Background. Management of patients with stable ischemic heart disease remains challenging, in part due to the inability of non-invasive testing to accurately identify those who may benefit from coronary revascularization. For decades, use of functional testing, such as nuclear perfusion imaging, stress echocardiography, and exercise electrocardiography, has remained a pivotal component of algorithms designed to evaluate anginal pain. Over the past several years, however, a growing body of evidence has developed to support anatomical imaging, with special attention given to coronary computed tomography angiography (CCTA) as the more diagnostically and prognostically accurate non-invasive testing modality. The results of several large randomized controlled trials, as well as their subsequent post hoc analyses, have led to the escalation of CCTA as the first-line test in international guidelines for the evaluation of stable chest pain in patients with low-to-intermediate risk of coronary artery disease. Moreover, recognition of CCTA and its role in improving patient outcomes has driven key change in healthcare policy coverage, leading to streamlined reimbursement and the elimination of prior authorization when utilized in the appropriate setting. Given the rapidly accumulating supportive evidence, the next iteration of the American College of Cardiology/American Heart Association guidelines for stable ischemic heart disease should position CCTA as the first-line test in qualifying patients. Here, we review current literature evaluating anatomical and functional imaging, and formulate a discussion on clinical implementation, limitations of currently available data, and direction for CCTA-based future research.
J INVASIVE CARDIOL 2021 March 26 (Ahead of Issue).
Key words: coronary computed tomography angiography, evaluation, functional imaging, ischemic heart disease
Cardiovascular disease remains the leading cause of mortality in the United States, with nearly 43% of deaths alone attributable to coronary artery disease (CAD). On a global scale, cardiovascular disease is expected to account for an estimated 22.2 million or more deaths by 2030.1 These statistics highlight the need for an accurate yet practical algorithmic approach to evaluate and manage suspected ischemic heart disease (IHD) before it progresses to acute coronary syndrome (ACS).2 However, the evaluation of IHD is complex, requiring a comprehensive clinical assessment of risk, stratification with pretest probability, and appropriate choice of non-invasive diagnostic testing.3 While cardiac catheterization remains the gold standard for the diagnosis of obstructive CAD in ACS, non-invasive testing serves an important gatekeeping role to ensure the catheterization laboratory remains an interventional tool rather than a diagnostic one.4,5 Non-invasive testing modalities can be categorized into functional testing, such as exercise electrocardiography (ECG), myocardial perfusion imaging, and stress echocardiography, or anatomical testing, such as coronary computed tomography angiography (CCTA). The diagnostic performance of these tests has not been well established, leading to disagreement between recommendations from the American Heart Association/American College of Cardiology (AHA/ACC), National Institute for Health and Care Excellence (NICE), and European Society of Cardiology (ESC) guidelines.6 Over the past decade, however, mounting evidence from large randomized controlled trials (RCTs) has created a need to reanalyze the strengths and weaknesses of non-invasive tests. We review the role of CCTA within these trials with particular attention to subtle key generalizable findings highlighting the utility of CCTA in 5 key areas. Consolidation of these data demonstrates the diagnostic accuracy of CCTA over functional imaging, thereby solidifying the position that CCTA should be the first-line test in the evaluation of stable IHD across all guidelines.
Review of RCTs Involving CCTA vs Functional Testing
Between 2014 and 2020, several large RCTs have taken place globally to better delineate the role of CCTA in stable IHD.7 Many were designed to directly compare CCTA with functional testing, with primary endpoints ranging from composites of cardiovascular morbidity and mortality to clinical diagnostic accuracy of non-invasive testing. Going beyond these well-known measures, these trials unearth subtle commonalities that are pragmatically applicable.
Safety and generalizability. CCTA was shown to be as accurate in cardiac imaging in obese and overweight patients and in those with atrial fibrillation8,9 — comorbidities that were once considered difficult to image with CT due to image noise and movement artifact, respectively.10,11 Patients undergoing CCTA, which typically requires 50-120 mL of iodinated contrast,12 did not develop post-study renal dysfunction.8,13 Radiation doses were comparable between CCTA and functional nuclear testing, and were even demonstrated to have lower all-cause radiation when compared with thallium-based myocardial perfusion imaging (MPI)13 and lower median cumulative radiation compared with nuclear stress testing.14 Some centers involved in clinical trials were able to dose-reduce CCTA to as low as 5.37-5.5 mSv per scan.15,16 Due to advances in tube-potential reduction, increased number of detectors (up to 320-detector systems), advances in detector materials, and software algorithmic optimization, radiation doses for CCTA have been routinely reported in the 1-3 mSv range.17,18 Additionally, focusing on the often less-tangible patient satisfaction, CCTA was rated the better clinical experience when compared with MPI, with fewer complaints and proportionally more patients willing to undergo future scans.13
Optimizing medical therapy. Although a diagnostic modality, CCTA also indirectly confers therapeutic effects.2 A common premise that surfaces in evaluating pharmacologic outcomes includes increased use of preventative therapies and intensification of baseline therapies used in the management of CAD.19 Patients with non-obstructive CAD are typically not the focus of non-invasive testing studies; however, one-half to two-thirds of these patients will suffer from myocardial infarctions, suggesting that early initiation of preventative medications is a key strategy.20,21
In the CATCH (Cardiac CT in the Treatment of Acute Chest Pain) trial, CCTA compared with standard care led to statistically significant changes in medication use, specifically, the addition of aspirin and antiplatelet agents, which was postulated as the main driver of change in clinical outcomes.22 Similarly, Jørgensen et al reviewed over 86,000 patients in the Danish National Registry and concluded that the use of CCTA was associated with increased use of aspirin and statin therapy, which may correlate with improved clinical outcomes, including lower risk of myocardial infarction.23
In a different approach than the preceding trials, the SCOT-HEART (Scottish Computed Tomography of the Heart) trial evaluated the certainty of diagnosis of anginal symptoms due to coronary heart disease with the use of CCTA compared with standard care. The departure from the head-to-head trials comparing CCTA vs functional testing was aimed to provide perhaps the most practical application of anatomical imaging in that it could guide clinical decision making, including medication optimization. The results of the 6-week follow-up period were notable for key changes in the use of preventative and antianginal treatments, including discontinuation of unneeded antianginal therapies and initiation of needed preventative therapies.8 Over the longer 5-year follow-up period of the same cohort, patients undergoing CCTA were more likely to have commenced preventative therapies (odds ratio [OR], 1.40) and antianginal therapies (OR, 1.27).20 Post hoc analyses of SCOT-HEART support that CCTA directly enables a “precision medicine approach,” targeting antiplatelet and statin therapy at proportions 3 times higher in patients with CAD vs those without CAD at the same cardiovascular risk level.24
The PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial paralleled the results of SCOT-HEART, demonstrating that at 60 days of follow-up, evaluation for CAD led to more patients initiated on preventative medications and healthier eating habits. Although overall cardiovascular outcomes were not statistically different, the CCTA cohort did have a higher proportion of patients initiated on aspirin, statins, and beta-blockers.25
Economic burden. With healthcare utilization, absolute cost, and disease-specific cost effectiveness at the forefront of discussions involving non-invasive testing, it is vital to dissect the economic outcomes from the larger context of CCTA trials. Although some may reference higher overall cost of CCTA-based evaluation of stable IHD, the PROMISE trial effectively demonstrated that CCTA did not result in increased cost over the median 2-year study period compared with functional testing.21 Additionally, individual costs of CCTA, including mean procedural cost and physician fees, were estimated to be lower compared with nuclear stress testing and stress echocardiography.14 The use of CCTA within the diagnostic algorithm of the CRESCENT (Comprehensive Cardiac CT Versus Exercise Testing in Suspected Coronary Artery Disease) trial led to a statistically significant 16% reduction in costs in cumulative testing over their 1-year study period.9 CCTA also has the advantage of diagnosing extracardiac conditions, potentially at earlier economically and clinically advantageous stages, which may clarify diagnosis for non-cardiac chest pain and procure pertinent diagnoses of pathologies such as pulmonary embolism, pulmonary nodules, hepatic pathology, and chest lymphadenopathy.8,13,21 Some studies quote a “warranty period” of 7 years after a negative CCTA given its very high negative predictive value, effectively conferring a favorable prognosis with less than 1% risk of major adverse cardiac event.2 The economic impact and cost savings of these latter two observations could benefit from additional specific investigation.
Downstream interventions. The ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial demonstrated that the sensitivity and specificity of CCTA to detect ≥70% stenosis when compared with invasive coronary angiography (ICA) was 94% and 83%, respectively.26 Tests with high sensitivity and moderate specificity can accurately rule out disease, but require additional higher-specificity testing to rule in disease. This has led to the conclusion that patients undergoing CCTA are more likely to undergo ICA, with higher costs and increased risk involved.27 The absolute numbers, however, carry less significance, as evidenced by trials involving CCTA and subsequent ICA. CCTA did not increase the number of ICAs not leading to revascularization,13 and in fact led to fewer normal ICAs.22 Effectively, the use of CCTA improved efficiency of the cardiac catheterization laboratory with fewer normal ICAs and higher proportions of percutaneous coronary intervention for those undergoing ICA.21,28,29 Use of CCTA also led to the reclassification of diagnoses, which was associated with the cancellation of unneeded functional tests and ICAs, and addition of needed ICAs.8 At the end of a 5-year follow-up period, the investigators for the SCOT-HEART trial demonstrated that CCTA did not result in significantly higher rates of ICA or coronary revascularization when compared with standard care alone.20
Stratification. Although not a direct comparison between functional and anatomic testing, the pitfalls of functional testing were highlighted by the results of the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial. A key component of the recruitment algorithm was the use of stress testing to select those with moderate-to-severe ischemia to undergo randomization to the invasive or conservative arms.30 A proportion of patients (approximately 18%) with moderate-to-severe ischemia by functional testing had no obstructive disease on subsequent CCTA, demonstrating a fundamental disconnect between functional information and anatomic reality. Using functional testing, event rates over a 4-year period were higher in the no/mild ischemia group and lower in the severe ischemia group (trend P=.04) for both invasive and conservative arms. Using anatomical testing, event rates over a 4-year period were higher in the triple-vessel CAD group and lower in the single-vessel CAD group (trend P<.001) for both invasive and conservative arms.31 The apparent reverse trend in the functional testing group has led to the questioning of the appropriateness of stress testing for stratification. Whereas an algorithm based on functional imaging failed to show benefit of invasive management as in ISCHEMIA, a study utilizing CCTA first may yield considerably different outcomes, especially given the lesion-specific data provided with CCTA.32 It is worthwhile to note that CCTA led to reduction in cardiac death or myocardial infarction at 18.7 months in the CATCH trial22 and death from coronary heart disease or non-fatal myocardial infarction at 5 years in the SCOT-HEART trial,20 further supporting the advantage of robust risk stratification.
Clinical implementation. Updated in 2016, the United Kingdom’s NICE guidelines for the “Assessment and Diagnosis of Recent Onset Chest Pain or Discomfort of Suspected Cardiac Origin” (CG95) recommended that CCTA should be the first-line investigation for all patients with angina and no prior history of CAD. Formal calculation of pretest probability of obstructive CAD based on the long-standing Diamond-Forrester model to determine the appropriate diagnostic testing was no longer advised.33 Neither the 2010 nor the updated 2016 guidelines recommended use of exercise ECG. These recommendations were based on a few key analyses at the center of NICE’s methodology, namely, non-invasive testing’s focus on angina criteria, diagnostic (not prognostic) performance, and cost effectiveness based on proportion of correct diagnoses across a range of pre-test probabilities.34 Although these recommendations were met with controversy, the clinical applications of the NICE guidelines were recently validated with a post hoc analysis of the SCOT-HEART trial. The authors concluded that the NICE approach appropriately selects patients, minimizes unnecessary testing, and within the cohort of patients with anginal chest pain, CCTA is associated with a statistically significant decreased risk of fatal and non-fatal myocardial infarction at 3 years.35
The ESC guidelines for the management of stable CAD were also refreshed with an update in 2019, along with a notable nomenclature change to “chronic coronary syndrome” to capture the continuum CAD pathogenesis. Previously, per the 2013 guidelines, CCTA was indicated in the evaluation of patients with suspected stable CAD with low-to-intermediate pretest probability of 15%-50%, mainly as an alternative to stress imaging as a class IIa level of evidence (LOE) C recommendation.36 The 2019 guidelines upgraded CCTA to a class I LOE B recommendation as the initial test to diagnose CAD in symptomatic patients, equivocal to functional imaging, but preferentially recommended when patient characteristics suggest acquisition of high-quality images. Also notable was the recommendation of an imaging diagnostic test (anatomical or functional), as opposed to exercise ECG as the initial test.37
The 2012 ACC/AHA guidelines for the diagnosis and management of patients with stable IHD remain the most current practice recommendations in the United States at the time of this writing. Much of the discussion involving CCTA parallels that of the older 2010 NICE and 2013 ESC guidelines. Exercise ECG is a class I LOE A recommendation in the evaluation of patients with stable IHD who require non-invasive testing, with supporting evidence dating back to 1989. CCTA is a class IIa LOE C for patients with intermediate pretest probability and deemed reasonable for patients with continued symptoms with a prior normal test, patients with inconclusive exercise or pharmacological stress test, or those unable to undergo stress with myocardial perfusion imaging or echocardiography.3 The American College of Cardiology Foundation (ACCF) Appropriate Use Criteria Task Force updated its 2006 appropriate use criteria for CCTA in 2010. CCTA was deemed “appropriate,” scoring 7 on the appropriate use score (scale 1 to 9) for low-to-intermediate pretest probability of CAD in patients with normal ECGs and cardiac biomarkers.38
Growing evidence for a CCTA-first strategy has started to change healthcare policy. United HealthCare has updated its policy coverage and will reimburse for CCTA when ordered to evaluate stable chest pain for members with low and intermediate risk for CAD.39 In 2008, the Centers for Medicare and Medicaid Services (CMS) published a national coverage decision memorandum for CCTA for the diagnosis of CAD, which was an update of the original national coverage decision regarding general use of CT from 1985. After extensive review, based on the lack of adequately powered studies and concern for the safety profile, a decision was made not to change the national coverage policy.40 Ten years later, in 2018, CMS approved coverage for CT-derived fractional flow reserve (CT-FFR) when used in the appropriate settings.41 Updated CMS national coverage decisions for CCTA have not been published at the time of this writing.
Direction for future research. A limitation of CCTA as an anatomical study is its inability to accurately gauge functional hemodynamic significance of a coronary artery stenotic lesion. Use of computational flow dynamics can yield CT-FFR, which would provide non-invasive quantitative delineation of lesions4 and increase specificity of CCTA when used in tandem.34 Advantages to CT-FFR include use of the same CCTA images without additional scans or additional contrast, as well as utility in multivessel or serial lesions.5 Additional studies that may hold value include investigations to correlate invasive FFR and CT-FFR, technological advances in image acquisition in traditionally difficult-to-assess lesions (such as highly calcified or previously stented lesions), as well as flow modeling with virtual stenting to estimate the impact of revascularization.
Many RCTs have also been undertaken to determine the role of CCTA in acute chest pain, including patients who present to an emergency department.42 Several multisocietal guidelines have integrated and designated CCTA as appropriate use in the evaluation of low-risk patients due in part to its rapidity, high negative predictive value, and cost effectiveness.43,44 Cost effectiveness, time to discharge, and impact on long-term cardiovascular outcomes are all potential areas of future investigation that have been gaining interest. Post hoc analyses of SCOT-HEART determined that patients without angina due to coronary heart disease had the greatest proportional benefit from CCTA, suggesting expanded indications in primary prevention to be investigated in the SCOT-HEART 2 trial.24
Providing additional insight into the physiology of intervention, CCTA is gaining favorability as a research modality, becoming a more cost-effective serial study to measure plaque characteristics compared with invasive intravascular ultrasound. In the EVAPORATE (Effect of Vascepa on Improving Coronary Atherosclerosis in People With High Triglycerides Taking Statin Therapy) trial, multidetector CCTA was used to evaluate the slowing of coronary atherosclerotic plaque progression for the cohort taking icosapent ethyl compared with placebo, adding a valuable mechanistic component to the results of the REDUCE-IT (Reduction of Cardiovascular Events With EPA — Intervention Trial) study.45-47
CCTA as a diagnostic modality in the evaluation of stable IHD has been rigorously scrutinized via multiple large RCTs. Departing from functional testing, which relies on inducible ischemia and the absence of remodeling or collateralization of coronary vasculature, anatomic data gained from CCTA serve to accurately capture lesion-level pathology. Detailed knowledge of coronary anatomy leads to early initiation of optimal medical management, cost efficiency, and improved patient-centered clinical outcomes. CCTA continues to garner interest as it transforms and simplifies traditionally complex algorithmic approaches. Outdated guidelines across the world have been revised in light of the growing body of evidence. A timely iteration of the next ACC/AHA guidelines must include a CCTA-first strategy. With widespread adoption and continued dedicated effort into technological advances, CCTA can evolve into a powerful tool to create lasting change in cardiovascular healthcare.
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From the 1St. Mary Medical Center, Long Beach, California; and 2Lundquist Institute Harbor-UCLA Medical Center, Torrance, California.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Budoff reports grant support from the National Institutes of Health and GE Healthcare. The remaining authors report no conflicts of interest regarding the content herein.
Manuscript accepted November 27, 2020.
Address for correspondence: Vishal I. Patel, MD, Lundquist Institute, 1124 West Carson Street, Torrance, CA 90502. Email: firstname.lastname@example.org