Despite advances in noninvasive imaging, no consensus currently exists on the most appropriate diagnostic test to evaluate patients with new-onset, stable chest pain. Given that approximately 4 million stress tests are performed annually in the U.S.,¹ this uncertainty has led to increased Medicare spending² and referral of low-risk patients without coronary artery disease (CAD) for angiography.³

Common diagnostic imaging modalities used for evaluation of stable chest pain include exercise stress testing, stress echocardiography, and single-photon emission computed tomography (SPECT). Although these tests are an integral part of the evaluation of chest pain, their accuracy is limited with respect to both sensitivity and specificity in the range of 70-90%.^4,5 Coronary computed tomographic angiography (CTA) provides an additional noninvasive option for the evaluation of suspected CAD. Unlike conventional stress testing that is categorized as functional testing, CTA, like invasive angiography, provides anatomical information. CTA has been found to have a high diagnostic accuracy in detecting CAD compared to invasive angiography. Furthermore, the negative predictive value of CTA is as high as 99%, essentially ruling out obstructive CAD,⁶ particularly among patients at low-to-intermediate pre-test likelihood of disease.

For the evaluation of chest pain, standard exercise electrocardiogram (ECG) testing carries a Class I recommendation in patients with an interpretable ECG, while stress echocardiography and SPECT are Class I in those without an interpretable ECG. In 2012 when the guidelines were last updated,⁷ CTA was given a Class IIb recommendation for patients with intermediate pre-test probability due to a number of factors, including the lack of clinical trial evidence in this population and concerns over radiation exposure and downstream testing. The Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial was, therefore, designed to evaluate the differences in clinical outcomes between anatomic testing with CTA and routine functional testing.

The PROMISE trial randomized 10,003 symptomatic patients with suspected CAD to anatomic or functional noninvasive testing. Anatomic testing consisted of CTA with a 64-slice or greater multidetector CT scanner. Functional testing included exercise ECG (used in 10% of subjects), stress echocardiography (22%), or nuclear stress testing (68%). The primary endpoint was a composite of all-cause mortality, myocardial infarction, hospitalization for unstable angina, and major complications from cardiovascular procedure (stroke, bleeding, renal failure, anaphylaxis). Secondary endpoints included a composite of the primary endpoint and invasive catheterization without obstructive CAD (<50% stenosis), other components of the primary endpoint, invasive catheterization without obstructive CAD at 90 days, and cumulative radiation exposure at 90 days. Median follow-up was 25 months with a maximum follow-up of 50 months.

The study found no difference in primary outcome between CTA and functional testing (3.3% vs. 3.0%, P = 0.75). Data presented in the supplementary appendix showed there was no difference in primary outcome between any of the functional tests and anatomic testing. Although more patients in the CTA group underwent invasive catheterization within 90 days, CTA was associated with lower rates of non-obstructive CAD on angiography (i.e., higher diagnostic yield) than the functional group (3.4% vs. 4.3%, P = 0.022). Small differences in radiation exposure were found, with median radiation exposure overall lower in the CTA group (10.0 mSv vs. 11.3 mSv), but with a higher mean exposure in the CTA group (12.0 mSv vs. 10.1 mSv). A follow-up presentation by Mark et al. on March 15, 2015, evaluated the economic outcomes of the PROMISE trial. Although the initial cost of a diagnostic CTA was lower than functional tests testing, the cumulative cost of a CTA, resulted in a small, non-significant increase in costs (<$500) compared to functional testing over a median of two-year follow-up.

The authors of the PROMISE trial should be commended for undertaking this important study to help elucidate the most appropriate diagnostic testing for patients with stable chest pain. There are a number of elements of the trial's methodology worth considering in coming to conclusions about the trial's clinical interpretation. The initial sample size calculation estimated 10,000 patients were needed for 90% power to detect a relative reduction of 20% for the primary endpoint, assuming an event rate of 8%. This proved optimistic as the primary event rate only occurred in ~3% of patients. Furthermore, only 12% of patients had typical angina, raising the question of whether a higher pre-test probability of CAD in the study population was needed to optimize the impact of functional versus anatomic diagnostic testing. Even more provocatively, an alternative design including a third study arm of no study-mandated diagnostic testing would have been helpful to determine whether any testing intent on refining the group of patients who may benefit from revascularization is beneficial in a low-likelihood/low-risk population on optimal medical therapy, similar to the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial⁸ results.

Another potential question was the choice of outcomes for a study evaluating strategies of diagnostic testing in stable chest pain. Outcomes such as the use of optimal medical therapy, avoidance of subsequent testing, optimization of the results of invasive testing, the patient experience, or quality of life may be more appropriate than assessing the incident cardiovascular outcomes among low-risk patients, thereby leading to a negative result due to both limited study power and limited relationship of the outcomes to the allocated study group.

How then should health care professionals clinically interpret the PROMISE trial? The similar findings with respect to hard outcomes, radiation, and cost lead one to conclude that when diagnostic testing is done for a patient with stable chest pain, other factors should drive the decision. These could include physician or center expertise and patient preferences. Moreover, an even more provocative interpretation may be that the study leads to further questions of which, if any, patients with atypical chest pain and a low pre-test likelihood of CAD require any testing, or how to optimally refine the testing population to a point that the diagnostic testing could lead to improved health outcomes.

How should PROMISE be used in practice? The PROMISE trial emphasizes the need for a careful history and physical examination in determining a patient's individual risk for CAD and the need to readdress who is being tested. When testing is indicated, clinicians can comfortably select either CTA or functional testing. With respect to CTA, the technology led to a lower incidence of catheterizations showing non-obstructive disease, suggesting a reasonable, outcomes-based alternative to functional testing in stable CAD. However, as a "base case," simple exercise stress testing, which has the lowest cost and no radiation exposure, may be the preferred testing strategy for the vast majority of patients, particularly when the pre-test likelihood is not high and the patient has atypical symptoms. Optimizing radiation exposure with CTA to levels far below those reported in PROMISE is now commonplace and will further enhance the safety of CT-based testing. Whether emerging methods in cardiac CT practice such as CT-based coronary blood flow determinations or stress CT-perfusion testing can more efficiently guide management of stable chest pain remains to be seen. How will future guidelines incorporate PROMISE? The authors of this Expert Analysis article propose that at this time, noninvasive anatomic OR functional testing is reasonable (Class IIa) in the initial evaluation of stable chest pain for the types of patients enrolled in PROMISE. And, along the way, remember to always emphasize adherence to good lifestyle and optimal medical therapy.

References

1. Ladapo JA, Blecker S, Douglas PS. Physician decision making and trends in the use of cardiac stress testing in the United States: an analysis of repeated cross-sectional data. Ann Intern Med 2014;161:482-90.
2. United States Government Accountability Office (U.S. GAO). Report to Congressional Requestors. Medicare Part B Imaging Services: Rapid Spending Growth and Shift to Physician Officers Indicate Need for CMS to Consider Additional Management Practices. 2008 (U.S. GAO website). Available at: http://www.gao.gov/assets/280/276735.pdf. Accessed 4/14/2015.
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. Fleischmann KE, Hunink MG, Kuntz KM, Douglas PS. Exercise echocardiography or exercise SPECT imaging? A meta-analysis of diagnostic test performance. JAMA 1998;280:913-20.
5. Heijenbrok-Kal MH, Fleischmann KE, Hunink MG. Stress echocardiography, stress single-photon-emission computed tomography and electron beam computed tomography for the assessment of coronary artery disease: a meta-analysis of diagnostic performance. Am Heart J 2007;154:415-23.
6. Budoff MJ, Dowe D, Jollis JG, et al. Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial. J Am Coll Cardiol 2008;52:1724-32.
7. 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.
8. Boden WE, O'Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1503-16.

Keywords: Anaphylaxis, Angina, Unstable, Appendix, Catheterization, Chest Pain, Consensus, Constriction, Pathologic, Coronary Angiography, Coronary Artery Disease, Diagnostic Tests, Routine, Drug Evaluation, Echocardiography, Stress, Electrocardiography, Follow-Up Studies, Life Style, Medicare, Myocardial Infarction, Patient Preference, Physical Examination, Prospective Studies, Quality of Life, Referral and Consultation, Renal Insufficiency, Stroke, Tomography, Emission-Computed, Single-Photon, Uncertainty

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