DEFINITION AND PATHOPHYSIOLOGY
Current guidelines define “ischemic equivalent chest pain syndrome” and “angina equivalent” as any of a variety of clinical presentations that suggest underlying coronary artery disease (CAD) such as chest pain, chest tightness, burning, left shoulder pain, jaw pain, dyspnea, or worsening effort tolerance.1 Chest pain secondary to angina pectoris is caused by myocardial ischemia, which occurs when there is an imbalance between myocardial oxygen demand and myocardial oxygen delivery. Demand is related to exertion, emotion, or mental stress, which increase heart rate, left ventricular wall stress, and contractility through release of norepinephrine from adrenergic nerve endings in the myocardium and vascular bed. The normal physiological response to increased demand is coronary artery vasodilation resulting in increased myocardial blood flow (coronary flow reserve); however, the majority of patients with stable chest pain suffer from fixed coronary artery stenoses as a result of atherosclerotic plaque. These lesions are maximally vasodilated at rest, decreasing the coronary flow reserve and resulting in ischemia during episodes of increased oxygen requirements.2 It has been reported that a stenosis between 75% and 95% of the cross-sectional area of a vessel (approximately 50% diameter) is necessary to decrease coronary flow reserve.3 This relationship between blood flow and coronary morphology provides the basis for anatomic imaging techniques such as invasive coronary angiography and coronary computed tomography angiography (CTA); however, other factors also play a role in the pathogenesis of myocardial ischemia, including ventricular hypertrophy, microvascular disease, the metabolic state of the myocardium itself, and transient vasoconstriction of fixed stenoses (secondary to release of vasoconstrictor substances from platelet thrombi and leukocytes and decreased vasodilator substance production from endothelial cells damaged by atherosclerosis).4 In addition, stenosis diameter is not an ideal indicator of resistance to blood flow, as entrance and exit angles, morphology, and length of lesions affect pressure gradients.5 These considerations help explain the value of functional imaging (ie, assessment of the ability of the coronary vasculature to provide adequate blood flow at rest and during periods of increased demand) in the detection and characterization of CAD.
EPIDEMIOLOGY AND COSTS TO SOCIETY
Despite advances in prevention and treatment, cardiovascular disease remains one of the most important health concerns in the world, accounting for more deaths in the United States compared with any other cause. Approximately 9,000,000 American adults are estimated to have angina pectoris,6 and, although the mortality from simple chest pain is negligible, chronic stable angina is the initial manifestation in approximately half of the patients who eventually develop ischemic heart disease.7,8 In addition, half of the patients presenting with myocardial infarction (MI) have preceding angina,9 and the rate of infarction in patients with chronic stable angina is 3% to 3.5% per year.8,10 CAD is already the most expensive condition treated in American hospitals,6 and its prevalence is expected to increase by 16.6% from 2010 to 2030, with a 198% increase in direct costs (from $35.7 to $106.4 billion) and a 53% increase in indirect costs (from $73.2 to $112.3 billion).11
The initial approach to patients presenting with chest pain or anginal equivalents is complex and dependent on many patient-specific factors. The first step is to exclude the diagnosis of acute coronary syndrome or unstable angina pectoris using history, electrocardiographic (ECG) findings, and laboratory tests. The major objectives are then to establish or exclude a diagnosis of CAD and, if present, develop a risk estimate for future cardiac events. Information is then used to develop a therapeutic management plan. The reader is referred to the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for management of patients with chronic stable angina for more detail.12,13
Choosing the appropriate diagnostic pathway is extremely reliant on developing the patient’s pretest probability estimate for significant CAD. Multiple predictive models have been developed,14–19 but the most widely accepted models are based on patient age, sex, and presenting symptoms. Chest pain should be characterized as typical angina, atypical angina, or noncardiac chest pain (Table 1).13 ACC/AHA guidelines provide an algorithm for determining the numerical probability of CAD, which is then used to classify the patient as having a low, intermediate, or high pretest likelihood (Table 2).13 The numerical definition of probability subsets is a matter of judgment and may be influenced by the specific situation; however, most studies and society guidelines define low probability as a <10% likelihood of CAD, intermediate as a probability of 10% to 90%, and high as a >90% probability.13 The most recent Appropriate Use Criteria for cardiac computed tomography (CT) provide a modified table based on the ACC/AHA guidelines that accounts for all age ranges and may prove useful in clinical practice (Table 3).1 Risk factor assessment, in addition to contributing to risk assessments for future adverse events, may also influence the pretest probability.
Depending on the clinical scenario, patients with a low probability for CAD may be treated conservatively or may warrant further testing. Patients with intermediate or high probability often require further noninvasive testing (in certain high-probability patients, direct referral for invasive coronary angiography may be indicated), both to confirm the diagnosis and to provide risk stratification. The choice of diagnostic testing is dependent on patient-specific, provider-specific, and institution-specific factors. Exercise ECG (ie, without imaging), exercise and pharmacologically stressed scintigraphy, exercise and pharmacological stress echocardiography, stress magnetic resonance imaging (MRI), and coronary CTA are available, each with its advantages and limitations.
The diagnostic accuracy of various noninvasive functional tests is dependent on the specific clinical scenario13; details are beyond the scope of this review. Exercise ECG provides incremental diagnostic accuracy over clinical assessment alone in identifying patients with CAD,20,21 in addition to providing information on functional limitations, which has prognostic value.22 Nuclear medicine techniques provide superior diagnostic accuracy in detecting CAD compared with exercise ECG and can identify multivessel disease, help localize disease, and quantify the extent of ischemic and infarcted myocardium.23 Valuable prognostic information is available through the evaluation of global left ventricular function and myocardial viability. Stress echocardiography may be preferred in patients in whom valvular disease, pericardial disease, or ventricular dysfunction is suspected. Diagnostic accuracy is similar to myocardial scintigraphy, and again there is prognostic value in the determination of global left ventricular function.12,13 Currently, stress MRI has limited indications, mainly serving as a tie-breaker and problem-solving tool.
Coronary CTA is a relatively recent diagnostic option, and it has shown promising results in both the diagnosis and risk stratification of patients with stable chest pain (see below). A major difference between the aforementioned tests and coronary CTA is the trade-off between functional (ie, blood flow) and anatomic (ie, stenosis detection) assessment. In addition to their diagnostic role, the prognostic value of functional tests has been well established24 and contributes to risk stratification, which guides therapeutic management. In contrast, coronary CTA is an anatomic study that has the appealing characteristics of speed, accuracy, and noninvasiveness. The information provided by coronary CTA can be incorporated into current management algorithms: the high diagnostic accuracy to detect or rule out CAD can aid clinical assessments in establishing basic medical management and in preventative strategies; the indication for revascularization (a major decision point from both a patient and societal perspective) is largely based on coronary anatomy; and the most important factor to predict survival in patients with CAD is left ventricular function,12,13 which may be evaluated with certain coronary CTA protocols. For these reasons, the major cardiology, radiology, and cardiovascular imaging societies have established coronary CTA as an acceptable modality in the following patients with chronic chest pain syndrome and without known CAD: patients with (1) low pretest probability and ECG uninterpretable or unable to exercise; (2) intermediate pretest probability and ECG uninterpretable or unable to exercise; and (3) intermediate pretest probability and ECG interpretable and able to exercise. It is currently considered inappropriate to use coronary CTA in the evaluation of patients with a high pretest probability who have an interpretable ECG and are able to exercise, and it is uncertain whether coronary CTA is appropriate in patients with a low pretest probability who have an interpretable ECG and are able to exercise or in patients with a high pretest probability who have an uninterpretable ECG or are unable to exercise.1
Although coronary CTA is gaining acceptance as a tool in the initial approach to patients with chronic stable angina, it is unlikely to completely replace functional techniques. Functional testing is still regarded as prognostically incremental to anatomic imaging in several clinical settings.25,26 In addition, it is often difficult to determine the clinical significance of intermediate coronary stenoses with anatomy alone.27–30 Ongoing and future work should help refine the optimal diagnostic and risk stratification algorithms for various clinical scenarios.
PubMed and Medline were searched for various combinations of the following subject headings: “coronary computed tomography angiography,” “stable chest pain,” “diagnostic accuracy,” “prognosis,” “outcomes,” “cost effectiveness,” and “safety.” Each subject was searched for in various forms—for example, “(‘cardiac OR coronary’) AND (‘computed tomography’ OR ‘computer tomography’ OR ‘computed tomographic’ OR ‘computer tomographic’ OR CT) AND (angiography OR angiographic).” Manual screening of retrieved publications’ keywords, authors, and references was performed. Key reviews on the current topics were also reference screened.
DISCUSSION OF ISSUES
Diagnostic Accuracy of Coronary CTA
The rapid rise of coronary CTA has begotten a plethora of studies on diagnostic accuracy; however, the implementation of these data into standardized clinical guidelines has been problematic. A number of obstacles exist.
- Most of the published reports concern single-center studies conducted at academic tertiary-care centers with extensive experience in acquisition and interpretation of coronary CTA, and the applicability of results to mainstream clinical practice is questionable.
- CT technology is improving at a rate that quickly renders results obsolete.
- Data are limited for newer techniques utilizing dose-saving techniques, indicating that the high diagnostic accuracy seen in most studies is accompanied by comparatively high radiation exposure.
- There is a large amount of variability in interpretation—whereas some utilize intent-to-treat designs, in which all coronary artery segments are included in analyses, others exclude segments that are small (generally <1.5 mm), highly calcified, or otherwise uninterpretable.
- Outcome variables are heterogenous and in some cases may provide questionable clinical utility.
- The majority of studies define “obstructive disease” on coronary CTA as coronary artery stenosis ≥50%; this is then compared with invasive coronary angiography findings. However, surgical interventions are usually considered at stenoses ≥70%.
- Anatomic endpoints may be inferior to physiological status (ie, functional ischemia) in guiding patient management.
- The greatest limitation in the available evidence involves the patient populations. Most studies contain inherent referral bias, as included patients were being referred for invasive coronary angiography. Asymptomatic patients, acutely symptomatic patients, and/or those with known CAD are sometimes included. These factors lead to wide variability in the pretest probabilities of CAD (most leading to cohorts with a high pretest probability) and diminish the generalizability and ability of the evidence to establish clear clinical prediction rules for patients with stable chest pain syndrome or angina equivalent.
With these limitations in mind, coronary CTA has consistently shown high diagnostic accuracy to detect obstructive CAD compared with invasive coronary angiography as the reference standard. The excellent sensitivity and negative predictive value (NPV) of coronary CTA are particularly notable, as many individuals advocate that the clinical value of coronary CTA lies in the ability to rule out disease and effectively eliminate further workup. Multiple meta-analyses have been performed on the available literature. An earlier investigation analyzed 28 studies involving 1286 patients and compared the ability of 64-slice multidetector CT with invasive coronary angiography in the detection of ≥50% coronary artery stenosis.31 Patients with suspected CAD, known CAD, prior percutaneous coronary interventions and coronary artery bypass grafting, and suspected acute coronary syndrome were included; unsurprisingly, CAD prevalence was high (median 58%) with a wide range (23% to 96%). Per-patient pooled sensitivity and specificity were 99% and 89%, respectively, with median positive predictive value (PPV) and NPV of 93% and 100%, respectively. Sensitivity and PPV were lower, specificity was higher, and NPV was unchanged in per-vessel analyses. Newer meta-analyses of studies using prospectively ECG-gated acquisitions have yielded similar numbers. Per-patient pooled sensitivity, specificity, PPV, and NPV of 99%, 91%, 94%, and 99%, respectively, were obtained in 14 such studies containing 910 patients with a mean CAD prevalence of 59.5%. The mean effective radiation dose in these studies was 3.3 mSV, suggesting that dose reduction strategies may not decrease diagnostic accuracy.32
In contrast to the multitude of single-center trials, prospective multicenter feasibility studies are limited. Only 4 such studies using exclusively 64-slice multidetector CT or higher are available in the current literature.33–36 CORE6436 and Meijboom et al35 included patients with known CAD and unstable patients, respectively, in addition to stable patients without known CAD. CAD prevalence was predictably high (56% in CORE64 and 68% in Meijboom and colleagues) in these cohorts. In contrast, ACCURACY33 included only stable patients being referred to invasive coronary angiography for stable chest pain syndrome and/or abnormal stress test results, with CAD prevalence of only 25%. OMCAS34 included 2 groups of patients: symptomatic patients with intermediate pretest probability of CAD referred for invasive coronary angiography and asymptomatic patients referred for nonanginal evaluation (aortic disease, congenital heart disease, cardiomyopathy, etc.). The group of symptomatic patients demonstrated a pretest likelihood of 51.2% for obstructive CAD; actual disease prevalence was 61%. Characteristics and findings of the 4 studies can be found in Table 4. The most applicable results, based on inclusion criteria, are ACCURACY and OMCAS; however, there was a large variation in the prevalence of disease (25% vs. 61%, respectively). This highlights the need for more robust clinical prediction rules. Notably, neither of these studies excluded patients on the basis of body mass index or calcium score, and all vessels were included, regardless of size or evaluability. Not surprisingly, ACCURACY demonstrated higher NPV (99%) in a lower-prevalence population, whereas the NPV of OMCAS was only 78%. Interestingly, the study with the highest prevalence (68%) also demonstrated excellent NPV (97%).35 The relatively lower sensitivity and NPV found in CORE64 may be partially explained by the investigators’ handling of unevaluable coronary artery segments, which were considered normal for purposes of analysis. In fact, this approach applies a much higher positivity threshold, with the risk of false-negative findings, whereas all other large trials classified any finding that was inconclusive as positive.
Application of this evidence to the clinical setting is complex. Although coronary CTA appears to be a feasible test for excluding the presence of disease in a lower-prevalence population, the lower PPV implies a risk that false-positive findings may lead to unnecessary invasive diagnostic procedures and interventions and associated costs. OMCAS found significant differences in operator characteristics at less experienced centers, a fact that highlights the necessity of well-trained readers and high measures of quality control. Also, there is no large-scale randomized trial available to comparatively evaluate differences between coronary CTA and other noninvasive imaging tests, such as exercise ECG-testing, MRI, or myocardial perfusion scintigraphy (MPS).
Both the Centers for Medicare and Medicaid Services37,38 and the most recent coronary CTA expert consensus statement5 have, justifiably, called for increased data on the prognostic value of coronary CTA. A growing body of literature is available with evident heterogeneity between studies. Patients with known CAD and questionable indications for coronary CTA referral are sometimes included, and there are large variations in risk factors and pretest probability for CAD between cohorts. Heterogeneity in the classification and reporting of coronary CTA findings renders the pooling of single-center studies difficult. For instance, obstructive disease may be defined as ≥50% or ≥70% stenosis; lesion location and plaque composition are not uniformly reported, and some studies have used segment/stenosis scoring indices that are not widely adapted. Endpoints also vary and include traditional major adverse cardiac events (MACE; MI, cardiac death, unstable angina requiring hospitalization, and coronary revascularization), hard events only (generally, MACE excluding revascularization), and all-cause mortality. These heterogeneities complicate meta-analyses attempting to increase the reliability of available data through pooled analysis. They also highlight gaps in the current evidence for coronary CTA and the difficulties in conducting high-quality, valuable prognostic studies:
- Most studies include coronary revascularization as an endpoint, which may not have been warranted or may have been performed as a result of coronary CTA findings (verification bias).
- Adverse cardiac outcomes have a low incidence, especially when revascularization is excluded, necessitating large cohorts with specific inclusion criteria that are followed up for long periods.39 Importantly, when applying all-cause mortality as an endpoint, the proportion of true cardiovascular-associated death is small according to recent data from the Framingham Heart Study.40
- There are numerous CAD characterization and reporting schemes available, many of which have shown prognostic value; however, the most compelling evidence for the diagnostic accuracy of coronary CTA is mostly limited to the detection or exclusion of ≥50% obstructive disease, calling into question the reliability of advanced characterizations.
- Generalizing available data is problematic, especially in light of evidence that there is variability in CAD prevalence and risks in certain subpopulations, such as African Americans,41 younger patients,42 female patients,43 and diabetics.44
Despite these problems, the current evidence is encouraging. Three meta-analyses39,45,46 and 2 studies based on the international multicenter CONFIRM registry have been published.42,47 The data uniformly demonstrate the utility of coronary CTA as a rule-out test. A normal coronary CTA was associated with 0.17% and 0.4% pooled annualized MACE rates in meta-analyses by Hulten and colleagues and Bamberg and colleagues, respectively, and a 0.5% cumulative MACE rate (21 mo mean follow-up) in a meta-analysis performed by Abdulla and colleagues. Follow-up data on 13,966 patients from the 12-center CONFIRM registry demonstrated annualized all-cause mortality rates of 0.36%,47 whereas another analysis of 23,854 patients from the CONFIRM registry found annualized death rates of 0.28%.42 These data compare favorably with prognosis after normal invasive coronary angiography,48 single-photon emission CT myocardial perfusion imaging (SPECT MPI),49 and stress echocardiography50 and support evidence demonstrating the high NPV of coronary CTA CAD detection in diagnostic accuracy studies. The length of protection implied by a negative coronary CTA is less clear. Subanalysis of patients in the CONFIRM registry with ≥4-year follow-up (1816 patients) showed annualized death rates of only 0.22% in those without atherosclerosis,42 suggesting that 4 years is a reasonable “warranty” period after a normal coronary CTA.
The prognostic value of obstructive disease detected by coronary CTA is also well established by the available literature. Abdulla et al45 recorded a significantly higher cumulative event rate of 16% in patients displaying obstructive (≥50% stenosis) CAD, whereas other meta-analyses found annualized MACE rates of 8.8%46 and 11.9%,39 respectively. Bamberg et al39 calculated a 10.7 hazard ratio for MACE in patients with ≥50% stenosis compared with those without stenosis. It must be emphasized that these results were largely driven by revascularizations; however, significant prognostic value remains when examining only death or MI (3.2% annualized event rate46) or MACE excluding revascularization (6.4% annualized event rate39). Similarly, the CONFIRM registry, which used all-cause mortality as the sole outcome measure, demonstrated increased risk in patients with obstructive disease, with annualized event rates of 4.95% in those with high-risk CAD and 2.9% in those with non–high-risk CAD (high-risk CAD defined as left main coronary artery stenosis ≥50%, 3-vessel stenosis ≥70%, or 2-vessel stenosis ≥70%, including the left anterior descending coronary artery; non–high-risk CAD defined as all others with at least 1 stenosis ≥50%).47 Min et al,42 in analyses of the expanded CONFIRM registry, showed risk-adjusted hazard ratios of 2.60 and 3.13 in patients with ≥50% and ≥70% stenoses, respectively, compared with patients with a normal coronary CTA.
The results of these meta-analyses, the CONFIRM registry, and smaller single-center studies also suggest that coronary CTA provides prognostic value beyond the detection or exclusion of obstructive disease. The most commonly analyzed secondary predictors of future events include plaque severity, location, extent, and morphology (ie, calcified, noncalcified, and mixed). Nonobstructive plaque (<50% stenosis) has consistently shown predictive ability, displaying annualized all-cause mortality of 1.99%47 and a cumulative MACE rate of 3.5% in the meta-analysis by Hulten et al.46 Unsurprisingly, nonobstructive plaque by invasive coronary angiography is also predictive of events,51 but the ability of coronary CTA to see early vessel wall remodeling may provide increased prognostic value. Accordingly, coronary CTA identification of nonobstructive disease has been advocated by some authors as an opportunity to improve risk stratification and secondary preventative measures in certain patients.52 Interestingly, the CONFIRM registry showed a similar mortality risk in patients with nonobstructive disease and in those with 1-vessel obstructive disease (hazard ratio 1.62 vs. 1.75, respectively).42 This points to the value of identifying disease extent in addition to severity and is supported by further analyses showing dose-response relationships for increased hazards of death in patients with 1-vessel, 2-vessel, and 3-vessel disease.42 Segmental analyses also show increased risks for MACE39 and death42 for each additional diseased coronary artery segment. Stenosis location, specifically, left main and proximal left anterior descending CAD, is another important predictor of adverse events.39,42,47 Finally, the ability to identify and characterize plaque morphology has been proposed as a major advantage of coronary CTA; however, the predictive value of this information is less clear compared with the above characterizations. Although most studies have shown that the presence and extent of mixed plaque portend a higher risk for adverse events, data on noncalcified and calcified plaque are inconsistent,53–58 and further studies will be necessary to elucidate the full role of plaque characterization in coronary CTA reporting and risk stratification schemes.
On the basis of the available data, it seems safe to assume that, although several different simplified stratification schemes have value, we may be able to maximize the prognostic value of coronary CTA with more advanced analyses. Chow et al47 used a method based on stenosis severity, extent, and location and found significantly higher annualized death and hazard ratios in patients with high-risk versus non–high-risk obstructive disease (see above). A modified Duke Prognostic CAD index, also accounting for stenosis severity, extent, and location, has shown the ability to predict death.59 Researchers with the CONFIRM registry are currently developing a new grading system that will incorporate classic Framingham risk predictors with plaque severity, extent, location, and morphology.60
Establishment of the incremental prognostic value of coronary CTA beyond more established diagnostic tests, such as coronary artery calcium scoring, invasive coronary angiography, and MPS, will also be important, especially considering the volume of literature supporting the alternative modalities and the costs and radiation associated with coronary CTA. To date, data are favorable but sparse. Multiple studies, including the meta-analysis by Bamberg and colleagues, have established the incremental prognostic value of coronary CTA over coronary artery calcium scoring.39,58,61–63 Shaw et al64 found comparable predictive value of coronary CTA findings (based on modified Duke Prognostic CAD index) and the percentage of ischemic myocardium detected on SPECT MPI in a matched cohort of 693 and 3067 patients undergoing coronary CTA and MPS, respectively, whereas another study demonstrated the increased predictive value of coronary CTA over SPECT MPI.65 A significant amount of work is still necessary to provide reliable clinical guidance for diagnostic modality selection.
Downstream Effects: Outcomes, Utilization, and Costs
The ultimate goal of any diagnostic evaluation is to improve patient outcomes; from a societal perspective, this should be done in a cost-effective manner. Randomized diagnostic trials comparing experimental decision models with the standard of care are the gold standard method for acquiring these data, allowing determination of how tests are used by physicians and comparisons of outcomes and costs.66 Although several randomized diagnostic trials are currently underway, none are currently available, and the available evidence on the downstream effects of coronary CTA is therefore limited. To date, most studies fall into 3 general categories: (1) small, usually single-center observational cohorts; (2) larger observational cohorts utilizing insurance claims data; and (3) simulation models based on prior data. All 3 designs have significant limitations; however, there are trends in data that may provide some insight into major questions: how does coronary CTA influence health outcomes? What effect does coronary CTA have on downstream resource utilization, in particular invasive coronary angiography and revascularization procedures? How do the costs of diagnostic strategies using coronary CTA compare with alternatives? How do the results of coronary CTA affect risk stratification and downstream medical management? All of these questions must be individually framed for various patient populations and clinical scenarios, even within the target population of stable patients with acute chest pain.
In a simulation model comparing 8 diagnostic strategies in base cases of 55-year-old men and women with 70% and 30% pretest probability of CAD, respectively, Ladapo et al67 found that strategies using coronary CTA (with or without additional testing) resulted in lower adverse events and subsequently improved longevity and quality-adjusted life years (QALYs); however, the effect was only marginal, with a 3% reduction in adverse events compared with the least effective strategy. Observational studies support these data. Two large studies, utilizing claims data in patients with low68 or intermediate69 risk for future cardiac events, compared coronary CTA with SPECT as an initial diagnostic tool for suspected CAD. Patients with low risk displayed no difference in rates of MI or hospitalization but significantly lower rates of angina during the 1-year follow-up period,68 whereas there was no difference in the rates of adverse events between intermediate-risk patients undergoing SPECT MPI or coronary CTA.69 Shreibati and colleagues evaluated the largest cohort to date, including 282,830 Medicare patients without known CAD who had undergone MPS, stress echocardiography, exercise ECG, or coronary CTA as their initial workup for stable chest pain. In this higher-risk population (mean age 73.6 y; high rates of diabetes mellitus, hypertension, and hyperlipidemia), patients undergoing coronary CTA had a slightly but significantly lower likelihood of hospitalization for acute MI compared with MPS; all-cause mortality was similar (180-d follow-up period).70 It is noteworthy that none of these claim-based studies were able to quantify the pretest probability of CAD in their population; they relied on inferences based on clinical risk models. In addition, both studies by Min et al68,69 may have included patients referred for acute chest pain.
Downstream Resource Utilization
Most studies have shown decreased rates of invasive coronary angiography and revascularization in diagnostic strategies using coronary CTA compared with alternative noninvasive tests in the initial workup of suspected CAD. Min et al71 performed a simulation model based on the results of the ACCURACY trial, with the base case being a 55-year-old man with 30% pretest probability of obstructive CAD, and found that coronary CTA followed by MPS resulted in the lowest number of subsequent invasive coronary angiographies compared with alternative diagnostic strategies (using various combinations of coronary CTA, MPS, and invasive coronary angiography). Claims data also showed lower rates of subsequent invasive coronary angiography in low-risk and intermediate-risk patients undergoing coronary CTA compared with SPECT MPI; however, downstream SPECT MPI utilization was increased.68,69 In comparison, Shreibati et al70 found that patients who had undergone coronary CTA (compared with MPS) were nearly 2 times more likely to receive subsequent invasive coronary angiography and nearly 2.5 times more likely to undergo revascularization; these differences persisted on multivariate analysis. Although these findings provoke concerning questions regarding real-world practice, they may be partially explained by the patient population, which probably had a high prevalence of disease. In addition, the appropriateness of examination interpretation and subsequent interventions could not be determined. Despite leading to higher rates of invasive coronary angiography compared with MPS, coronary CTA also resulted in a higher proportion of those cases undergoing subsequent revascularization, suggesting revascularization underutilization in the MPS group or overutilization in the coronary CTA group that is not necessarily examination dependent.70 Real-world observational studies from more controlled, academic institutions show that coronary CTA lowers downstream testing, possibly as a result of more appropriate patient selection and/or clinical management. In 1 study, the introduction of coronary CTA into a large urban cardiology practice led to a decrease of 45% in annual invasive coronary angiography utilization, whereas the proportion of invasive coronary angiography requiring percutaneous coronary intervention increased from 19% to 28%72; another retrospective observational study showed downstream testing rates of 20% after coronary CTA compared with 32% after exercise-stress testing in patients with suspected angina.73
The cost-effectiveness of coronary CTA as a triage test in patients with stable angina reflects the above-mentioned data on health outcomes and downstream resource utilization. Simulation models have uniformly found cost advantages; unsurprisingly, these are dependent on test costs, disease prevalence, and willingness-to-pay thresholds. Genders and colleagues found that dual-source coronary CTA reduced health care and direct non–health care costs compared with direct invasive coronary angiography when pretest probability was <87% to 92%. From a societal standpoint, coronary CTA was cost-effective with a pretest probability of up to 44% in men and 37% in women, with a willingness-to-pay threshold set at €80,000/QALY.74 Dorenkamp et al75 also found that dual-source coronary CTA was more cost-effective than direct invasive coronary angiography up to a CAD prevalence of 55%. Dewey and colleagues used a microsimulation model to compare the cost-benefit (cost/correct diagnosis) of coronary CTA, stress MRI, stress echocardiography, exercise ECG, and invasive coronary angiography and found that coronary CTA was most cost-effective with pretest probabilities from 10% (€4425/correctly diagnosed patient with CAD) to 50% (€1469/patient). Invasive coronary angiography was equally cost-effective at 60% pretest probability and was the most effective strategy when pretest likelihood was ≥70%. Importantly, this study did not evaluate SPECT MPI.75 Min and colleagues, basing a model on data from ACCURACY, found that coronary CTA followed by SPECT MPI for equivocal findings was the least expensive strategy per correct diagnosis ($1770/patient); however, coronary CTA only (ie, coronary CTA followed by invasive coronary angiography for positive or equivocal findings) was slightly more effective, resulting in the most favorable incremental cost-effectiveness ratio (ICER; $17,516/correct diagnosis). Similarly, coronary CTA only was the most cost-effective long-term strategy, with ICER of $20,429/QALY. These data reflect results from the base cases (30% pretest probability of obstructive CAD). Acceptability curves from probabilistic sensitivity analysis showed that coronary CTA (with or without subsequent SPECT MPI in equivocal cases) was the most cost-effective at 30% and 50% CAD prevalence with a willingness-to-pay threshold of up to $50,000/QALY; at 80% CAD prevalence, direct invasive coronary angiography became the most cost-effective strategy.71 Ladapo and colleagues, in a similar simulation model (base cases of 55-y-old men and women with atypical chest pain and pretest probability of 70% and 30%, respectively), found that women received the most favorable health outcomes per unit cost when strategies using stress ECG, followed by coronary CTA or coronary CTA, followed by stress ECG, were used, whereas coronary CTA followed by stress ECG was the most cost-effective in men. ICER for coronary CTA followed by stress ECG was $35,000/QALY in women and $26,200/QALY in men.67
Real-world studies using insurance claims data have shown similar results. Decreased CAD-related costs were seen 1 month, 6 months, and 12 months after initial evaluation with coronary CTA compared with SPECT (adjusted costs 25.9% lower, with an average cost of $1075/patient over the first 12 mo) in patients with a low risk for future adverse cardiac events based on traditional risk factors,68 and a similar study in patients with intermediate risk for future events showed a 27% decrease in total health care costs and a 33% decrease in CAD-related expenditures in the 9 months following coronary CTA compared with SPECT MPI.69 In comparison, Shreibati et al70 found that total and CAD-related costs were significantly higher in the 180 days after coronary CTA compared with SPECT MPI, stress echocardiography, or exercise ECG, even after multivariate analysis. This seems to be largely driven by the increased rates of invasive coronary angiography and revascularization seen in this population that could be driven by a high prevalence of disease (see above) and supports simulation models that find coronary CTA not to be cost-effective in populations with a high pretest likelihood of CAD.
Effects on Management
The effect of coronary CTA performance on actual clinical management (beyond referral for invasive coronary angiography or revascularization) is not clear from the available data. Theoretically, the discovery of subclinical disease could prompt primary care physicians to increase their emphasis on preventative strategies such as lifestyle modification. Chow et al47 found that coronary CTA provided incremental value to traditional risk factors and left ventricular ejection fraction in stratifying patients into low-probability, intermediate-probability, and high-probability groups for future CAD, with a net reclassification improvement of 17.8%. Ovrehus et al76 found decreased rates of antiplatelet therapy in patients who had a normal coronary CTA and increased lipid-lowering agent and antiplatelet therapy use in patients with an abnormal coronary CTA. Future randomized trials should provide more information.
Coronary CTA After Equivocal or Abnormal MPS
Coronary CTA has been proposed as a “gatekeeper” to invasive coronary angiography after an inconclusive or suspected abnormal SPECT MPI evaluation performed for the evaluation of stable chest pain, as reflected by the most recently published appropriateness criteria.1 The few available studies suggest that this may be a cost-effective strategy, with up to a 4-fold reduction in costs driven by reductions in unnecessary invasive coronary angiography77,78; however, these are limited to small, single-center observational studies.
The robust anatomic information provided by coronary CTA has prompted concerns over the costs associated with incidental findings. Real-world data showing decreased total health expenditures in patients receiving coronary CTA provide some evidence that incidental findings may not have a major economic impact69; in addition, simulation models have found that follow-up of incidental findings accounts for a small component of overall costs.67 In a small observational study, Lee et al79 found that a large proportion of patients (43%) receiving coronary CTA had incidental findings of some sort, but only 4% of patients actually underwent follow-up imaging or interventions, at an average cost of $17.42 per patient receiving coronary CTA.
Current data suggest that coronary CTA for the initial diagnostic evaluation of patients with stable chest pain provides incremental cost-benefit (cost/correct diagnosis) and cost-effectiveness (cost/QALY) compared with alternative strategies in populations with a low to intermediate prevalence of disease. Findings are variably driven by improved outcomes, decreased costs, or some combination thereof; however, importantly, none of the available data show an adverse effect on clinical outcomes when coronary CTA is used. There are substantial methodological weaknesses in all the published data, but future randomized controlled trials should answer some of the remaining questions. It is important to recall that cost-effectiveness analysis is inherently dependent upon certain assumptions and variables that may be dynamic and/or uncontrollable, such as reimbursement rates and current clinical practice guidelines, and results will be affected by changes in health policy or clinical management. In addition, the cost-effectiveness of a given test is highly sensitive to patient-sensitive and operator-dependent factors, most notably the pretest probability of CAD as well as the prevalence of incidental findings, patient compliance, quality of examination acquisition and interpretation, and actions taken by the treating physicians as a result of the report.
The hypothetical specter of harm associated with radiation exposure from coronary CTA has been a focus of medical and lay press alike. If real, the risk of inducing cancer would have to be factored in all models aimed at measuring coronary CTA effectiveness. One large multicenter study showed a median effective dose from coronary CTA of 12.1 mSv across 50 sites in 2007 (compared with technetium 99m sestamibi MPS, thallium MPS, and invasive coronary angiography, with average effective doses reported to be 9 to 12 mSv, 18 to 21 mSv, and 5 to 7 mSv, respectively80–82). The variability between sites was high, with median effective doses ranging from 5 to 30 mSv.83 The lifetime cancer risk for a 20-year-old woman undergoing coronary CTA was calculated as 1 in 143 in 1 model. Younger age and female sex are thought to be associated with a higher risk: the lifetime risks for a 60-year-old man and 60-year-old woman were calculated as 1 in 1911 and 1 in 715, respectively.82 However, vast uncertainties exist regarding cancer induction by CT radiation, and the American Association of Physicists in Medicine considers risks of medical imaging at effective doses below 50 mSv for single procedures or below 100 mSv for multiple procedures over short time periods too low to be detectable and possibly nonexistent.84 The Association further advices that discussion of risks related to radiation dose from medical imaging procedures should be accompanied by acknowledgment of the benefits of the procedures and states that predictions of hypothetical cancer incidence and deaths in patient populations exposed to CT radiation are highly speculative and should be discouraged. This stance is supported by recent findings that suggest that risk of future cancers associated with CT scans is not remotely as serious as the risk of dying from the diseases that CT is used to diagnose.85
Regardless, data suggest that radiation dose reduction strategies are available and feasible. A prospective study involving 400 nonobese patients receiving 100 kV (n=202) or 120 kV (n=198) coronary CTA showed a 31% relative reduction in radiation exposure without compromising image quality86; similarly, protocols with the newest-generation dual-source scanners allow low-dose (100 kV), prospectively triggered, high-pitch acquisitions in select patients that approach 1 mSv effective radiation dose without compromising image quality.87 Perhaps more encouraging is real-world data showing that dose reduction programs are effective; Raff et al88 examined 4995 patients at 12 sites and demonstrated a reduction in median effective dose from 21 to 10 mSv 1 year after implementation of a collaborative radiation dose reduction program. Increased awareness and availability of existing dose reduction techniques combined with future hardware and software advances should further decrease the radiation exposure associated with coronary CTA.
Future Work and Outlook
There is no doubt that CAD will continue to have an enormous societal impact, both in terms of morbidity and health care utilization.11 The challenge for researchers is to improve the detection and risk stratification of individuals in order to improve patient outcomes, and the looming burden of increased expenditures and limited resources mandates that this be done in a cost-effective manner. The exact role coronary CTA will play in the assessment of patients with chronic stable angina is unknown and will be determined by new technical developments (dose reduction, increased diagnostic accuracy, and expanded diagnostic capabilities) and real-world trials comparing outcomes and costs of coronary CTA with those of other diagnostic strategies.
The relatively moderate PPV of coronary CTA (both in terms of CAD detection and the ability to predict future adverse events) is one area being targeted by researchers. Although some of the problems may be attributable to image quality (eg, beam-hardening artifacts, temporal and spatial resolution, etc.), which should improve with hardware and software developments, the inherent limitations of anatomic assessments are also to blame. Diagnostic algorithms combining anatomic and functional imaging are 1 solution; however, the economic impact of such strategies raises concern. Therefore, there has been considerable interest in evaluating the feasibility of coronary CTA to provide combined functional and anatomic assessments. Researchers are evaluating the ability of coronary CTA to assess coronary artery fractional flow reserve,89 detailed myocardial functional analysis,90 and left ventricular blood supply (at rest, stress, and delayed imaging).91 In addition, dynamic acquisition protocols have been developed for the quantification of myocardial perfusion,92 and researchers attempt to use dual-energy techniques for evaluating the myocardial blood pool.93 One can expect a major paradigm shift should any of these techniques prove to be comparable or superior to traditional functional imaging.
Although the aforementioned developments are exciting, a more immediate priority is providing high-level evidence supporting the use of coronary CTA to improve patient outcomes in a cost-effective manner. Two large multicenter randomized diagnostic trials are currently underway that should provide some answers. The RESCUE trial will enroll 4300 patients with stable angina or angina equivalent and without known CAD; patients will be randomized to receive either coronary CTA or SPECT MPI for their initial diagnostic workup and will be treated according to imaging results. Outcomes and utilization will be compared.94 Similarly, the PROMISE trial will enroll 10,000 symptomatic patients with low to intermediate pretest probability of CAD and randomize them to receive either coronary CTA or traditional stress testing (exercise ECG, stress echocardiography, or stress scintigraphy). Again, patients will be followed up to compare outcomes and costs.95 Until these data are available, clinicians should use the currently available evidence and societal guidelines, personal and institutional experience, and the specific clinical situation to guide their approach to the patient presenting with chronic stable angina.
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