The objective of the Working Group was to provide advice to the National Heart, Lung, and Blood Institute about research that is currently needed to inform clinical guidelines for the use of subclinical cardiovascular disease testing to identify persons at high risk for CVD and to target intervention. The group met in Bethesda for a day and a half, July 13-14, 2004, followed by a one-hour conference call on July 23 among a subset of members and NHLBI staff. A list of the Working Group members is at the end of this report.
A major focus of cardiovascular epidemiology research has been the identification of risk factors, singly or in combination, that enhance the ability to predict clinical cardiovascular disease events. Such research has provided insights into the pathophysiology of the development of cardiovascular disease and, in the case of the ?traditional? risk factors, into direct avenues for prevention through interventions targeted at factors such as smoking, high blood pressure, and high cholesterol. In recent years, a variety of other measures, ranging from serum and urinary markers to direct vascular imaging, have been documented to predict cardiovascular disease events independent of traditional risk factors, although the magnitude of the additional prediction is generally modest. Several of these measures, most recently C-reactive protein and coronary calcium imaging, appear to be becoming become widespread clinical tools. The projections for cardiovascular disease care forecast dramatic increases in utilization and expenditures in the near future. At the same time, there is widespread confusion among clinicians regarding when to use such tests and what the appropriate response to test results is. Much of the testing is performed outside of the clinical setting through direct to consumer marketing. The fact that the health consequences and downstream costs of testing and treatment strategies are not known was deemed a major consideration by the Working Group.
The meeting began with an overview of the recommendations that have addressed this issue offered since 2000 by the American Heart Association, the American College of Cardiology, and the US Preventive Health Services Task Force. Several groups have suggested that the group in which testing is most likely to be useful in making treatment decisions is that at ?intermediate? risk, based on the Framingham risk score ? that is, a 10-year risk for coronary heart disease of 6-20%. Data regarding the distributions of these measures in persons at intermediate risk were presented. The possible research questions and designs for a clinical trial were discussed. Information about possible measures, particularly the strength of their associations with cardiovascular disease and how well each met criteria as possible screening tools, was presented. Possible clinical algorithms for screening and treatment, issues regarding the population to be included in a clinical trial, types of outcomes to be measured, and the types of treatments that might be offered to high risk individuals were discussed. Finally, alternate designs for a clinical trial were debated.
Drs. Greenland and Taylor noted that approximately 650,000 persons in the United States have first coronary heart disease events annually, and that 25% of all coronary heart disease patients present with sudden death. Numerous studies have documented the effectiveness of targeting and treating high risk patients. However, a large proportion of cases arise from persons at intermediate risk. The question now is whether risk prediction can be refined and treatment targeted more effectively among those at intermediate risk. One challenge is to identify tests that are powerful enough to discriminate ? particularly beyond our current ability to discriminate ? between persons who will and will not develop CVD.
Drs. Greenland and Taylor reviewed existing guidelines for risk reduction of CHD aimed at those at high and intermediate risk, including the following:
It was also noted that Blue Cross/Blue Shield issued a medical policy in 2000 that did not recommend use of coronary calcium imaging. A group promoting the concept of the ?vulnerable patient? was also acknowledged, but this approach appears to be aimed at extremely high risk patients.
Conclusions from review of these recommendations and discussion were:
Dr. Kronmal reviewed data from the Multi-Ethnic Study of Atherosclerosis (MESA), an ongoing multicenter cohort study examining the relationship of subclinical CVD measures to each other, progression of subclinical CVD, and the relationship of subclinical CVD to clinical CVD. The Framingham risk score was most strongly related to coronary calcium and carotid IMT measures in both men and women, in the whole cohort and in those at intermediate Framingham risk. He also presented data on ankle-brachial index, CRP, and left ventricular mass from MRI.
Dr. Califf noted that the rate of growth of heart disease and expenditures for treatment during the next several decades will be considerable, due to aging in the population. The number of Medicare enrollees is expected to increase from 40 million in 2002 to 77 million in 2030. The Center for Medicare and Medicaid Services (CMS) is beginning to put more emphasis on cost-effectiveness. Without evidence-based guidelines, marketing of subclinical disease testing is untethered, and there is the potential for enormous gaps to be created in utilization: third party payers will not pay for unproven procedures, which will be obtained only by the economically advantaged.
The following hypothesis was submitted as the basis for a clinical trial: Subclinical disease testing will improve patient outcome compared with current standard screening for CAD risk factors. He proposed a design that randomized patients into testing vs. no testing, following a clinical screen. Those who tested positive would be further randomized into aggressive vs. conservative care, and the no test group would receive usual care. All groups would be followed for events.
Several issues were discussed:
Outcomes to be considered should include both morbidity and mortality, procedures and interventions, psychological outcomes, including quality of life, costs, and changes in care in both intervention and control groups. It was noted that subclinical disease diagnosis may lead to surgical interventions as well. The issue of outcomes was discussed in more detail by Dr. Criqui (see below).
The consequences of not conducting a trial were considered: This would leave clinicians and patients with no evidence base for making rational decisions regarding newly proposed, and sometimes expensive, methods to identify and treat persons at high risk. The unrestrained growth of imaging services in the community is of considerable concern. If testing is not an effective tool, such clinical testing represents an enormous waste of expenditures. It was generally felt to be unlikely that the imaging industry would fund a diagnostic efficacy trial in this arena.
Dr. Califf suggested that the potential costs and benefits of screening could be modeled using existing data, an exercise that may be very informative although would be far less likely to be accepted by the medical community than actual clinical trial results.
Coronary calcium. Dr. Raggi presented data on the association of coronary calcium, measured by computed tomography, with traditional CVD risk factors, and its incremental value in predicting CVD risk over that of traditional risk factors. Data from the South Bay Heart Watch, a cohort of adults who had at least one risk factor, showed that a score of 300 or over effectively ?moved? some persons at intermediate risk into a high risk category. Data recently published by Shaw et al in 10,377 subjects screened with EBCT showed that coronary artery calcium scores are predictive of all cause mortality and that they provide incremental prognostic information over traditional risk factors. It would be useful to further analyze these and similar data sets to determine the frequency of this occurrence. He recommended employing age-specific cut points to determine high risk. Approximately half of persons at intermediate risk may be expected to have scores of zero. This test is easy and well-tolerated, and readings are highly reproducible. The scanning does involve low-dose radiation, and during the discussion the problem of handling incidental findings, particularly lung nodules, was raised. Coronary calcium is considered a likely candidate as a test to identify those at high risk. During discussion, it was stated that consideration might also be given to including aortic calcium, which has a much higher prevalence. Previous research has shown that aortic calcium on plain abdominal films shows a strong independent association with CVD events.
C-reactive protein. Dr. Wilson reviewed considerations for a new risk factor, including the need for standardized measurement, low variability, low correlation with existing risk factors, observational data that demonstrate a relationship between the risk factor and outcomes, clinical trial data, improvement in overall risk prediction, and measurement costs. Among several markers of inflammation, CRP appears to meet more of these criteria than do other tests, such as fibrinogen. Overall, the association with CVD is modest, however, particularly in relation to other risk factors. The AHA/CDC Panel concluded that CRP is an independent marker of CVD risk and that in persons at intermediate risk (defined as 10-20% over 10 years), hsCRP measurement may help direct further evaluation and primary prevention. The JUPITER Trial is currently examining whether statins are beneficial in persons with low LDL and high CRP. He recommended that CRP not be used as the basis for a new clinical trial.
Microalbuminuria. Dr. Flack presented NHANES data showing that the prevalence of microalbuminuria is higher in women than men, is less than 10% among persons age 20-29 and increases to over 20% in persons aged 80 and older. The prevalence is higher in African Americans and Hispanics than Whites. It is associated with hypertension and diabetes and has been associated with all-cause and CVD mortality, independent of other risk factors. ACE inhibitors can reduce albumin excretion. He recommended that microalbuminuria be measured in a clinical trial but that it not be the basis for randomization to treatment.
Carotid intima-media wall thickness (IMT.) Dr. O?Leary discussed the basis for measurement of carotid IMT and showed the relationship of IMT to CVD. Among persons in the highest quintile of IMT, the age and gender-adjusted 7-year CVD rates in CHS were approximately 25%, compared to approximately 5% in the lowest quintile. IMT can be obtained in virtually all people, it is a continuous variable, and the procedure has no risk. Standardized measurement is difficult, although a technician using a relatively inexpensive machine in a physician?s office can probably categorize patients into low, medium and high. IMT is considered a good candidate for consideration as a test to identify persons at high risk.
Ankle-brachial index (ABI). Dr. Criqui stated that ABI is simple and inexpensive to measure in a reproducible manner. There is no risk to the procedure. The prevalence of an abnormal ABI, defined as <0.9, ranges from 3% among those aged 45-64 to 27% among elderly men and women, in different studies. Overall, the prevalence is likely to be <10% among persons at intermediate risk. Stress testing, such as toe rises, can increase the sensitivity of the test. ABI is strongly predictive of CVD death, and the current NCEP guidelines recommend that a low ABI be treated as a CHD risk equivalent. This would complicate its inclusion as a basis for randomization in a trial, unless a borderline level or a positive exercise test (e.g., toe rises) in persons with normal ABIs was included as a criterion for a positive test.
Functional capacity. Dr. Lauer discussed treadmill stress testing for assessment of functional capacity, which has been shown to discriminate well between persons at high and low risk for all-cause and cardiovascular mortality. Worse functional capacity is correlated with older age, female gender, and obesity, yet independently predicts death independent of the Framingham risk score. Furthermore, functional capacity has been shown to identify those subjects most likely to benefit from aggressive treatments like coronary bypass grafting. Testing must be symptom-limited, and age- and gender-specific cut points for abnormality should be used. One problem is linking an effective intervention with low functional capacity. While persons may improve functional capacity through exercise, this may be difficult to accomplish. Exercise testing was not considered a candidate as a measure to identify high risk patients in this trial. Nonetheless, it may have value as a baseline variable since, as with the case with CABG, it may identify those people most likely to benefit from a screening strategy.
Left ventricular hypertrophy (LVH). Dr. Flack discussed methods for measuring LVH. The electrocardiogram is insensitive and may overestimate the prevalence of LVH in African Americans. Echocardiogram may be difficult to obtain in a large proportion of people, particularly the elderly, and reproducibility is only fair. The prevalence of LVH increases with body mass index and blood pressure and is higher in African Americans than Whites. Prevalence estimates range from 1% of young White adults to 4% of young African American adults (CARDIA) to 28% of the middle-aged ARIC cohort. The relative risk of CVD for LVH in the Framingham Study was approximately 1.5. Magnetic resonance imaging provides much more reproducible measures of LV mass, but the cost is higher and many people cannot tolerate or are excluded from the procedure. A measure of ventricular size may also be made from cardiac CT scans. LVH was not considered a candidate test to identify high risk patients in this trial but should be considered as a possible effect modifier of intervention.
Other measures. Dr. Herrington discussed the potential for genetic variants or genetic or protein profiles to be used to identify high risk persons or to identify treatment responses. Individual variants have generally been found to have small effects, but multiple variants in combination (genomics) may have large effects. The costs of performing genetic scans and proteomics are currently high but are declining. Vascular MRI, SPEC imaging, flow-mediated vasodilation, arterial stiffness, and CT angiography may provide better opportunities for prediction in the future, but currently there is a lack of data on predictive ability, high costs, unknown test characteristics, and limited standardization.
During discussions, mild renal failure was noted to carry strong independent risk for CVD and may be synergistic with other risk factors. Cystatin C appears to be a promising risk factor. Another point o f discussion was the ?street credibility? of the chosen test ? that is, clinicians are more aware of and likely to adopt some tests over others. From this perspective, there is relatively more interest in coronary calcium, CRP, and carotid IMT than the other measures discussed.
Dr. Newman discussed the main goal of screening ? to target more specific preventive treatment. The screening test should identify high risk individuals among those initially deemed to be at intermediate risk, and may be used to reinforce aggressive risk factor management and/or allow persons defer treatment if their risk is estimated to be lower (therapeutic avoidance). Knowledge of the test might enhance adherence to treatment.
The following considerations should be made in planning a screening strategy:
Special consideration should be given to persons with chronic renal insufficiency, lupus, rheumatoid arthritis, polycystic ovaries, type 1 diabetes, and other low prevalence conditions that are associated with high risk. Age alone is a major factor; after age 65 in men and age 75 in women, the average risk for CHD is >20% in 10 years. Consideration should also be given to defining intermediate risk as 10-20% to assure a sufficient number of events in a trial. Dr. Newman recommended that for each test considered, the sensitivity, specificity, cost, availability, reproducibility and risk be examined, but that it appears that coronary artery calcium, IMT and perhaps CRP are the most likely candidates for study.
Dr. Taylor addressed the question of treating global risk vs. risk based on individual factors. He considered the arguments for and against including low or high risk persons in a clinical trial; the intermediate risk approach appears to have the highest likelihood of clinical yield ? that is, changing the risk category of individuals based on test results. It is estimated that approximately 25% of persons at intermediate risk could be re-classified based on coronary calcium results; thus, there would be plenty of persons in this group for a study. The issue of studying whether therapeutic avoidance is beneficial in persons classified as low risk based on test results was discussed; this appears unfeasible as it would require abandoning current established guidelines. Also, according to the South Bay Heart Watch data, persons at high Framingham risk remain at high risk, even if their calcium scores are zero.
Consideration should be given to the gender composition of the population included in a trial, since women are at lower Framingham risk than men. African Americans have a lower prevalence of coronary calcium than Whites, and the risk associated with calcification in this group is not clear. However, they should not be excluded.
Dr. Greenland proposed using a ?polypill? ? a combination of medications to lower blood pressure and LDL-cholesterol, and possibly including aspirin ? as the intervention for persons identified to be at high risk. Aspirin does have a relatively high incidence of side effects, however. An alternative would be to create complicated treatment guidelines based on individual risk factors, and treat to specific blood pressure and LDL targets. Consideration should also be given to aggressive lifestyle modification, as several types of dietary and exercise interventions have been shown to be as effective as drug therapy in lowering blood pressure and modifying the lipid profile.
Dr. Criqui reviewed the possible outcomes that could be measured in a trial, either as primary or secondary endpoints, or even as ancillary studies. These include:
Combined outcomes should be considered as a primary endpoint; total mortality is always the most important hard clinical endpoint, however. Consider not only the number needed to treat to prevent one event, but also the number needed to treat to harm one person. Finally, cost-effectiveness may be a major trial result, particularly in the assessment of technology.
Based on the experience of other CVD intervention trials, this study is likely to require >10,000 subjects to test one type of screening test.
The following recommendations and issues emerged during the meeting and the post-meeting conference call regarding the motivation for and design of a clinical trial.
Several Working Group members noted that more aggressive treatment will likely reduce CVD risk. The central question is at what cost this risk reduction would be achieved and whether a test and treat strategy would have a more acceptable cost-benefit ratio than alternative strategies.
The Institute will work with these recommendations to explore possible trial designs. Ultimately, the decisions to conduct a trial and the type of trial to conduct are driven by factors of feasibility, including cost, as well as science and public health. Working Group members may be consulted in the future to provide more specific advice on trial design.
Previous Recommendations for Subclinical CVD Testing
Smith SC, Greenland P, Grundy SM. AHA conference proceedings. Prevention V: Beyond secondary prevention: Identifying the high-risk patient for primary prevention. Executive Summary. Circulation 2000;101:111-116.
Greenland P, Smith SC, Grundy S.M. Improving coronary heart disease risk assessment in asymptomatic people: role of traditional risk factors and noninvasive cardiovascular tests.Circulation. 2001;104:1863-1867.
Taylor AJ, Merz CN, Udelson JE. 34th Bethesda Conference: Executive summary--can atherosclerosis imaging techniques improve the detection of patients at risk for ischemic heart disease?J Am Coll Cardiol. 2003;41:1860-1862.
Greenland P, Abrams J, Aurigemma G, Bond M, Clark L, Criqui M, Crouse J, Friedman L, Fuster V, Herrington D, Kuller L, Ridker P, Roberts W, Stanford W, Stone N, Swam J, Taubert K, Wexler L. Prevention Conference V. Beyond secondary prevention: identifying the high-risk patient for primary prevention. Noninvasive tests of atherosclerotic burden.Circulation 101, 111-116. 1-4-2003
U.S. Preventive Services Task Force. Screening for Coronary Heart Disease: Recommendation Statement. Ann Intern Med. 2004;140:569-572.
Information on CVD Risk Distribution
Ford, ES, Giles WH, Mokdad AH. The distribution of 10-Year risk for coronary heart disease among U.S. adults. Findings from the National Health and Nutrition Examination Survey III.Journal of the American College of Cardiology 2004;43:1791-1796.
Greenland P, LaBree L, Azen SP et al. Coronary artery calcium score combined with Framingham Score for risk prediction in asymptomatic individuals.JAMA. 2004;291:210-215.
Working Group on Determining the Role of Subclinical Cardiovascular Disease
Testing in Patients at Intermediate Risk
Robert M. Califf, MD (Co-Chair)*
Professor of Medicine
Associate Vice Chancellor for Clinical Research
Duke Clinical Research Institute
Trent Drive, Box 3850
Durham, NC 27710
Allen Taylor, MD (Co-Chair)*
Walter Reed Army Medical Center
6900 Georgia Avenue, NW
Building 2, Room 4A
Washington, DC 20307-5001
Michael Criqui, MD, MPH
University of California, San Diego
Stein Clinical Research Building
9500 Gilman Drive
Room 349La Jolla, CA 92093-5004
Site Phone: 858-534-3722
Office Phone: 858-534-3722
Alternate Phone: 858-534-8625
John Flack, MD, MPH
Professor and Associate Chair
Wayne State University
Department of Medicine
2E 4201 St. Antoine
Detroit, MI 48201
Philip Greenland, MD*
Feinberg School of Medicine
680 North Lake Shore Dirve
Chicago, IL 60611
Office Phone: 312-908-1723
David Herrington, MD, MHS
Wake Forest University
School of Medicine
Department of Internal
Medical Center Blvd.
Winston-Salem, NC 27157
Site Phone: 336-716-4950
Office Phone: 336-716-4950
Alternate Phone: 336-716-9124
Richard Kronnal, PhD
University of Washington
Collaborative Health Studies
Building 29, Suite 310
6200 NE 74th Street
Seattle, WA 98115-8160
Office Phone: 206-685-7123
Michael S. Lauer, MD, MPH
Director of Clinical Research and
Director of Stress
Laboratory, Desk F25
Cleveland Clinic Foundation
9500 Euclid Avenue
Cleveland, Ohio 44195
Anne B. Newman, MD, MPH
Associate Professor of Medicine
Healthy Aging Research Program
Bellefield Professional Building
130 North Bellefield Avenue-Room 532
Pittsburgh, PA 15213
Daniel O'Leary, MD
tufts-New England Medical Center
Department of Radiology
750 Washington Street, Box 380
Boston, MA 02111
Site Phone: 617-636-8050
Office Phone: 617-636-8050
Alternate Phone: 617-636-0041
Paolo Raggi, MD
1430 Tulane Avenue SL-48
New Orleans, LA 70112
Charleston, SC 29425
Peter W.F.Wilson, MD
Medical University of South Carolina
Medicine Division of Endocrinology
PO Box 250624
96 Jonathan Lucas Street
Charleston, SC 29425
*participant on 7/23 conference call
Working Group on Determining the Role of Subclinical Cardiovascular Disease
Testing in Patients at Intermediate Risk
Diane Bild, MD, MPH*
Lawton Cooper, MD, MPH
Jeffrey Cutler, MD*
Michael Domanski, MD
Teri Manolio, MD, Ph.D
Merle Myerson, MD, EdD.
Christopher O'Donnell. MD
Peter Savage, MD
Denise Simons-Morton, MD, Ph.D*
Eser Tolunay, Ph.D.
Momtaz Wassef, MD
*participant on 7/23 conference call