Author + information
- aVA Boston Healthcare System and the Massachusetts Veterans Epidemiology, Research, and Informatics Center, Boston University School of Medicine, Boston, Massachusetts
- bVA Connecticut Health Care System, Yale University School of Medicine, Division of Cardiology, New Haven, Connecticut
- ↵∗Address for correspondence:
Dr. William E. Boden, VA Boston Healthcare System and the Massachusetts Veterans Epidemiology, Research, and Informatics Center, VA New England Healthcare System VA Boston, Jamaica Plain Campus, 150 South Huntington Avenue, Boston, Massachusetts 02130.
- comparative effectiveness research
- coronary CT angiography
- myocardial perfusion imaging
- stable ischemic heart disease
There have been profound advances in the primary and secondary prevention of coronary artery disease (CAD) over the past 4 decades that have resulted in significant, sustained decreases in cardiovascular mortality and incident cardiac events. This has been paralleled by a shift in prevalence from an acute disease presenting as ST-segment elevation myocardial infarction to one of chronicity manifested as stable ischemic heart disease (SIHD) and heart failure (1,2). Coincident with this evolution in the natural history of CAD, there has been an expansion of research involving newer imaging modalities and a concomitant increase in resource use associated with these techniques to better and more effectively address and tailor SIHD management. This, in turn, has inevitably led to an era of unconstrained cardiac diagnostic imaging use and has understandably raised concerns about the cost and the downstream consequences of more sophisticated and expensive testing. Thus, clinical imaging science is experiencing internal and external pressures to use diagnostic testing appropriately, as evidenced by proliferation of appropriate use criteria, declining reimbursement, and federal regulatory programs, such as the Medicare Access and CHIP Reauthorization Act of 2015 (3).
Against this backdrop of the explosive growth and maturation of imaging techniques to detect and manage obstructive CAD, it is relevant to trace the evolution of the early randomized controlled trials (RCTs) of myocardial imaging that focused largely on comparisons of different imaging modalities to assess test characteristics for equivalence or superiority when compared with the gold standard of invasive coronary angiography to detect obstructive CAD. Robust studies of functional testing, such as exercise treadmill testing and single-photo emission computed tomography myocardial perfusion imaging, demonstrated that these modalities are efficacious at prognostic stratification. With the advent of coronary computed tomography angiography (CTA), the next generation of multimodality imaging RCTs became increasingly fueled by the debate to address the roles of functional and anatomic testing in assessing the diagnosis and prognosis of CAD.
The current era in imaging research represents a further evolutionary shift from a comparison of technology to an integration of global diagnostic strategies. Comparative effectiveness research (CER) of imaging assesses the degree to which an imaging test can confer meaningful improvement in therapeutic decision-making and patient outcome. The design and execution of CER assume that imaging findings should be prospectively linked to care algorithms that use evidence-based therapies and presumes adherence to therapy. Thus, CER studies complete the “holy trinity” of imaging study goals, namely that of diagnosis, prognosis, and guidance of management.
In this issue of iJACC, the comprehensive review article by Shaw et al. (4) presents a detailed summary of the changing landscape of CER in the imaging of SIHD. The authors primarily include trials that use newer techniques of coronary CTA and stress magnetic resonance imaging in comparison with more traditional functional stress testing. Although the foundational principles of risk stratification in RCTs embody the use of hard clinical events, the real world reality of observed low event rates and the chronic natural history of SIHD require trial designs with large sample sizes and long-term follow-up (>5 years) that often result in exorbitant costs and that may be difficult logistically to complete. In the aggregate, a comparison of anatomic and functional testing confirms gross equivalency in prediction of clinical events. Perhaps not surprisingly, functional testing has resulted in a higher rate of downstream angiography than anatomic imaging with coronary CTA. CER imaging studies have demonstrated that coronary CTA is superior to other functional modalities in identification of patients with obstructive CAD, yet the implicit assumption in interpreting such data is that the detection of obstructive CAD is the sole target for appropriate invasive angiography and revascularization. Further to this point, the combined assessment of anatomic and physiologic significance of a coronary obstruction by coronary CTA-fractional flow reserve is associated with a reduction in unnecessary angiography compared with anatomy alone. Conversely, the CE-MARC 2 trial incorporated the use of pre-test probability of CAD as a determinant of diagnostic strategy. The pre-test probability driven–strategy performed worse than perfusion testing alone with either myocardial perfusion imaging or stress magnetic resonance imaging. This highlights the need for a recalibration in traditional pre-test probability models, which may overcategorize risk of obstructive CAD in the low-intermediate population (5).
Beyond hard clinical endpoints, CER imaging studies also permit the assessment of patient factors (quality of life, functional tolerance, angina, change in medical therapy) and system factors (cost, downstream testing, diagnostic certainty). Although there is no significant change in patient symptoms between functional and anatomic strategies, coronary CTA is associated with minimal cost savings and improvement in diagnostic certainty, along with higher rates of medical therapy intensification.
The discordance between the essential equivalence of functional and anatomic imaging in prediction of clinical events as compared with the superiority of coronary CTA in prediction of obstructive CAD sets the stage for potentially highlighting the next frontier of imaging to enhance SIHD management: nonobstructive CAD. Obstructive CAD has been the historical focus and serves as the framework for imaging study design and professional society guidelines. In recent years, however, there has been an accumulation of evidence that has uncoupled the direct and simple relationship between the severity of obstructive CAD and other prognostic factors (6), which include severity of flow limitation, ischemia and flow heterogeneity, angina and functional tolerance, plaque characterization, global measures of CAD burden, and measures of microvascular dysfunction. The multitude of ways in which CAD is characterized reflects the growing understanding of the complexity of CAD disease manifestations, and the corollary need to adapt novel imaging to identify and quantify ischemia that occurs in the absence of obstructive epicardial CAD. Ischemia in the absence of angiographic flow-limiting epicardial coronary stenoses is common clinically, is prognostically significant, and is often challenging to diagnose and manage clinically. Future advances in the management of SIHD will depend critically on linking imaging technologies with well-designed clinical studies to better characterize this phenotypic diversity paired with translational research as the means to understand the pathways that underlie variability in CAD manifestation.
Successful CER incorporates outcomes that are influenced by test interpretation and post-test care, such that the imaging research field must move forward in hand with thoughtfully designed SIHD studies that seek to define effective disease modification therapies, inclusive of intensive risk factor modification, symptom management, and revascularization, along with systems of care to promote adherence. Past imaging studies were designed pragmatically with post-imaging test care at the discretion of the treating physician, for which publications have reported undertreatment in trials and real-world registries (7). The role of revascularization in post-test care remains unclear given the discordant findings between observational studies and RCTs (8,9). The results of the ongoing ISCHEMIA study of SIHD patients with moderate-severe ischemia, a comparative effectiveness trial of an invasive approach with revascularization versus a conservative approach of optimal medical therapy, with catheterization and revascularization in that arm reserved only for a failure of medical therapy, may well inform clinical practice regarding the complementary roles of an invasive strategy and myocardial imaging, which are importantly linked to clinical endpoints and part of comprehensive post-test care (10).
Finally, what are the key takeaways for the practicing cardiologist based on all of these considerations? First, despite the allure of the most recent technologies, traditional stress testing, even standard exercise treadmill testing, continues to demonstrate an overall equivalence to anatomic testing, although the combination of anatomic and functional information may be superior to either alone. Second, the superiority of coronary CTA may be grounded in higher rates of implementation of intensive secondary prevention, identification of nonobstructive CAD, which merits risk reduction therapies, and which is only slightly less expensive and provides more efficient care. Third, there remains limited consensus on best testing strategy. There are challenges to the design and implementation of CER imaging studies in SIHD, particularly the need for updated models of risk in this era of low event rates; a broader understanding of CAD beyond the prevailing paradigm of obstructive epicardial CAD; inclusion of novel, patient-centered and efficiency outcomes; and the need for evidence of optimal post-test treatment. Finally, given the inherent variability in patient phenotypes and clinical presentations, there is a compelling need to translate group data derived from RCTs to individual patient management, such as distinguishing between modifiable and nonmodifiable risk factors, accounting for competing comorbidities, and better defining patient-centered measures.
Importantly, the application of CER in this scientific arena permits the combined use of cardiac imaging and post-test management of SIHD to assess for optimal strategies of care. The elegant and comprehensive review of imaging-guided approaches to management by Shaw et al. (4) provides a timely and important overview of the current landscape of imaging in patients with SIHD. As we look to the future application of how imaging can guide decision-making and short- and long-term care decisions, we must be willing to chart new terrain by ensuring that noninvasive testing, with both traditional and novel approaches, is linked closely to and centered on clinical outcomes assessment. Given the chronicity of SIHD and its appreciable direct and indirect costs, CER trial design needs to incorporate traditional clinical trial and “real world” observational evidence, adopt pragmatic trial design through the leveraging of existing registries and electronic medical records outcomes data, and embrace the continued development of learning health environments that may more effectively enhance care and treatment decisions at the point of care for patients with CAD.
↵∗ Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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