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Key concepts in risk stratification and cost-effectiveness using nuclear scintigraphy in stable coronary artery disease
KEY POINTS
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Radionuclide MPI using SPECT or PET techniques is a widely used approach to identify the presence of CAD-related perfusion abnormalities and assess LV function.
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There exists an extensive literature supporting the use of these techniques in prognostication, and SPECT and PET have been shown to contribute incremental value over and above clinical historical and stress test information.
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MPI’s risk stratification contribution is made through the identification of low-risk patients vis-à-vis a normal MPI study; gradations of increasing risk are identified by the presence of worsening abnormalities of LV perfusion and function.
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In addition to the use of LV perfusion and function, the use of PET-assessed quantitative coronary flow and coronary reserve greatly enhance the value of testing and extend its use to the realm of vascular function and atherosclerosis assessment.
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Studies examining post-MPI resource utilization yield insights into the appropriateness of post-MPI patient management and how physicians use MPI results.
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Although MPI’s clinical application for many years has been in the realm of prognostication and risk stratification, increasing evidence points to a potential role for MPI in identifying which patients may benefit from revascularization after testing.
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Although RCTs and their substudies to date have not defined such a role for radionuclide MPI, additional studies with more appropriate designs are needed to better address this question.
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Although the area of cost-effectiveness is methodologically controversial and challenging, numerous papers have claimed that the use of radionuclide MPI in appropriate populations is cost-saving compared with other testing strategies.
Introduction
For almost a half century, radionuclide myocardial perfusion imaging (MPI), often using single photon emission computed tomography (SPECT) and, more recently, positron emission tomography (PET), has been a reliable mainstay in the assessment of patients with known or suspected coronary artery disease (CAD). In the current era with its technical advances in coronary computed tomographic angiography (CCTA) and with perfusion, magnetic resonance imaging (MRI), and contrast stress echocardiography entering the clinical realm—as complementary and alternative approaches—the evaluative armamentarium of clinicians has expanded accordingly. These modalities are widely applied to a diverse group of patients with varying presentations, characteristics, and history. Nevertheless, the basis of identifying optimal candidates for testing, as well as the management of patients after testing, is directed by estimating patient risk based on all clinically relevant information and considering the risks and potential benefits of available therapies. In this chapter, the principles of prognostication and risk stratification in the context of radionuclide MPI will be reviewed, and the relevant biomarkers of risk and applicable guidelines and appropriateness statements will be presented. Finally, recent relevant randomized clinical trials (RCTs) impacting cardiovascular imaging and the cost-effectiveness of MPI compared with alternative strategies will be presented.
Risk stratification and incremental prognostic value
Early studies of radionuclide MPI examined the association of imaging results (resting and peak stress perfusion) with posttesting patient outcomes on follow-up. These studies, although relatively small and underpowered, found that the extent and severity of perfusion defects had a significant association with adverse cardiac outcomes. Multiple studies supported the superior prognostic value of both planar and SPECT MPI compared with other information available at the time of testing.
Importantly, these older studies did not address whether the radionuclide MPI prognostic results were still significant after clinical, demographic, and other previously known information about the patient, also known as the incremental value of the patient, was considered. , This approach was first shown by examining the global chi-square of a multivariable model when MPI information was added to a model consisting entirely of pre-MPI data. This approach, first shown in patients undergoing stress-redistribution 201 thallium (Tl), , was later confirmed with SPECT using a dual-isotope approach. Subsequently, an incremental risk stratification was used as well, as demonstrated by successful, successive stratifications initially by pre-MPI data (thus divided into low, intermediate, and high preimaging risk), followed by further risk stratifications by MPI data in each of the subgroups. , Emerging at a time of increasing concerns regarding the costs of testing and issues of cost containment, the concept of incremental value resonated in the noninvasive imaging literature as a paradigm to better demonstrate the value that imaging was providing. Numerous publications that followed demonstrated the added value of MPI compared with demographic, clinical, historical, and stress test information in different patient subsets ( Table 17.1 ).
TABLE 17.1
High-Risk Markers
| Category | Important Markers of Increased Risk |
|---|---|
| Demographic |
|
| Clinical |
|
| Historical |
|
| Stress test |
|
| Data from other imaging modalities | Significant markers from echocardiography, coronary computed tomographic angiography, coronary artery calcium |
Principles of prognostication and risk stratification
Although, in its earlier years, stress radionuclide MPI was clinically used and assessed based on an anatomic end point (i.e., accuracy for identifying obstructive CAD as defined by invasive catheterization), by the 1990s the focus had shifted to prediction of risk for adverse events and risk stratification. This differs from the traditional anatomy-based approach in that the criteria for success is replaced by the value of the test results to accurately define the risk for adverse events. By defining increased risk for untoward preventable events using MPI, the results of testing can be used to guide subsequent management with an eye to reducing patient risk via appropriate therapies and management approaches. A key element in applying this approach to testing is carefully defining thresholds as low, intermediate, and high risk for adverse cardiovascular events. These thresholds were first put forward as part of guidelines defining low risk as an annual cardiac mortality rate less than 1%, intermediate risk as an annual cardiac mortality of 1% to 3%, and high risk as an annual cardiac mortality rate greater than 3%. There are several limitations, however, to defining thresholds of risk in this way. First, with decreasing rates of cardiac mortality over the past 20 years, there is an increasing use of composite cardiac end points for both observational studies and RCTs. Thus these thresholds often cannot be applied to published data. Furthermore, these rates are heavily dependent on the cohort examined. For example, a 1% mortality rate may be intermediate to high risk in a younger population without prior CAD and few risk factors, whereas it may be very low risk in an elderly cohort. Similarly, the applicability of these thresholds to various relevant patient subgroups is unclear (e.g., women, patients with diabetes, patients with prior CAD, and patients with atherosclerotic disease without obstructive lesions).
Based on the extensive available literature examining the prognostic implications of radionuclide MPI, a framework for understanding patient risk assessment emerges. Three general factors drive patient risk after radionuclide MPI (or any test)—the result of the study, the patient’s underlying clinical risk, and the posttest therapeutic strategy.
Radionuclide MPI result and patient risk
Understanding post-MPI risk stratification begins with an understanding of the prognostic implications of a normal radionuclide MPI. An extensive literature exists documenting the low risk for adverse events after a normal radionuclide SPECT or PET MPI. A meta-analysis of almost 30,000 patients who were followed up after a normal stress SPECT revealed that the annual risk for myocardial infarction (MI) or cardiac death after a normal result was 0.5% (95% confidence interval, 0.3% to 0.7%), a finding also seen in other studies of pooled data. These results have been extended to outcomes after a normal PET study as well. , This low event rate—long associated with normal stress MPI—has been interpreted as implying that, in the absence of significant or limiting symptoms, patients with these findings can be managed conservatively. Importantly, the results of a normal MPI study differ considerably from a normal, zero score coronary calcium score. The former provides information regarding obstructive CAD, whereas the latter indicates the absence of atherosclerotic disease, a far earlier pathophysiologic stage with profoundly different implications.
Impact of clinical characteristics on risk after a normal stress radionuclide MPI
Although the risk for cardiac events is consistently lower in patients with normal SPECT MPI and PET MPI than in those with abnormal results, there are multiple subsets of patients in whom the risk associated with a normal, relative to an abnormal, MPI is low, but the absolute risk is not. For example, a study of 7376 patients with normal exercise or adenosine stress SPECT MPI—a cohort long considered low risk—who were followed for cardiac death or nonfatal MI examined the prognostic “warranty” of a normal MPI. Specifically, what is the temporal component of risk—that is, for how long after the initial study does risk remain low? Two important results emerged. First, not all normal studies were low risk, and specific patient characteristics identified in which patient subgroups this was the case. Second, the characteristics associated with increased risk and shortened time to a hard event (a warranty period of a normal MPI) included patient age, diabetes mellitus (DM; in particular, women with diabetes), known CAD, and the use of pharmacologic stress testing (the inability to exercise to a target heart rate) ( Fig. 17.1 ). Subsequent studies confirmed this concept , and the importance of DM and reduced left ventricular ejection fraction (LVEF) in this process. , Similarly, a meta-analysis supported the finding that event rates after a normal pharmacologic stress study are greater than those after a normal exercise stress MPI.
These studies support a paradigm that posttest patient risk is contextual by nature. As previously mentioned, the difficulty in defining thresholds of risk is that these definitions are inaccurate without consideration of the cohort to which they will be applied. No statement regarding absolute risk is valid in the absence of consideration of other available information. A discrepancy between observed risk after a normal MPI and the defined “low-risk” threshold has been frequently reported, particularly in studies examining elderly populations and those with diabetes. , , , A previous study examining post-SPECT risk in 5200 elderly patients revealed that annual cardiac mortality rates after normal MPI in this study were 1.0% in patients aged 75 to 84 years and 3.3% in those older than 85 years. Although these rates are greater than often reported after normal MPI, they are less than or equal to mortality rates for heart disease and major cardiovascular (CV) disease reported in the overall US population for individuals in these age groups ( Fig. 17.2 ). Furthermore, specific lower clinical risk groups have significantly lower mortality risk than the age-matched US population (e.g., exercise stress, normal resting electrocardiogram [ECG]). Conversely, studies have also shown that patients with prior CAD, abnormal resting ECG, and pharmacologic stress all had greater event rates after a normal MPI. Similar results were also observed in the setting of low exercise capacity, dyspnea, and multiple atherosclerotic risk factors. , These findings suggest that although MPI yields incremental value over clinical, historical, and demographic data, the converse is true as well. Estimation of risk after MPI must consider both the underlying risk of the population being examined and the MPI results.
These findings reported using SPECT MPI are generalizable to the results of PET MPI as well. Both single and multicenter studies with PET MPI have revealed normal MPI results to be associated with low risk for adverse events. , This finding has been confirmed in a meta-analysis. Interestingly, although the rates of cardiac death have been shown to be low after normal PET MPI, the rates of all-cause death, generally felt to be a more valid end point for observational studies, are greater in some studies. It is important to note that this is a reflection not of the modality (or of an inability of the modality to identify a low-risk cohort) but of the patient population referred to testing. With greater baseline risk and a high prevalence of significant noncardiac comorbidities, these patients are at greater risk for experiencing noncardiac deaths.
Risk for adverse events after abnormal MPI
Compared with event rates after normal MPI, the rates of adverse events after abnormal stress SPECT or PET MPI studies have been shown to be increased both in relative and absolute terms. The risk for adverse outcomes increased with worsening extent and severity of perfusion abnormality. It is this progressive increase of risk with worsening abnormalities that provides both incremental prognostic value over prior information and enhanced risk stratification. This finding has been found to be present irrespective of the end point used, the cohort examined, the type of stress used, the approach to MPI imaging, or the approach to interpreting perfusion abnormalities.
Importantly, at any level of MPI abnormality, patient risk varies with underlying patient risk. That is, clinical and historical patient information yields incremental value over MPI results ( Fig. 17.3 ). This pattern of graded risk extends to PET MPI as well. Indeed, the rates of cardiac death after stress PET MPI across categories of mild ischemia (5% to 10% of the left ventricle [LV]), moderate ischemia (10% to 20% of the LV), and severe ischemia (>20% of the LV) in a study of medically treated patients in a multicenter registry ( Fig. 17.4 A) suggest that increasing amounts of ischemia are associated with a stepwise increase in the risk for cardiac death. Second, the risk associated with any level of ischemia increases with an increase in underlying patient risk (e.g., increasing age, pharmacologic versus exercise stress). The increasing mortality rates across categories of stress perfusion defects have been reported with SPECT MPI as well. Third, there is an increase in unadjusted rates of cardiac death and all-cause death across the continuum of test results (i.e., normal and mildly, moderately, and severely abnormal; see Fig. 17.4 B). After risk adjustment, the hazard ratios for cardiac death (black numbers at the base of bars using normal PET MPI as comparator) across the abnormal MPI categories significantly increase with worsening test results. Interestingly, these hazard ratios do not increase as much with respect to all-cause death, probably because of the greater mortality rate in the normal MPI category. This pattern of results is similar to prior studies using SPECT MPI in a variety of patient subsets.
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