CLINICAL STUDIES
Coronary calcification by electron beam computed tomography and obstructive coronary artery disease: a model for costs and effectiveness of diagnosis as compared with conventional cardiac testing methods
John A. Rumberger, PhD, MD, FACC*  ,
Thomas Behrenbeck, MD, PhD* ,
Jerome F. Breen, MD and
Patrick F. Sheedy, II, MD
* Department of Cardiovascular Diseases, Mayo Clinic and Foundation, Rochester, Minnesota, USA
Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, Minnesota, USA
Department of Diagnostic Radiology, Mayo Clinic and Foundation, Rochester, Minnesota, USA
Manuscript received March 31, 1998;
revised manuscript received September 1, 1998,
accepted October 22, 1998.
Reprint requests and correspondence: Dr. John A. Rumberger, Diagnostic Cardiovascular Consultants, Inc., Suite 1400, Columbus, Ohio 43215
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Abstract
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Objectives
The purpose of this study was to determine if electron beam computed tomography (EBCT) has potential as a cost-effective approach to diagnosis of obstructive coronary disease.
Background
Coronary calcification quantified by EBCT is closely related to the extent of atherosclerosis.
Methods
A model based upon published sensitivities (Se)/specificities (Sp) for diagnosis in an ambulatory patient of obstructive coronary disease ( 50% stenosis) and population prevalence was tested for angiography alone, or treadmill exercise, stress echocardiography, stress thallium or predetermined EBCT calcium score outpoints, followed by angiography if indicated.
Results
Total direct testing costs increased in proportion to disease prevalence whereas cost-effectiveness, direct costs/patient diagnosed correctly with disease, decreased as a function of prevalence. Using an EBCT calcium score of 168 (Se/Sp = 71%/90%) provided for the least costly and most cost-effective noninvasive pathway. Calcium scores of 80 (Se/Sp = 84%/84%) and 37 (Se/Sp = 90%/77%) were also cost-effective when prevalence of disease was  70%; but results for a >0 calcium score (Se/Sp = 95%/46%) cutpoint were not superior to conventional methods. Calcium score cutpoints of 37, 80 or 168 provided similar or superior overall negative and positive predictive values to conventional noninvasive testing pathways across all prevalence subgroups.
Conclusions
In ambulatory patients evaluated for obstructive coronary disease, a testing pathway utilizing quantification of coronary calcium by EBCT as an initial noninvasive testing approach minimized direct costs, and maximized cost-effectiveness in population groups with low/moderate disease prevalence (70%); as expected, direct angiography as the first and only test proved most cost-effective in patients with a high prevalence (>70%) of disease.
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Abbreviations and Acronyms
| | ANGIO | = selective coronary arteriography | | EBCT | = electron beam computed tomography | | ECHO | = treadmill exercise testing and two-dimensional echocardiography | | Se | = sensitivity | | Sp | = specificity | | THALLIUM | = treadmill exercise testing with thallium scintigraphy | | TMET | = treadmill exercise testing |
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Spiraling health care costs and the projection of reduced reimbursement for physician and procedural expenses have created a cogent issue of "cost-effectiveness" resulting in design of disease-specific diagnostic pathways and algorithms. Concerns are particularly germane in the ambulatory patient presenting de novo with possible obstructive coronary disease, where the consulting physician must decide on the most prudent diagnostic workup. The problem is to employ a testing pathway with maximum initial triage effectiveness, which also allows for minimization of costs.
Electron beam computed tomography (EBCT) and quantification of coronary artery calcification have emerged as a powerful tool to detect coronary atherosclerosis. Coronary calcification is closely associated with mural atheromatous plaque (1–3). Recent studies have demonstrated that intramural calcium can be observed in many phases of atherosclerotic involvement, and its presence denotes an active process of plaque development (4). Our laboratory and others have shown an association between EBCT calcium content or "score" and severity or extent of luminal coronary disease (5–9). Furthermore, the amount of calcium correlates directly with the amount of coronary atherosclerotic plaque (2,3) and the calcium "score" has potential to identify patients at risk for cardiac events (10–12). However, an important question remains as to whether EBCT can play a role similar to the more traditional noninvasive testing methods in detecting obstructive coronary artery disease.
The purpose of the current study was to determine if an algorithm using EBCT and the quantification of coronary calcium, applied to a prototypic ambulatory patient population, would have potential as an initial cost-effective testing pathway for the diagnosis of obstructive disease. The analysis examined application of four separate calcium "scores" as a function of variable prevalence of obstructive coronary disease in the population under examination and compares results with currently established conventional methods for invasive and noninvasive diagnosis.
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Methods
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Diagnostic testing methods.
Electron beam computed tomography
Electron beam computed tomography has been extensively validated regarding noninvasive identification and quantification of coronary calcification (2,3,5–12). Scanning is completed within minutes, and requires minimal cooperation and no contrast media administration. Forty consecutive, single slice, 3-mm thick, nonoverlapping, electrocardiographically triggered, 100-ms scans are performed. Depending on the patient’s pulse rate, two serial breath holds may be required to acquire scans from the root of the aorta and the origin of the left main coronary artery through distal portions of the right coronary artery. The appearance of high density intramural coronary calcium deposits adjacent to low density soft tissue and surrounding fat facilitates the identification and quantification of calcium by EBCT.
Traditional "stress testing"
The commonly applied "conventional" forms of noninvasive testing for obstructive coronary disease include treadmill exercise, stress echocardiography and stress thallium-201. Numerous publications on each method have established sensitivities and specificities for angiographic diagnosis of obstructive coronary disease in an otherwise ambulatory population. For the current comparative calculations, literature regarding traditional noninvasive methods to diagnose "obstructive" coronary disease was consulted if the definition of "disease" was the presence of a 50% or greater narrowing on a subsequent coronary angiogram.
Model of diagnostic testing pathways and direct costs analysis.
The testing model chosen for analysis was adapted from the original publication by Patterson et al. (13), which examined the cost-effectiveness of four separate clinical policies for the diagnosis of coronary artery disease as a function of the pretest likelihood (i.e., prevalence) of disease. This model was later extended to examine specifically the costs and cost-effectiveness of traditional treadmill exercise, stress thallium and positron emission tomography for the diagnosis of obstructive coronary disease (14). Specific equations and detailed algorithms for these applications were provided in the appendices of each publication and are not repeated here.
Briefly, the current model proposed to evaluate prototypic groups of patients presenting with a clinical history suggestive of obstructive coronary disease and requiring further evaluation. It was assumed that this was a de novo presentation and that the patient was ambulatory with a normal resting electrocardiogram without contraindications to perform a maximal treadmill exercise. The model would then have the clinician, in turn, perform a single noninvasive diagnostic test. The diagnostic pathways were: 1) a standard, graded treadmill exercise test with electrocardiographic monitoring (TMET); 2) a graded exercise test combined with rest and stress imaging with two-dimensional echocardiography (ECHO); 3) a graded exercise test combined with rest and stress imaging using single-photon emission computed tomographic imaging with thallium-201 (THALLIUM), or 4) an EBCT scan to quantify the degree of coronary calcification.
A schematic of the model applied here and the testing pathways is given in Figure 1. If the initial noninvasive test was negative, no further testing was undertaken, and no further direct diagnostic costs were incurred. However, if the initial noninvasive test was deemed positive or nondiagnostic, the patient directly underwent selective coronary angiography, for confirmation of the diagnosis. The total initial costs for each noninvasive pathway, as a function of disease prevalence (i.e., pretest likelihood), included the initial fee for the noninvasive test (done in all patients), the cost of any complication associated with performance of the noninvasive test, the costs of angiography (if performed) and the costs for any complications from angiography. For comparison to noninvasive testing strategies, a pathway that involved initial invasive angiography alone (selective coronary arteriography [ANGIO]) was analyzed separately. Cost-effectiveness was defined as the ratio of the total costs for any given testing pathway to the total number of patients within that prevalence group correctly identified with obstructive coronary disease (13,14).
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Figure 1 Schematic of cost-effectiveness model for diagnosis of obstructive coronary artery disease. EBCT = electron beam computed tomography; ECHO = treadmill exercise testing and two-dimensional echocardiography; THALLIUM = treadmill exercise testing with thallium scintigraphy; TMET = treadmill exercise test.
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Input to costs and effectiveness model.
Electron beam computed tomography
Application of traditional stress testing methods have employed specific criteria for a positive versus a negative or normal test; an example is using the development of 1 mm of horizontal electrocardiographic ST segment depression beyond baseline as a positive treadmill exercise response for ischemia. Such criteria are not currently established for EBCT, but are required for the current model. One potential criteria for a positive EBCT study is to define this as the presence of "any" quantifiable coronary calcium (that is, a calcium score >0). Several studies have shown that the presence of any coronary artery calcium detected by EBCT is highly sensitive for obstructive coronary artery stenosis, albeit with a low associated specificity (6–8). However, use of this criteria could still provide for a cost-efficient screening test for obstructive coronary disease. To determine an applicable sensitivity and specificity for "any" coronary calcium (calcium scores >0) for input to the model, data from three separate laboratories and patient populations were analyzed. Listed sensitivities and specificities of a positive EBCT for detection of a 50% stenosis on coronary angiography were noted, and a weighted average for the three studies was determined. The weights assigned to these calculations were the number of patients with obstructive disease identified in the study for sensitivity and the number of patients without obstructive disease identified in the study for specificity (15). Individual data from these studies are shown in Table 1. For a calcium score >0, the weighted averaged sensitivity was 95%, and the weighted averaged specificity was 46% for at least a 50% or greater angiographic stenosis.
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Table 1 Survey of Three Previously Published Studies Using EBCT and "Any" Coronary Calcium (i.e., a Score >0) for the Diagnosis of Obstructive Coronary Disease (50% Stenosis at Angiography)
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Additional criteria for a positive EBCT calcium scan to diagnose obstructive disease are available in addition to those discussed above to provide for a comprehensive comparison to conventional stress testing pathways. The coronary artery calcium content or "score," originally introduced by Agatston (16), is a product of the area of calcification (at least two contiguous pixels [2,5,6,9] with a computed tomography density >130 Hounsfield units) per coronary segment and a factor rated 1 through 4 dictated by the maximum calcium density within that segment. Since the calcium score is a continuous variable, receiver operating characteristic analysis can be used to define sensitivity and specificity of a variety of calcium score "cutpoints," which may be considered for the detection of obstructive coronary disease by EBCT in the current model.
To assess variable EBCT coronary calcium scores and the sensitivity and specificity for detecting obstructive coronary disease, results from patients who underwent both EBCT scanning and direct coronary angiography at the Mayo Clinic were analyzed. The patient population consisted of men and women who had no prior documented obstructive coronary disease, most of whom had undergone prior conventional noninvasive testing, and who had been scheduled by their cardiologist for a diagnostic coronary angiogram. Results from these patients and the establishment of specific values or ranges for calcium scores as a function of angiographic disease severity have been published previously (9).
Details of the patient population are found elsewhere (9), but briefly 213 consecutive patients were included as part of the analysis (152 men and 51 women, average age 50 ± 9 years). Seventy-five percent (n = 160) underwent angiography for assessment of chest pain, 12% (n = 25) had abnormal stress tests but no angina, 8% (n = 17) had unexplained heart failure and the remainder (5%, n = 11) had a questionable history of prior infarction, pericarditis or unexplained dyspnea. Angiography demonstrated maximum luminal diameter stenoses from 0 to 100%, with 47% having "nonobstructive" disease and 53% with at least one 50% or greater diameter stenosis. Each EBCT scan was analyzed as previously discussed (6–8,16–18). For each study a total (whole heart) calcium "score" was determined (16). Calcium scores in the 213 angiographic patients ranged from 0 to 4091. The arithmetic mean calcium score was 440 ± 756; the 25th percentile was a score of 2.4 and the 75th percentile was a score of 541.3.
Receiver operating characteristic analysis (5,6,9) was used to establish relationships between total EBCT coronary calcium score and the presence of at least one 50% or greater coronary artery narrowing at angiography. In general, sensitivity decreases whereas specificity increases as calcium score increases above zero (9). Which calcium score value and, indirectly its associated sensitivity (Se) and specificity (Sp) for obstructive disease, would provide for comparisons of costs and cost-effectiveness to conventional testing methods was the basis for the current investigation. To conduct a variable sensitivity analysis, in addition to the mere presence of coronary calcium (i.e., score >0 as discussed above), three additional calcium score cutpoints were included for analysis. The calcium scores chosen represent values or ranges that are "optimal" (i.e., matched sensitivity and specificity) versus high specificity (but moderate sensitivity) versus high sensitivity (but moderate specificity). From reference 9, these values are: a score 37 of (Se = 90%, Sp = 77%), a score of 80 ("optimal" Se and Sp of 84% respectively) and a score of 168 (Se = 71%, Sp = 90%).
Table 2 shows the data used for input to the model for EBCT and the four separate calcium "scores." Since there is no risk to the patient for this noncontrast CT scan, the complication rate is given as 0%. A nondiagnostic scan in a patient with normal sinus rhythm and no additional medical problems, as is the prototypical patient for all noninvasive tests in the current model, is unusual and estimated to be 2% at most. Electron beam computed tomographic scanning for coronary calcium is a limited computed tomographic scan of the chest, without contrast, and the fee is currently $377 at our institution. Local non-Medicare fees for conventional cardiac testing, referenced to that for EBCT, are shown on Table 2.
Conventional stress testing
Input to the model included the fee for the initial noninvasive test, the fee for angiography (outpatient, limited hospital stay, diagnostic only, no ventriculography), the sensitivity and specificity for each noninvasive test, the rate of any additional hospitalization costs for any clinically important cardiovascular complications associated with performance of the noninvasive test or angiography (death, ventricular fibrillation, myocardial infarction, cerebral infarction, vascular surgical repair, estimated at $40,000/event [14]) and the nondiagnostic rate for each test in the testing pathway. Modifications of some input parameters from the study by Patterson (14) were made to reflect local fees and experience. Previously published meta-analyses or review articles were used for definition of sensitivity and specificity for TMET (15), ECHO (19) and THALLIUM (20). Issues such as potential variations in the accuracy of exercise testing as a function of patient gender (21), the potential for referral bias to alter sensitivity and specificity (seen in all noninvasive tests when compared with a "reference standard" such as angiography) or other potentially confounding clinical factors that may influence interpretation (e.g., hypertension) were not used to modify the input data for the current model. Input parameters for the model are given in Table 2 for TMET, ECHO, THALLIUM and ANGIO.
Costs analyses.
Data for "total direct costs" represent the combined expenses for the noninvasive test and any of its complications, and for angiography and costs of its complications (if performed). Cost-effectiveness was determined by dividing the total direct costs at a given disease prevalence by the number of patients correctly diagnosed with obstructive coronary disease for that same pretest likelihood (14). Five separate obstructive disease prevalence groups were examined; these were 0.1 (10%), 0.2 (20%), 0.5 (50%), 0.7 (70%) and 1.0 (100%). Comparisons of the total number of patients with a positive noninvasive test versus angiography, and the total number of patients correctly diagnosed for any testing pathway were analyzed, as a function of disease prevalence, using a one-to-one comparison of proportions. A value of p < 0.05 was considered to achieve statistical significance. Assuming 100 patients entering each portion of the testing pathway, the absolute number of false negative, false positive, true positive and true negative studies was determined for all prevalence subgroups, and the positive and negative predictive values were calculated. These were expressed as a percentage as: negative predictive value = 100 x (total true negatives)/(true negatives + false negatives), and positive predictive value = 100 x (total true positives)/(true positives + false positives) (22).
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Results
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Total numbers of patients undergoing angiography for each testing pathway.
The model assumed for convenience of calculations that 100 patients in each prevalence group underwent each of the eight testing pathways (ANGIO, TMET, THALLIUM, ECHO, and four separate criteria for a "positive" EBCT). Since sensitivities, specificities and nondiagnostic rates for each of the noninvasive pathways were variable, differences in the total number out of 100 tested who had an abnormal test, and thus went on to coronary angiography, would be anticipated, as dictated by model design. Table 3 shows the number of patients out of 100 tested in each prevalence group referred for angiography, for each of the testing pathways. For ANGIO alone, all 100 had an invasive procedure. As would be expected due to model design, across all prevalence groups there were significantly fewer individuals referred for angiography following any initial noninvasive testing pathway than for angiography alone. There were also differences, as a function of disease prevalence, in the numbers of patients referred for angiography between various noninvasive testing pathways. At 100% disease prevalence there were fewer patients referred for angiography using a calcium score of 168 than for any other noninvasive strategy except for TMET and a calcium score of 80. At a prevalence of 70%, fewer patients required angiography using a calcium score of 168 as a threshold for a positive test than using a calcium score of >0 as a positive test. For patients with prevalence of 0.5, 0.2 and 0.1 more initial angiograms were performed for the pathway using EBCT and a calcium score >0 as criteria for a positive test than for any other initial noninvasive strategy. At a prevalence of 0.7 more angiograms were done using a calcium score >0 than for ECHO, EBCT at a score of 80, EBCT at a score of 168 and TMET. At prevalence of 1.0, more angiograms were done using a calcium score of >0 than for a score of 80, for ECHO and for TMET noninvasive pathways.
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Table 3 Number of Patients out of 100 in Each Prevalence Group and for Each Testing Pathway Undergoing Angiography Directly or for a Positive or Nondiagnostic Noninvasive Test
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Total direct costs for each testing pathway as a function of prevalence of disease.
Table 4 gives results for the combined (total) direct costs per patient (in dollars) according to the model for each of the seven noninvasive testing pathways, and for ANGIO alone. The costs for angiography alone (as per model design) were flat across the entire prevalence range. All noninvasive testing pathways, however, showed costs that increased in direct proportion to the prevalence of disease in the population. The lowest total costs across all prevalence ranges was for the pathway using an EBCT calcium score of 168. For prevalence groups of 0.1, 0.2, 0.5 and 0.7, the pathways using an EBCT calcium score of 80, an EBCT calcium score of 37, TMET, ECHO, THALLIUM (except at prevalence of 0.7) and an EBCT score >0 were, respectively, the second, third, fourth, fifth and sixth least costly noninvasive pathways. At a prevalence of 1.0 ANGIO as an initial testing strategy involved less total costs than the noninvasive pathways, except for TMET and an EBCT calcium score of 168.
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Table 4 Total Combined Costs per Patient for Each of the Eight Diagnostic Testing Pathways as a Function of Prevalence of Coronary Artery Disease in the Population Tested
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Number of patients correctly diagnosed with obstructive disease for each pathway.
Table 5 shows the absolute number of patients (out of 100 tested) for each prevalence group who had a correct diagnosis of obstructive disease at the end of any one of the eight testing pathways. The "true positive rate" is given in parentheses next to each absolute number. For disease prevalence of 0.7 or less, the number of patients in each testing pathway diagnosed using an initial noninvasive strategy was not proportionally different than the number diagnosed by angiography alone. The only exceptions were at a prevalence of 0.7 (as with a prevalence of 1.0), where proportionally fewer patients had a correct diagnosis by undergoing TMET or use of an EBCT score of 168 than any other noninvasive or invasive testing pathway. At a disease prevalence of 1.0 (100%), fewer patients had a correct diagnosis by undergoing any noninvasive test first rather than proceeding directly to angiography. The only exception was for an EBCT calcium score >0 as criterion for a positive test, where 95 out of 100 would have been referred for angiography.
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Table 5 Percentage of Patients Correctly Diagnosed (True Positive Rate) and Absolute Number (in Parentheses) With Obstructive Coronary Disease out of 100 Tested in Each Prevalence Group at Completion of Any Testing Pathway
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Cost-effectiveness for each testing pathway.
Table 6 gives the "cost-effectiveness" in dollars per patient correctly diagnosed with obstructive disease for each testing pathway. These data are the total direct costs given in Table 4 divided by the corresponding absolute number of patients correctly diagnosed for each prevalence and pathway as given in Table 5. These costs, rather than progressively increasing, as for total direct costs (Table 4), decreased as prevalence of disease rose from 0.1 to 1.0. For prevalence of disease 0.7, examinations using EBCT with a score of 168, a score of 80 or a score of 37 were generally the first, second and third most cost-efficient initial diagnostic testing pathways, respectively. These were followed in order by TMET as fourth, ECHO as fifth and THALLIUM as sixth. The testing pathway using an EBCT calcium score >0 was actually the least cost-efficient of the noninvasive testing strategies. However, in the highest prevalence group (>70% with obstructive disease), initial angiography with no prior noninvasive testing became the most cost-effective strategy for the diagnosis of obstructive coronary artery disease.
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Table 6 "Cost-Effectiveness" (Total Direct Costs in Dollars per Patient Correctly Diagnosed With Obstructive Coronary Artery Disease) for the Individual Diagnostic Testing Pathways
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Negative and positive predictive values of each testing pathway.
Tables 7 and 8 show the calculated negative and positive predictive values for the combined noninvasive/angiography testing pathways as compared with the use of angiography alone. By study design, angiography was the reference standard for obstructive disease and thus has both 100% negative and 100% positive predictive values. In general for the initial noninvasive strategies, negative predictive value (as expected) decreased as disease prevalence increased in the population undergoing testing. Just the opposite was seen for positive predictive value as a function of prevalence.
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Table 7 Negative Predictive Value of Testing Pathway as a Function of Prevalence of Disease in the Population Tested
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Table 8 Positive Predictive Value of Testing Pathways as a Function of Prevalence of Disease in the Population Tested
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For low prevalence (0.1 and 0.2), the negative predictive value of all testing pathways was very high, ranging from 91% to 100%. For the initial noninvasive testing and intermediate (0.5) or higher prevalence of disease, use of an EBCT score >0 showed the highest negative predictive value followed in order by an EBCT score of 37, THALLIUM, ECHO, EBCT score of 80, EBCT score of 168 and TMET. Except for these latter two testing pathways, these values ranged from 83% to 92%. The negative predictive value of all tests except angiography fell off precipitously as prevalence approached 0.7 or greater; this is reflective of the dominance of true coronary disease in that population.
For the noninvasive testing pathways, the positive predictive value, up to disease prevalence of 0.7, was generally highest using an EBCT score of 168, but was in general quite poor when prevalence was low. Overall, positive predictive values were very similar for ECHO and an EBCT score of 80, followed in order by an EBCT score of 37, THALLIUM and TMET.
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Discussion
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Seven different noninvasive testing pathways and one involving coronary angiography alone were evaluated in a model that examined initial diagnostic costs of prototypic ambulatory, symptomatic patients undergoing de novo evaluation for obstructive coronary disease. The major aims of the analyses were assessment of total diagnostic workup costs, cost-effectiveness and the overall predictive values of the various testing pathways, as a function of prevalence (pretest likelihood) of disease. Several conclusions can be drawn based upon the results presented. First, three out of the four EBCT models (calcium score of 168, score of 80 and score of 37, respectively) were the least costly of the eight pathways examined for the diagnosis of obstructive coronary disease, across all prevalence groups. However, the EBCT model using a score >0 (i.e., any calcium) was actually the most costly, except for direct ANGIO alone. Second, these same three least costly EBCT pathways were also the most cost-effective for low (0.1, 0.2) and moderate (0.5, 0.7) prevalence groups. The negative predictive values, regardless of the noninvasive pathway chosen, were very high for low prevalence groups but fell precipitously as prevalence increased to moderate (0.5, 0.7) and high (1.0) values. Pathways using EBCT and calcium scores cutpoints of 168, 80 and 37 had negative predictive values comparable to the more expensive diagnostic paths of ECHO, THALLIUM and ANGIO. Positive predictive values were low for all paths at low prevalence and increased as prevalence increased. The same three pathways using EBCT provided positive predictive values, however, comparable to those of the THALLIUM and ECHO noninvasive pathways. Third, when the prevalence of disease in the population was high (exceeding 0.7 or 70%), the least costly, maximum cost-effective and most predictive pathway for the establishment of obstructive coronary disease was direct invasive angiography, with no prior noninvasive studies.
Limitations.
There are several limitations of the current presentation. First, the analysis was "theoretical"; that is, conclusions were not based upon prospective clinical investigations comparing EBCT, THALLIUM, ECHO, TMET and ANGIO, but on a mathematical model. The current model does not provide input for secondary parameters derived from traditional noninvasive studies such as duration of exercise, heart rate modulation, blood pressure response, incidence of dysrhythmias with exercise or increased thallium-201 lung uptake. Such data provide important prognostic information, but do not enter into an analysis examining solely costs of the initial diagnostic workup. Thus confirmation remains via direct clinical comparisons. Certainly a "late" positive stress test may have different clinical implications from an "early" positive stress test, but a diagnosis of obstructive coronary disease would remain unchanged. The current computer model data, however, do provide a framework for obligatory clinical investigations. Second, the analysis examined direct diagnostic costs only and did not consider additional, albeit less tangible parameters. Thus, the potential for additional costs as a consequence of delaying the diagnosis of obstructive disease was not included as an outcome for an initially falsely negative noninvasive test. The initial model proposed by Patterson and colleagues (13,14) also estimated changes in quality of life in subjects, both with and without a correct diagnosis of coronary artery disease at completion of testing. Additional issues along these lines to estimate additional indirect costs associated with different (long-term) clinical outcomes were not presented here. Although the model is robust, and these calculations could have been incorporated, they required additional theoretical (and more tenuous) estimates, which were not the primary objective of this direct costs economic analysis.
Third, only prespecified EBCT calcium score cutpoints were examined. Electron beam computed tomography coronary calcium scores of >0, 37, 80 and 168 were used as thresholds for a positive test in the sensitivity analysis. Patients with scores of <168, <80, <37 or even no coronary calcium would be called "negative" within their respective testing pathways, and yet, as pointed out by prior studies, may still have coronary plaque disease (2,3). The cutpoint of 80 was chosen because it resulted in maximizing both sensitivity and specificity based upon 213 clinical studies comparing EBCT calcification and maximal luminal stenoses seen at angiography (9). Two additional EBCT cutpoints were chosen to allow analysis of thresholds with either a high sensitivity and moderate specificity (calcium score of 168) or a high sensitivity and moderate specificity (calcium score of 37) (9). The calcium score of >0, demonstrating the highest overall sensitivity (95%) but lowest overall specificity (46%) for any noninvasive test, was actually one of the most expensive pathways. Objective and subjective guidelines for negative and positive tests are also applied using the more traditional forms of noninvasive cardiac testing. The development of 1-mm or more horizontal ST segment depression beyond baseline is commonly used to define a "positive" TMET. If the amount of ST depression is below this threshold, the test is termed "negative" although the patient may, in fact, have disease. Analogous criteria are used to define a positive stress echocardiogram or a positive stress thallium. Here subjective, operator-dependent parameters, such as changes in regional wall motion (stress echocardiography) or visual assessment of radioisotope uptake (stress thallium), are often used in clinical decision making. However, these criteria are based on application of these techniques across an extensive clinical spectrum representing a large number of patients. Such broad clinical application and experience is not available using EBCT. Although calculation of the total calcium score using EBCT is quantitative (2,3,8–11) and operator independent (23), reproducibility varies (24,25) depending on the laboratory. Thus it is possible with application of EBCT to these purposes that alternative calcium scores, particularly for the most cost-efficient values of 37, 80 or 168, may prove to be more appropriate in clinical practice.
Fourth, the fees used for determination of costs were based upon current clinical charges at our institution, which includes a large, Midwest primary cardiology and referral practice. These are reflective of regional fees and should be interpreted cautiously to other practices in which fees for traditional diagnostic cardiac testing are higher or lower.
Limitations of the presentation also relate to comparisons with the more traditional stress testing methods. The values of sensitivity and specificity cited for these examinations were based upon current literature and reflect studies that involved large numbers of patients and also were either reviews or meta-analyses. However, these conventional forms of stress testing also have limitations when applied to the general adult population. In the current model, all members of the populations studied, regardless of prevalence, were assumed to have normal resting electrocardiograms, to be ambulatory and to be able to undergo maximal treadmill exercise using an appropriate graded stress protocol. This is not the case in all patients who may present de novo to a clinician with symptoms suggesting exercise-induced ischemia. Stress electrocardiography, with or without imaging with radionuclides or two-dimensional echocardiography, relies on inducible limitations of blood flow to the myocardium in association with "physiologically" significant coronary obstructive disease. However, a 50% or greater stenosis on angiography may or may not be sufficient to result in myocardial ischemia or inducible regional wall motion abnormalities with increased demand. In addition, medications, particularly beta-adrenergic blocking agents, may reduce the probability to correctly identify the potential for ischemic disease. Electron beam computed tomography on the other hand, examines the extent of disease based upon anatomic information. It is not surprising that the receiver operating characteristic curve areas for EBCT and obstructive coronary disease reported in prior publications from our laboratory (5,6,9) and elsewhere (7) show very high areas under the curves, since they compare associations between atherosclerotic plaque and angiographic anatomy. Furthermore, EBCT scanning can be done regardless of resting electrocardiographic abnormalities, regardless of the presence of cardiotonic medications used to treat hypertension or other noncardiac conditions and regardless of the individual’s ability to perform a maximum stress test.
Recommendations.
The current study provides data that support the application of EBCT and quantification of coronary artery calcification as a minimum cost and maximum effectiveness approach to the diagnosis of obstructive coronary disease in specific subsets of the general population. These data should be interpreted as reflecting only the short-term economics for the diagnosis of coronary disease in a large regional cardiology practice. Furthermore, they are not meant to impugn the value of physiologic testing for obstructive disease or potential for localization of ischemia to specific anatomic sites, as these studies clearly add information on patient prognosis and response to therapy. Additionally, the analyses were theoretical, being calculated from a computer model, and limited to evaluation of initial diagnostic workup costs only. Issues of long-term considerations regarding outcomes and quality of life issues were intentionally not incorporated into the model. Based upon the data presented, use of "any" coronary calcium by EBCT (excellent sensitivity, low specificity) as an initial screening test for obstructive coronary disease in the ambulatory symptomatic patient, although demonstrating the highest negative predicative value of any initial noninvasive pathway regardless of disease prevalence, was more costly and less cost-effective than TMET, ECHO or THALLIUM. The least costly and most cost-efficient pathway was use of a calcium score of 168. This was associated with a high specificity (90%) and a moderate sensitivity (77%). The results, however, were quite similar to those of a score of 80, with both a high sensitivity and specificity (84% for both). Overall, the negative and positive predictive values of using a calcium score of 80 as a positive test were comparable to THALLIUM and ECHO, across all prevalence groups, and thus diagnostic accuracy may not be compromised by using this moderate calcium score value. Direct clinical application, however, would be required to examine the value of any calcium score as compared with conventional methods of diagnosing obstructive coronary disease. Calcium scores of 100 or greater have been shown to provide information regarding the medium-term prognosis for cardiac events in symptomatic (10) and asymptomatic (11,12) individuals, thus suggesting that a moderate calcium score may have diagnostic, as demonstrated herein, as well as prognostic potential in symptomatic, ambulatory individuals undergoing evaluation for obstructive coronary disease. As anticipated, direct coronary angiography with no prior noninvasive testing in the highest prevalence groups was actually the most cost-effective approach to diagnosis of obstructive coronary disease. Specific recommendations for other subsets of the general adult population not included in the analyses and the potential influences of geographic differences in fee schedules for noninvasive tests and angiography will await extension of the principles put forward here into the clinical environment.
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Footnotes
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Supported by the Mayo Clinic and Foundation, Rochester, Minnesota and NIH-HL 46292.
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References
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