Ischemic heart disease remains a national health burden, with over 28.4 million adults in the United States diagnosed with heart disease in 2015.¹ The 2012 American College of Cardiology and American Heart Association guidelines for patients with stable ischemic heart disease provide an algorithm for risk stratification of patients presenting with angina. A pre-test assessment of one's risk is segregated into 3 categories, low (<10%), intermediate (10-90%), or high (>90%), to guide the decision for further evaluation with noninvasive stress testing to detect coronary artery disease (CAD). Although invasive coronary angiography remains the standard for the detection of CAD, it is reserved for patients whose clinical risk is assessed as high or when stress testing indicates significant ischemic burden.² Despite this known algorithm in our guidelines, there are two major concerns for the intermediate-risk patient:

1. Coronary angiography is over-used and low-yield.
2. Stress imaging has improved diagnostic accuracy compared with history alone and can avoid invasive procedures.

Appropriate utilization of noninvasive diagnostic testing is important to ensure that patients with CAD are referred to angiography for diagnosis and that patients who do not have CAD can avoid unnecessary invasive testing.

A retrospective analysis by Patel et al. from the National Cardiovascular Data Registry (NCDR) CathPCI Registry found that only 40% of patients had obstructive CAD on diagnostic angiography and concluded that angiography was a "low-yield" diagnostic test.³ There are a few limitations in this study that challenge the generalizability of this conclusion. First, the cohort included both symptomatic and asymptomatic patients, with only 68.6% having a positive noninvasive test result including resting electrocardiography, computed tomography (CT), echocardiography, or exercise stress testing. A positive noninvasive test result or a major clinical Framingham risk factor were both significantly associated with obstructive CAD at the time of angiography. Additionally, the cohort referred for angiography included 17.1% of low-risk and 15.9% of intermediate-risk patients who had not completed noninvasive testing prior to the referral for an angiogram. The study also excluded patients with prior CAD, acute coronary syndrome, or elective angiography prior to cardiac or transplant surgery. When these criteria were included, the diagnostic yield of angiography detecting obstructive CAD increased to 60%. The most important distinction in the conclusion is that the yield of an angiogram can only be as great as the clinical indication for the test. The data presented in this study confirm that coronary angiography is high-yield for obstructive CAD when appropriate noninvasive testing is performed in a patient with strong clinical risk factors for CAD.³

The CE-MARC 2 (Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease 2) trial followed the NCDR study to evaluate if cardiac magnetic resonance- (CMR-) guided care is superior to UK National Institute of Health Guidelines- (NICE-) directed care or myocardial perfusion stress (MPS) imaging. The trial randomly assigned a cohort of patients with suspected angina and low-, intermediate-, or high-risk factors for CAD to three strategies of care (NICE, CMR, or MPS) to guide further testing with coronary angiography. The study group included a symptomatic population with at least two major CAD risk factors. The results showed that an unnecessary angiogram occurred 28.8% in the NICE-guided group, 7.1% in MPS-guided group, and 7.5% in CMR-guided group. Of the 240 patients assigned to the NICE guidelines group, 35.4% were referred for coronary angiogram directly, and 13.4% of 142 patients who underwent testing in the NICE-guided group were sent after a positive noninvasive result. One concern about the primary endpoint in the NICE-guided group is the substantial number of patients sent directly to angiography and the relatively lower number of patients referred after positive testing. Functional imaging as a first-line strategy for patients with a 60-90% pre-test probability of CAD led to a statistically significant reduction in the number of patients referred for unnecessary angiography compared with NICE-guided care (9.4 vs. 62.2%, respectively). It is important to highlight the increased diagnostic yield of coronary angiography in a high-risk patient who undergoes functional testing prior to angiography. There was no difference in major adverse cardiac event rates at 1 year among the 3 strategies.⁴

From our perspective, imaging services have an important but overused role in the diagnostic algorithm of patients with chest pain. A review of Medicare Part B spending on imaging services paid under the physician fee schedule increased from $7 to $14 billion from 2000 to 2006. Much of that growth in spending was on advanced imaging procedures, including CT scans, magnetic resonance imaging, and nuclear medicine studies. These data are inclusive of noncardiac studies, but a portion of the growth in spending and ordering of studies should be extrapolated to outpatient cardiac studies.⁵ From 1993 to 2001, the use of imaging stress tests had a threefold increase, with an average increase of 6.1 per 1000 Medicare beneficiaries per year. This increase in testing occurred when the rate of acute myocardial infarction remained constant, suggesting that increased testing was not due to increased disease burden.⁶ A more recent report of Medicare services from 1999 to 2008 found a 44% increase in the number of services provided by cardiologists. Although the growth of invasive procedures contributed only 5%, noninvasive imaging contributed 78%, of which nuclear imaging contributed 16%.⁷ The rates of "inappropriate" testing have been found to be as high at 14% in both outpatient and academic settings. There is a substantial amount of radiation risk associated with nuclear MPS testing and psychological stress of a false-positive result. Of equal concern regarding overutilization and inappropriate testing is the personal financial incentive that physicians receive from these imaging services.^8,9

Despite the positive findings of a CMR-guided strategy in the CE-MARC 2 trial, we recommend that the use of stress imaging modalities be reserved for those patients with a clinical indication as described by the guidelines.² Although the original CE-MARC trial found a CMR-guided strategy to have superior diagnostic accuracy compared with an MPS-guided strategy and has the additional benefit of no radiation, its availability is limited to major medical centers, and it is expensive.¹⁰ Standard Bruce protocol exercise stress testing is still a useful screening modality that uses no radiation, is inexpensive, and provides information about functional capacity. As for the use of cardiac CT as an alternate, less-invasive screening strategy, the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial found that a coronary CT-guided strategy in evaluating patients with chest pain led to increased rates of coronary angiography; however, this was largely due to the presence of coronary calcium obscuring accurate anatomic assessment.¹¹ The greatest value of a coronary CT-guided strategy is in its negative predictive value: people who do not have disease are accurately identified. An ideal imaging modality to screen patients who are symptomatic or have risk factors for CAD would provide an accurate anatomic assessment of the coronary arteries with functional assessment that is readily accessible, radiation-free, and affordable. One potential screening test that meets these criteria is the use of the coronary artery calcium (CAC) scan with exercise testing. Using the CAC score to predict atherosclerotic risk has the advantage of curtailing further testing if the score is low and the exercise test is negative. An additional benefit of this strategy is the identification of subclinical CAD to allow for aggressive medical therapy despite a normal exercise test. Currently, CAC scanning in conjunction with exercise testing has not been studied as a first-line test for the assessment of CAD.^12,13

This discussion of screening for CAD would not be complete without a comment about the newest modality: CT fractional flow reserve (FFR). This method, although it uses radiation, adds important functional data to the anatomic assessment from a coronary CT scan and has been shown to have close correlation to invasive FFR. This improvement in diagnostic accuracy and specificity has been demonstrated in three prospective multicenter trials (DISCOVER-FLOW [Diagnosis of Ischemia-Causing Stenoses Obtained Via Noninvasive Fractional Flow Reserve], DeFACTO [Determination of Fractional Flow Reserve by Anatomic Computed Tomographic Angiography], and NXT [Analysis of Coronary Blood Flow Using CT Angiography: Next Steps]) when compared with coronary CT assessment alone.^14-16 While CT FFR could replace other forms of noninvasive testing, including nuclear or magnetic resonance imaging, the major limitation is that it is a proprietary technology requiring off-site data analysis by the company's software.¹⁷ Although there has been a lot of promotion from the company for this technique, we suggest a more circumspect approach until more clinical studies are done. The concern with CT FFR is that there is no new acquisition of information: it uses computer algorithms to massage the anatomic data. If the anatomic information is obscured by calcium, then a sophisticated algorithm may be just processing inaccurate incoming data.

The Holy Grail for noninvasive CAD screening remains elusive.

References

1. Summary Health Statistics: National Health Interview Survey, 2015 (Centers for Disease Control and Prevention website). 2017. Available at: https://ftp.cdc.gov/pub/Health_Statistics/NCHS/NHIS/SHS/2015_SHS_Table_A-1.pdf. Accessed 04/15/2017.
2. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2012;60:e44-164.
3. Patel MR, Peterson ED, Dai D, et al. Low diagnostic yield of elective coronary angiography. N Engl J Med 2010;362:886-95.
4. Greenwood JP, Ripley DP, Berry C, et al. Effect of Care Guided by Cardiovascular Magnetic Resonance, Myocardial Perfusion Scintigraphy, or NICE Guidelines on Subsequent Unnecessary Angiography Rates: The CE-MARC 2 Randomized Clinical Trial. JAMA 2016;316:1051-60.
5. Medicare Part B Imaging Services: Rapid Spending Growth and Shift to Physician Offices Indicate Need for CMS to Consider Additional Management Practices (U.S. Government Accountability Office website). Jul 14, 2008. Available at: http://www.gao.gov/products/GAO-08-452. Accessed 04/15/2017.
6. Lucas FL, DeLorenzo MA, Siewers AE, Wennberg DE. Temporal trends in the utilization of diagnostic testing and treatments for cardiovascular disease in the United States, 1993-2001. Circulation 2006;113:374-9.
7. Andrus BW, Welch HG. Medicare services provided by cardiologists in the United States: 1999-2008. Circ Cardiovasc Qual Outcomes 2012;5:31-6.
8. Hendel RC, Cerqueira M, Douglas PS, et al. A multicenter assessment of the use of single-photon emission computed tomography myocardial perfusion imaging with appropriateness criteria. J Am Coll Cardiol 2010;55:156-62.
9. Gibbons RJ, Miller TD, Hodge D, et al. Application of appropriateness criteria to stress single-photon emission computed tomography sestamibi studies and stress echocardiograms in an academic medical center. J Am Coll Cardiol 2008;51:1283-9.
10. Greenwood JP, Maredia N, Younger JF, et al. Cardiovascular magnetic resonance and single-photon emission computed tomography for diagnosis of coronary heart disease (CE-MARC): a prospective trial. Lancet 2012;379:453-60.
11. Douglas PS, Hoffmann U, Patel MR, et al. Outcomes of anatomical versus functional testing for coronary artery disease. N Engl J Med 2015;372:1291-300.
12. Rozanski A, Berman DS. New Algorithms for the Prediction of Cardiovascular Risk: The Post-Diamond-Forrester Era. JAMA Cardiol 2017;2:359-60.
13. Rozanski A, Cohen R, Uretsky S. The coronary calcium treadmill test: a new approach to the initial workup of patients with suspected coronary artery disease. J Nucl Cardiol 2013;20:719-30
14. Koo BK, Erglis A, Doh JH, et al. Diagnosis of ischemia-causing coronary stenoses by noninvasive fractional flow reserve computed from coronary computed tomographic angiograms. Results from the prospective multicenter DISCOVER-FLOW (Diagnosis of Ischemia-Causing Stenoses Obtained Via Noninvasive Fractional Flow Reserve) study. J Am Coll Cardiol 2011;58:1989-97.
15. Min JK, Leipsic J, Pencina MJ, et al. Diagnostic accuracy of fractional flow reserve from anatomic CT angiography. JAMA 2012;308:1237-45.
16. Nørgaard BL, Leipsic J, Gaur S, et al. Diagnostic performance of noninvasive fractional flow reserve derived from coronary computed tomography angiography in suspected coronary artery disease: the NXT trial (Analysis of Coronary Blood Flow Using CT Angiography: Next Steps). J Am Coll Cardiol 2014;63:1145-55.
17. GE Healthcare and HeartFlow Announce Global Cardiovascular Collaboration (HeartFlow, Inc. website). July 6, 2017. Available at: https://www.heartflow.com/wp-content/uploads/2017/07/7.06.17-HeartFlow-GE-Collaboration_FINAL.pdf. Accessed 04/15/2017.

Keywords: Coronary Angiography, Exercise Test, Risk Factors, Angiography, Coronary Vessels, Acute Coronary Syndrome, Nuclear Medicine, Constriction, Pathologic, Diagnostic Tests, Routine, Electrocardiography, Myocardial Perfusion Imaging, Angina Pectoris, Chest Pain, Coronary Disease, Magnetic Resonance Imaging, Myocardial Infarction, Echocardiography, Magnetic Resonance Spectroscopy, Registries, Algorithms, Stress, Psychological, Cohort Studies

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