Author + information
- James K. Min, MD∗ (, )
- Erica C. Jones, MD and
- Jessica M. Peña, MD, MPH
- Departments of Medicine and Radiology, Weill Cornell Medical College, Dalio Institute of Cardiovascular Imaging at New York Presbyterian Hospital, New York, New York
- ↵∗Reprint requests and correspondence:
Dr. James K. Min, Dalio Institute of Cardiovascular Imaging, 413 East 69th Street, New York, New York 10021.
Nearly 40 years ago, single-photon emission computed tomography (SPECT) and echocardiography formed the cornerstone of coronary artery disease (CAD) diagnosis. These techniques identify high-grade coronary stenoses by proxy, through identification of stress-induced ischemia or wall motion abnormalities (1). That these 2 modalities target different points within the ischemic cascade appears negligible for differences in accuracy for coronary stenosis detection and prognosis. Single-center follow-up studies with SPECT and echocardiography have suggested a threshold of ischemia above which revascularization may portend benefit, a hypothesis that is being tested in the ongoing ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) trial.
Nearly 20 years later, Ambrose et al. (2) astutely observed that lesions implicated in future myocardial infarctions often do not cause ischemia or exhibit high-grade stenosis prior to the event. This finding motivated Topol and Nissen to urge us to reconsider our “preoccupation with coronary luminology,” and to starkly amplify the incongruity between ischemia, stenosis, atherosclerosis, and outcomes (3).
In 2005, the advent of 64-detector row coronary computed tomographic angiography (CCTA) allowed for direct visualization of coronary artery lumen and atherosclerosis. Early studies of CCTA focused on the former, observing generally high performance compared with invasive coronary angiography. Later studies demonstrated a disconnect between CCTA and stress test findings, wherein high-grade luminal stenoses by CCTA correlated unreliably with ischemia. Proponents of stress testing thus dismissed CCTA, maintaining that the goals of CAD evaluation should lie in the identification of ischemic stenoses rather than luminal encroachment alone. Since then, several multicenter studies reported the prognostic utility of CCTA luminal findings independent of and incremental to ischemia. Further studies expanded CCTA evaluation to atherosclerosis itself, with quantitation and characterization yielding important prognostic information. CCTA advocates maintained that it should be considered a first-line test in CAD evaluation, shifting the focus from “high grade” CAD to atherosclerosis itself.
These differences in viewpoints between CCTA proponents and opponents fueled a great amount of debate, with moderators calling for a randomized controlled trial for stable patients with suspected CAD undergoing physiological ischemia testing versus anatomic CCTA. This trial was performed twice, with generally different conclusions (4,5). In the PROMISE trial (n = 10,003), the primary outcome was endpoints-driven, a composite of death, myocardial infarction, major complications from testing and unstable angina. In contrast, the SCOT-HEART trial (n = 4,146) was diagnosis-driven, testing the hypothesis of improved diagnostic certainty by CCTA, with an endpoint of the proportion of patients correctly diagnosed with angina as a function of coronary disease at 6 weeks. The PROMISE (PROspective Multicenter Imaging Study for Evaluation of chest pain) was reported as “negative” for 2-year superiority of CCTA over functional testing for higher event-free survival, whereas the SCOT-HEART (Scottish COmputed Tomography of the HEART) study was reported as “positive” for improved diagnostic certainty of CAD.
Despite these different conclusions, most of the observed outcomes were similar in both trials. In both, a lower rate of normalcy was observed for patients undergoing invasive coronary angiography after CCTA, suggesting a higher diagnostic accuracy for CCTA; in addition, higher rates of primary prevention medication initiation for statins and aspirin were observed in the CCTA arms for both trials (6). These findings were paralleled by improvements in prognostic risk assessment through CCTA-driven care (7). Moreover, both trials reported trends toward lower event rates for patients undergoing CCTA (34% for PROMISE [p = 0.049] and 38% for SCOT-HEART [p = 0.06]), findings that were examined in greater detail by Williams et al. (8) in this issue of the Journal.
Williams et al. (8) aimed to determine the hard clinical outcomes of patients undergoing a CCTA-based strategy versus a standard of care strategy at 12 months, dissecting the clinical outcomes associated with each strategy as a function of the timing of post-test medical care. Until 50 days—the average time to the post-test clinic visit and initiation of preventive medical therapies after CCTA—Williams et al. (8) noted no differences in coronary outcomes between individuals enrolled to CCTA and to standard of care. Beyond the 50-day mark, when preventive therapies had been initiated on the basis of CCTA findings, a marked 50% reduction in fatal and nonfatal myocardial infarction at 12 months was observed for patients undergoing evaluation by CCTA compared with standard of care.
These findings also emphasize important concepts in trial design. It is possible that the lack of superiority of CCTA over functional testing in the PROMISE trial stems not from an inefficacy of a CCTA-based diagnostic strategy to positively influence downstream treatments, but rather from a follow-up period too short to enable realization of the salutary effects of preventive therapy, particularly in the trial’s population with a low prevalence of CAD. As described by Williams et al. (8), the time to event following the initiation of therapy—rather than the initial test performance—may be a more important time to “start the clock” to event observance.
This secondary analysis of SCOT-HEART is the highest-quality evidence to date for the comparative benefit of CCTA over standard-of-care approaches. As the authors noted, their findings are in direct concordance with other large-scale multicenter studies of patients with both “obstructive” and “nonobstructive” anatomic CAD by CCTA. In aggregate, these studies suggest that not only may CCTA be considered a reasonable alternative to stress testing for initial diagnostic CAD evaluation, but it may actually be preferred.
Importantly, to date, anatomic imaging by CCTA has been generally thought of in binary terms as “obstructive” versus “nonobstructive.” Yet, these classifications are oversimplistic as the dichotomy between CAD “anatomy” and “physiology,” with recent studies highlighting a graded prognostic importance of many factors, including increasing CAD severity, atherosclerotic plaque burden, and high-risk plaque features. The ability to identify, quantify, and characterize atherosclerosis may be a distinguishing feature of CCTA that allows transcending beyond traditional lumen-based CAD assessments.
This “new” paradigm is not actually new, but simply encourages diagnostic CAD evaluation by a forward rather than backward-looking stance, reflecting the natural history of atherosclerosis progression; namely, that disease severity should be gauged hierarchically: 1) plaque versus no plaque; 2) high-risk plaque features versus non-high-risk plaque features; 3) high-grade stenosis versus non–high-grade stenosis; and finally, 4) ischemia versus no ischemia.
Adoption of this forward-looking approach should not mitigate the importance of ischemia-causing CAD, given the wealth of observational data for stress testing. However, it is possible that the addition of information related to stenosis and atherosclerosis may complement or, on the basis of the current study results, be superior to stress testing for improving outcomes. Germane to this, the recent introduction of noninvasive fractional flow reserve from CCTA may afford the opportunity to obtain all of this information from CCTA, with the ability to integrate lesion-specific ischemia and attain the oft-discussed “1-stop shop” of coronary evaluation.
George Bernard Shaw remarked: “Progress is impossible without change, and those who cannot change their minds cannot change anything” (9). Williams et al. (8) should be commended for performing a high-quality study that considers this change in the context of physician practice patterns and patient behavior, and have identified a distinct advantage of initial diagnosis of “anatomy” over “physiology.” The exact reason as to why improvements in event-free survival are observed amongst those undergoing CCTA is unknown and likely complex, but perhaps relate to the other findings noted by the SCOT-HEART and PROMISE investigators related to diagnostic accuracy, risk stratification, prediction of therapeutic benefit, or simply a better understanding of a patient’s specific atherosclerotic disease process. Pertaining to the latter, these “new” concepts considered by our colleagues >20 years ago appear to now both be possible with CCTA, and seem to be the relevant ones that should dictate our future. The present report’s results are deserving of, and perhaps will serve as, a beginning to change.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Min is supported by grants from the National Institutes of Health (NIH/NIHLBI R01HL111141, NIH/NIHLBI R01HL115150, NIH/NIHLBI R01HL118019, NIH/NIHLBI U01HL105907) and from the Qatar National Research Foundation (NPRP09-370-3-089); serves as a consultant to HeartFlow Inc. and GE Healthcare; is on the medical advisory board of Arineta; retains ownership in MDDX and Autoplaq; and has a research agreement with GE Healthcare. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
- Shaw L.J.,
- Berman D.S.,
- Picard M.H.,
- et al.
- Topol E.J.,
- Nissen S.E.
- ↵Ladapo JA, Hoffmann U, Lee KL, et al. Changes in medical therapy and lifestyle after anatomical versus functional testing for coronary artery disease: the PROMISE trial. Paper presented at: American Heart Association Scientific Sessions; November 9, 2015; Orlando, Florida.
- ↵Hoffmann U, Ferencik M, Udelson JE, et al. Prognostic value of anatomic versus functional diagnostic testing in symptomatic patients with suspected CAD: the PROMISE trial. Paper presented at: American Heart Association Scientific Sessions; November 9, 2015; Orlando, Florida.
- Williams M.C.,
- Hunter A.,
- Shah A.S.V.,
- et al.,
- on behalf of the SCOT-HEART Investigators
- ↵BrainyQuote. George Bernard Shaw quotes. Available at: http://www.brainyquote.com/quotes/quotes/g/georgebern386923.html. Accessed February 26, 2016.