuals: the additive prognostic value of electron beam tomography? J Am Coll Cardiol. 2000;36:1261-1264.
13. Hoff JA, Chomka EV, Krainik AJ, Daviglus M, Rich S, Kondos GT. Age and gender distributions of coronary artery disease detected by electron beam tomography in 35,246 adults. Am J Cardiol. 2001;87:1335-1339.
14. Smith Jr SC, Greenland P, Grundy SM. AHA Conference Proceedings. Prevention conference V. Beyond secondary prevention: identifying the high-risk patient for primary prevention. Executive summary. American Heart Association. Circulation. 2000;101:111-116.
15. Scanlon PJ, Faxon DP, Audet AM, et al. ACC/AHA guidelines for coronary angiography: executive summary and recommendations. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Coronary Angiography) developed in collaboration with the Society for Cardiac Angiography and Interventions. Circulation. 1999;99:2345-2357.
16. 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.
17. Enos WF, Holmes RH, Beyer J. Landmark article, July 18, 1953: Coronary disease among United States soldiers killed in action in Korea. Preliminary report. JAMA. 1986;256:2859-2862.
18. Davies MJ. Anatomic features in victims of sudden death. Coronary artery pathology. Circulation. 1992.;85(suppl 1):I19-I24.
19. Strong JP, Malcom GT, McMahan CA, Tracy RE, Newman WP III, Herderick, et al. Prevalence and extent of atherosclerosis in adolescents and young adults. JAMA. 1999;281:727-735.
20. Berenson GS, Srinivasan SR, Bao W, Newman WP III, Tracy RE, Wattigney WA. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. N Engl J Med. 1998;338:1650-1656.
21. Chaitman BR, Bourassa MG, Davis K, et al. Angiographic prevalence of high-risk coronary artery disease in patient subsets (CASS). Circulation. 1981;64:360-367.
22. DeFilippi CR, Rosanio S, Tocchi M, et al. Randomized comparison of a strategy of predischarge coronary angiography versus exercise testing in low-risk patients in a chest pain unit: in-hospital and long-term outcomes. J Am Coll Cardiol. 2001;37:2042-2049.
23. Gensini GG, Kelly AE. Incidence and progression of coronary artery disease. An angiographic correlation in 1, 263 patients. Arch Intern Med. 1972;129:814-823.
24. Leung DY, Dawson IG, Thomas JD, Marwick TH. Accuracy and cost-effectiveness of exercise echocardiography for detection of coronary artery disease in patients with mitral valve prolapse. Am Heart J. 1997;134:1052-1057.
25. Enbergs A, Burger R, Reinecke H, Borggrefe M, Breithardt G, Kerber S. Prevalence of coronary artery disease in a general population without suspicion of coronary artery disease: angiographic analysis of subjects aged 40 to 70 years referred for catheter ablation therapy. Eur Heart J. 2000;21:45-52.
26. Carey WD, Dumont JA, Pimentel RR, et al. The prevalence of coronary artery disease in liver transplant candidates over age 50. Transplantation. 1995;59:859-864.
27. Thurnheer R, Muntwyler J, Stammberger U, et al. Coronary artery disease in patients undergoing lung volume reduction surgery for emphysema. Chest. 1997;112:122-128.
28. Arnett EN, Isner JM, Redwood DR, et al. Coronary artery narrowing in coronary heard disease: comparison of cineangiographic and necropsy findings. Ann Intern Med. 1979;91:350-356.
29. Kemp HG Jr, Evans H, Elliott WC, Gorlin R. Diagnostic accuracy of selective coronary cinearteriography. Circulation. 1967;36:526-533.
30. Vlodaver Z, Frech R, Van Tassel RA, Edwards JE. Correlation of antemortem coronary arteriogram and the postmortem specimen. Circulation. 1973;47:162-169.
31. Grondin CM. Dyrda I. Pasternac A. Campeau L, Bourassa MG, Lesperance J. Discrepancies between cineangiographic and postmortem findings in patients with coronary artery disease and recent myocardial revascularization. Circulation. 1974;49:703-708.
32. Hutchins GM, Bulkley BH, Ridolfi RL, Griffith LS, Lohr FT, Piasio MA. Correlation of coronary arteriograms and left ventriculograms with postmortem studies. Circulation. 1977;56:32-37.
33. Johnson MR. A normal coronary artery: what size is it? Circulation. 1992;86:331-333.
34. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med. 1987;316:1371-1375.
35. St. Goar FG, Pinto FJ, Alderman EL, et al. Detection of coronary atherosclerosis in young adult hearts using intravascular ultrasound. Circulation. 1992;86:756-763.
36. Ge J, Erbel R, Gerber T, et al. Intravascular ultrasound imaging of angiographically normal coronary arteries: a prospective study in vivo. Br Heart J. 1994;71:572-578.
37. Erbel R, Ge J, Gorge G, et al. Intravascular ultrasound classification of atherosclerotic lesions according to American Heart Association recommendation. Coron Artery Dis. 1999;10:489-499.
38. Nissen SE, Yock P. Intravascular ultrasound: Novel pathophysiological insights and current clinical applications. Circulation. 2001;103:604-616.
39. Bruschke AV, Proudfit WL, Sones FM. Clinical course of patients with normal and slightly or moderately abnormal coronary arteriograms: a follow-up study on 500 patients. Circulation. 1973;47:936-945.
40. Proudfit WL, Bruschke AVG, Sones FM. Clinical course of patients with normal or slightly or moderately abnormal coronary arteriograms: 10-year follow-up of 521 patients. Circulation. 1980;62:712-717.
41. Proudfit WL, Welch CC, Siqueira C, Morcerf FP, Sheldon WC. Prognosis of 1000 young women studied by coronary angiography. Circulation. 1981;64:1185-1190.
42. Kemp HG Jr, Kronmal RA, Vlietstra RE, Frye RL. Seven year survival of patients with normal or near normal coronary arteriograms: a CASS registry study. J Am Coll Cardiol. 1986;7:479-483.
43. Papanicolaou MN, Califf RM, Hlatky MA, et al. Prognostic implications of angiographically normal and insignificantly narrowed coronary arteries. Am J Cardiol. 1986;58:1181-1187.
44. Lichtlen PR, Bargheer KB, Wenzlaff P. Long-term prognosis of patients with angina-like chest pain and normal coronary findings. J Am Coll Cardiol. 1995;25:1013-1018.
45. Dawber TR. The Framingham Study: The Epidemiology of Atherosclerotic Disease. Cambridge: Harvard University Press; 1980:73,133-135.
46. Gensini GG, Esente P, Kelly A. Natural history of coronary disease in patients with and without coronary bypass graft surgery. Circulation. 1974;50(suppl 2):II98-II102.
47. Bruschke AV, Wijers TS, Kolsters W, Landman J. The anatomic evolution of coronary artery disease demonstrated by arteriography in 256 nonoperated patients. Circulation. 1981;63:527-536.
48. Kimbiris D, Lavine P, Van Den Broek H, Najmi M, Likoff W. Devolutionary pattern of coronary atherosclerosis in patients with angina pectoris. Coronary arteriographic studies. Am J Cardiol. 1974;33:7-10.
49. Rosch J, Antaonovic R, Trenouth RS, Rahimtoola SH, Sim DN, Dotter CT. The natural history of coronary artery stenosis. A longitudinal angiographic assessment. Radiology. 1976;119:513-520.
50. Marchandise B, Bourassa MG, Chaitman BR, Lesperance J. Angiographic evaluation of the natural history of normal coronary arteries and mild coronary atherosclerosis. Circulation. 1978;41:216-220.
51. Cox I, Schwartzman RA, Atienza F, Brown SJ, Kaski JC. Angiographic progression in patients with angina pectoris and normal or near normal coronary angiograms who are restudied due to unstable symptoms. Eur Heart J. 1998;19:1027-1033.
52. Jacobellis v Ohio, 378US 184(1964) USSC.
53. Little WC, Constantinescu M, Applegate RJ, et al. Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild-to-moderate coronary artery disease? Circulation. 1988;78:736-745.
54. Ambrose JA, Tannenbaum MA, Alexopoulos D, et al. Angiographic progression of coronary artery disease and the development of myocardial infarction. J Am Coll Cardiol. 1988;12:56-62.
55. Davis K, Kennedy JW, Kemp HG Jr, Judkins MP, Gosselin AJ, Killip T. Complications of coronary arteriography from the collaborative study of coronary surgery (CASS). Circulation. 1979;59:1105-1112.
56. Kennedy JW. Complications associated with cardiac catheterization and angiography. Cathet Cardiovasc Diagn. 1982;8:5-11.
57. Johnson LW, Lozner EC, Johnson S, et al. Coronary arteriography 1984-1987: a report of the Registry of the Society for Cardiac Angiography and Interventions. Cathet Cardiovasc Diagn. 1989;17:5-10.
58. Sonnenberg A, Delco F, Inadomi JM. Cost-effectiveness of colonoscopy in screening for colorectal cancer. Ann Intern Med. 2000;133:573-584.
59. Lewis JD. Prevention and treatment of colorectal cancer: Pay now or pay later. Ann Intern Med. 2000;133:647-649.
60. Winawer SJ, Fletcher RH, Miller L, et al. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology. 1997;122:594-642.
61. Neaton JD, Blackburn H, Jacobs D, et al. Serum cholesterol level and mortality findings for men screened in the Multiple Risk Factor Intervention Trial. Multiple Risk Factor Intervention Trial Research Group. Arch Intern Med. 1992;152:1490-1500.
62. Kuntz KM, Fleischmann KE, Hunink MG, Douglas PS. Cost-effectiveness of diagnostic strategies for patients with chest pain. Ann Intern Med. 1999;130:709-718.
63. Garber AM, Solomon NA. Cost-effectiveness of alternative test strategies for the diagnosis of coronary artery disease. Ann Intern Med. 1999;130:719-728.
64. Shaw LJ, Hachamovitch R, Berman DS, et al. The economic consequences of available diagnostic and prognostic strategies for the evaluation of stable angina patients: an observational assessment of the value of precatheterization ischemia. Economics of Noninvasive Diagnosis (END) Multicenter Study Group. J Am Coll Cardiol. 1999;33:661-669.
65. Hunink MGM, Kuntz KM, Fleischmann KE, Brady TJ. Noninvasive imaging for the diagnosis of coronary artery disease: focusing the development of new diagnostic technology. Ann Intern Med. 1999;131:673-680.
66. Keavney B, Maider YA, McCance AJ, Skehan JD, Normal coronary angiograms: financial victory from the brink of clinical defeat. Heart. 1996;75:623-625.
67. Gotto JR AM, Boccuzzi SJ, Cook JR, et al. Effect of lovastatin on cardiovascular resource utilization and costs in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Am J Cardiol. 2000;86:1176-1181.
68. Jacobson TA. The lower the better in hypercholesterolemia therapy: a reliable clinical guideline? Ann Intern Med. 2000;133:549-554.
69. Cohen DJ, Becker ER, Culler SD, et al. Impact of patient characteristics, complications, and facility volume on the costs and time of cardiac catheterization and coronary angioplasty in 70 catheterization laboratories. Am J Cardiol. 2000;86:595-601.
70. Anonymous. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-1389.
71. Gould KL. Coronary arteriography and lipid lowering: limitations, new concepts, and new paradigms in cardiovascular medicine. Am J Cardiol. 82:12M-21M.
72. Brown GB, Zhao XQ, Sacco DE, Albers JJ. Atherosclerosis regression, plaque disruption, and cardiovascular events: a rational for lipid lowering in coronary artery disease. Annu Rev Med. 1993;44:365-376.
73. Byrington RP, Jukema JW, Salonen JT, et al. Reduction in cardiovascular events during pravastatin therapy. Pooled analysis of clinical events of the Pravastatin Atherosclerosis Intervention Program. Circulation. 1995;92:2419-2425.
74. Herd JA, Ballantyne CM, Farmer JA, et al. Effects of fluvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol elevations (Lipoprotein and Coronary Atherosclerosis Study [LCAS]). Am J Cardiol. 1997;80:278-286.
75. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. New Engl J Med. 1996;335:1001-1009.
76. Blumenthal RS, Cohn G, Schulman SP. Medical therapy versus coronary angioplasty in stable coronary artery disease: a critical review of the literature. J Am Coll Cardiol. 2000;36:668-673.