According to the 2009 American Heart Association Heart Disease and Stroke Statistics Update,1 1 of every 3 U.S. adults — almost 100 million individuals — possesses at least one type of cardiovascular disease (CVD), accounting for more than one-third of all deaths in the United States. Among the 800,000 patients who will experience a new myocardial infarction (MI) this year, more than 20% will be clinically unrecognized. This fact is underscored by the observation that almost half of all patients suffering sudden cardiac death or acute MI have no preceding signs or symptoms of CVD. It is therefore of critical importance to identify at-risk patients, in order to implement appropriate therapies aimed at prevention of CVD events.
For this challenge to be achieved requires improved diagnostic algorithms that permit earlier identification of patients with modifiable forms of disease. One potential means for diagnostic evaluation of the at-risk individual involves noninvasive diagnostic imaging and guiding management. In this regard, cardiac computed tomographic angiography (CCTA) has recently joined single-photon emission computed tomography myocardial perfusion imaging (SPECT MPI) and positron emission tomography (PET) MPI as a potentially promising modality for risk assessment. In this review, we discuss the use of these imaging modalities for the assessment of symptomatic patients presenting with chest pain (CP) syndromes and an intermediate likelihood of coronary artery disease (CAD). Of potential interest to the reader, revised appropriate use criteria for radionuclide imaging were recently published, providing an additional perspective on the applications discussed in this review.2
Role of presenting symptoms and demographic factors in determining the need for testing. CP is one of the most frequent complaints encountered in clinical practice, both acutely in the emergency department (ED), and as a chronic symptom in the outpatient setting. Since the consequences of a missed or untreated MI or undetected chronic obstructive CAD can be potentially fatal outcomes, clinicians tend to be meticulous about the investigation of these patients. As the majority of individuals presenting with symptoms do not, in fact, have obstructive CAD, contemporary diagnostic algorithms are often directed toward the exclusion of obstructive CAD as a cause of pain.2 In the acute setting, this assessment relies heavily on clinical history, 12-lead electrocardiography (ECG) and laboratory evidence of myocyte necrosis with at least two consecutive negative cardiac enzyme values. The addition of clinical risk scores (e.g., thrombolysis in myocardial infarction [TIMI] risk score) help the clinician to assess the symptomatic patient.
In the evaluation of the symptomatic patient with suspected CAD, clinicians have generally employed a three-level clinical classification of chest discomfort, dependent upon the degree to which the discomfort resembles typical angina with respect to location, precipitation and relief. A simple set of questions then differentiates typical angina from either atypical angina (two of three angina characteristics or non-anginal CP (less than two characteristics).3,4 These general categories of CP, coupled with a patient’s age and gender, are then integrated as predictors of pre-test likelihood of anatomically obstructive CAD, estimated using either an original Diamond-Forrester,3,5 CASS6 (coronary artery surgery study) or modified ACC/AHA (American College of Cardiology/American Heart Association) classification. While not formally incorporated into the aforementioned assessments of CAD likelihood, clinicians further account for the number and type of CAD risk factors to classify individuals as having a low, intermediate and high pre-test likelihood of CAD.7
The intermediate likelihood of CAD, which is the focus of this review, has been defined in various ranges extending from 10–90%,2 15–85%,8,9 20–80% and 30–70%. Cardiac imaging in these patients generally provides the most significant diagnostic yield and support in the clinical decision-making process, as illustrated by the patient example in Figure 1. In contrast, in patients with a low likelihood of CAD, cardiac imaging for CAD is not considered warranted, since the testing would not be cost effective. Furthermore, in patients with a high likelihood of CAD, the diagnosis of CAD is usually considered established, and cardiac imaging for diagnostic purposes alone would be unlikely to be useful.10
In general, the intermediate pre-test likelihood patient population is comprised of middle-aged patients with atypical angina, younger patients with typical angina or older patients with nonanginal chest pain, with the caveat that the likelihood of CAD in a woman for any category of chest pain and risk factors is similar to that of a man 10 years younger. In recent years, noninvasive stress testing has been used to further evaluate these intermediate-risk patients, since direct referral of such patients to invasive coronary angiography (ICA) is associated with significant cost and diminished effectiveness for identifying obstructive CAD when compared to a stress cardiac imaging-guided strategy10,11 (Figure 2).12
Selecting the right test for the right patient. Example A.
Establishing the diagnosis. When a patient, upon classification of the pre-test in the appropriate setting, presents with symptoms suspicious for CAD, the first objective is to determine the cause of the patient’s symptoms; that is, establishing a diagnosis. In the acute setting, these diagnoses allow triaging of patients for admission or discharge from the ED or the hospital if the patients have already been admitted. In stable patients, usually in the outpatient setting, establishing the diagnosis can guide the decision as to whether medical or invasive therapy is warranted. When the diagnosis of CAD is known, the principal role of noninvasive imaging, particularly the stress-imaging modalities, is risk assessment in which the extent, severity and reversibility of perfusion deficits can be employed to determine a patient’s future prognosis. These data can also be used to appropriately guide management decisions, which chiefly deal with whether coronary revascularization should be considered.13 In general, patients with stable, symptom-limiting angina refractory to medical therapy in the outpatient setting may proceed directly to coronary angiography, while those with intermediate or high suspicion of acute coronary syndromes (ACS) presenting in the ED are hospitalized for direct referral to coronary angiography. On the other end of the likelihood spectrum, patients with vague symptoms or a low likelihood of CAD (Risk-based approach for selecting patients for invasive coronary angiography.
Possible ACS. In the acute CP patient, if the likelihood of an ACS is low, but insufficiently low to simply discharge the patient, it has become common practice to perform a resting imaging study (most commonly with myocardial perfusion imaging [MPI], but also possibly with echocardiography or magnetic resonance imaging [MRI]). If the MPI rest study is abnormal, the patient is generally admitted directly for further observation and evaluation. If the MPI rest study is normal, however, an MPI stress study is generally advocated, as normal resting perfusion does not preclude reversible myocardial ischemia.18,19 This diagnostic evaluation algorithm is highly successful for evaluation, as the negative predictive value of the rest/stress MPI studies for ACS exceeds 99%.17
An alternative approach realizing increasing utilization is the performance of CCTA in this group of patients. In this regard, a single-center pilot randomized study of 200 patients presenting with acute CP demonstrated the time- and cost-effectiveness of this approach compared to rest/stress MPI, albeit in a lower-risk population.20 As with SPECT-MPI, the normal CCTA in this setting has a negative predictive value of > 99%. Further confirmation of these initial results is being examined by the CT-STAT study, a recently completed multicenter trial of 750 low-risk patients randomized to either CCTA or rest/stress MPI that is currently in the stages of data analysis. Since a large proportion of the patients seen for imaging in this setting have normal test results, the vast majority of the patients studied with either of these techniques can be safely discharged.
Risk-based approach for selecting patients for invasive coronary angiography.
Stable patients. For the patient with an intermediate pre-test likelihood of CAD presenting for office-based CP evaluation, a CCTA-based diagnostic strategy can be similarly employed (Figure 3).21 After CCTA performance, the need for further testing and therapy may be guided by the extent and severity of the observed disease. If the CCTA is normal (e.g., no coronary artery stenosis, no coronary calcium), the patient could be reliably reassured that the etiology of the CP is not related to coronary atherosclerosis. If the CCTA is mildly abnormal (e.g., mild coronary stenosis or minimal coronary calcium), primary prevention may be initiated. Given that the negative predictive value of CCTA approaches 99% across a wide CAD prevalence range,14,15 the ability to successfully exclude obstructive CAD is a principle attribute of this CCTA-based strategy. In contrast, if a critical proximal coronary artery stenosis is observed, direct referral for selective coronary angiography may be most appropriate, particularly if revascularization is being considered for relief of symptoms. It is worth mentioning that the rather modest specificity and positive predictive values of CCTA in individuals without known CAD — underlying excessive rates of false-positives — may promote unnecessary ICA if judicious selective catheterization criteria are not applied.
As the information provided by present-day CCTA is limited to anatomic findings, it is often unclear whether “positive” CCTA scans — as defined by the presence of a ≥ 50% epicardial coronary artery stenosis — are a cause of a hemodynamically significant limitation of epicardial coronary artery blood flow. Indeed, several studies have observed that a stenosis by CCTA at the 50% threshold is not highly predictive of ischemia on stress SPECT or positron emission tomography (PET) MPI.22–24 Thus, if a coronary stenosis is defined by CCTA, but the anatomy is not “compelling” regarding the need for revascularization, referral for stress ischemia testing (e.g., MPI) may be appropriate in certain cases to determine the hemodynamic consequence of the observed stenosis.
The concept that additional testing for ischemia might be needed following positive CCTA examinations raises a concern of the layering of testing. While this combined testing is likely necessary in some cases, there are ways in which the frequency of its use can be reduced. One method is to interpret the CCTA based upon a spectrum of % coronary artery stenosis, rather than as a binary dichotimization of “normal” and “abnormal”. In this regard, a recent manuscript25 has shown that a graded classification of results of CCTA can reduce the need for additional testing for ruling out hemodynamically significant CAD. With this approach, if lesions by CCTA exhibit 70% is highly unlikely. If a lesion is considered ≥ 70% narrowed, ICA is unlikely to show Conclusions
Given the recent emergence of CCTA as an effective noninvasive procedure for CAD detection, it is as yet unclear whether CCTA or MPI is the most beneficial initial test for the evaluation of the symptomatic patient with suspected CAD. At present, both strategies are highly effective for the diagnosis and exclusion of CAD, although future studies evaluating CCTA and MPI in isolation, as well as in combination, will be necessary to definitively determine which clinical evaluation algorithms should be routinely employed. In parallel, current research suggests that in the future the field of molecular imaging will add additional complementary information to that which is already provided by CCTA or MPI.
Acknowledgement. The authors wish to acknowledge the editorial assistance of Xingping Kang, MD, in the preparation of this manuscript.
From the aDepartment of Imaging and Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California; bDepartment of Medicine, David Geffen School of Medicine, UCLA, Los Angeles; cHeart Center, William Beaumont Hospital, Royal Oak, Michigan; dWeill Medical College of Cornell University, The New York Presbyterian Hospital, New York, New York; and eEmory University School of Medicine, Atlanta, Georgia.
The authors report no conflicts of interest regarding the content herein.
Manuscript submitted June 8, 2009 and final version accepted June 12, 2009.
Address for correspondence: Daniel S. Berman, MD, Professor of Medicine, UCLA School of Medicine, Director, Nuclear Cardiology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Room 1258, Los Angeles, CA 90048. E-mail bermand@cshs.org
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