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We sought to identify prospectively the prevalence of significant ischemia (≥10% of the left ventricle (LV)) on exercise SPECT imaging relative to workload achieved in consecutive patients referred for myocardial perfusion imaging (MPI).
High exercise capacity is a strong predictor of a good prognosis, and the role of MPI in patients achieving high workloads is questionable.
Prospective analysis was performed on 1,056 consecutive patients who underwent quantitative exercise gated 99mTc-SPECT MPI, of whom 974 attained ≥85% of their maximum age-predicted heart rate (MAPHR). These patients were further divided based on attained exercise workload (<7, 7-9, or ≥10 METS) and were compared for exercise test and imaging outcomes, particularly the prevalence of ≥10% LV ischemia. Individuals reaching ≥10 METS but <85% MAPHR were also assessed.
Of these 974 subjects, 473 (48.6%) achieved ≥10 METS. This subgroup had a very low prevalence of significant ischemia (2 of 473, 0.4%). Those attaining <7 METS had an 18-fold higher prevalence (7.1%, p<0.001). Of the 430 patients reaching ≥10 METS without exercise ST-depression, none had ≥10% LV ischemia. In contrast, the prevalence of ≥10% LV ischemia was highest in the patients achieving <10 METS with ST-depression (14 of 70; 19.4%).
In this referral cohort of patients with an intermediate to high clinical risk of CAD, achieving ≥10 METS with no ischemic ST-depression was associated with a 0% prevalence of significant ischemia. Elimination of MPI in such patients, who represented 31% (430/1396) of all undergoing exercise SPECT in this laboratory, could provide substantial cost-savings.
The sequelae of coronary artery disease continue to cause significant morbidity and impose high economic costs. Identifying those at highest risk of major adverse cardiac events is imperative for guiding therapy and maximizing the benefits of revascularization. Noninvasive diagnostic imaging assists with this process and consequently has grown more than any other physician service under Medicare reimbursement (1). In 2005 alone, 9.3 million nuclear myocardial perfusion studies were performed at significant cost to the healthcare system (2). Improved pretest risk stratification is essential in order to utilize this expensive imaging modality in a cost-effective manner. The incremental value of stress myocardial perfusion imaging (MPI) is small for patients with a low-risk stress test, a low-risk Duke Treadmill Score, or a high rate-pressure product without ST-depression (3-5).
Exercise capacity measured in metabolic equivalents (METS) alone is a powerful predictor of cardiovascular events (6). Higher workloads achieved during exercise stress predict improved survival rates, irrespective of age and gender (6-8). A cutpoint of 10 METS achieved predicts low mortality, even in the setting of significant coronary artery disease (9,10). It’s association with the prevalence of significant ischemia by quantitative SPECT, as compared to the Duke Treadmill Score, would be of interest (11,12).
Accordingly, the primary objective of this study was to determine prospectively the relationship of cardiac workload attained to the prevalence and extent of myocardial abnormalities by gated SPECT in patients with known or an intermediate to high probability of CAD who achieved ≥85% of their maximum age-predicted heart rate (MAPHR). The hypothesis tested was that individuals reaching diagnostic heart rates (≥85% of their MAPHR) and ≥10 METS have a low prevalence of significant ischemia (≥10% of the left ventricle). A second hypothesis tested was that individuals achieving ≥85% of their MAPHR with lower workloads have a greater prevalence of ischemia. The third hypothesis was that patients reaching <85% of their MAPHR but ≥10 METS would still have a low prevalence of significant ischemia but greater than that seen in those attaining their target heart rate.
Prospectively-collected data from the University of Virginia Nuclear Databank (UVAND) were analyzed in a cohort of consecutive patients undergoing exercise testing and single-photon emission computed tomography (SPECT) imaging at the University of Virginia Medical Center.
This prospective study cohort comprised 2,794 consecutive patients who underwent 99mTc SPECT MPI between February, 2006, and January, 2007. After excluding those who underwent pharmacologic stress or achieved <10 METS and <85% of their MAPHR, our final study cohort included 1,056 subjects (see Figure 1). Patients reaching <10 METS and <85% of their MAPHR were not studied, as it is well recognized that such patients are at high risk for CAD and future cardiac events due to deconditioning and other factors. Imaging provides added diagnostic and prognostic information in this patient population (13).
Patients achieving ≥85% of their MAPHR (n=974) were subdivided into three groups (<7 METS (n=267), 7-9 METS (n=234), and ≥10 METS (n=473)). To test the third hypothesis, a second group of 82 individuals who attained ≥10 METS but <85% of their MAPHR were also examined.
Clinical information was collected from patients at the time of their exercise test and entered into the UVAND, including demographics, comorbidities, physical examination and baseline ECG findings. Exercise test parameters and SPECT results (volumes, perfusion, and function) were also recorded (14,15). Protocol approval and waiver of informed consent were obtained from the University of Virginia Institutional Review Board.
All subjects underwent exercise treadmill stress with electrocardiographic monitoring using standard exercise protocols; 1,033 of 1,056 (99%) exercised according to a Bruce or modified Bruce protocol. The decision of whether to stop anti-ischemic medication prior to testing was left up to the discretion of the referring physician. Testing was symptom-limited unless prematurely terminated for reasons recommended in the exercise testing guidelines (16). Exercise workload was defined as the total metabolic equivalents (METS) achieved (17). Ischemic ST-depression was defined as ≥1mm horizontal or down-sloping depression of the ST-segment ≥80ms after the J-point for 3 consecutive beats.
Subjects underwent 99mTc Sestamibi rest-stress gated-SPECT MPI using either a one- or two-day protocol (for a body mass index (BMI) ≥36). Using the one-day protocol, patients received first 10 mCi of 99mTc Sestamibi at rest, and images were acquired after a 60-minute delay. They subsequently received 30 mCi of 99mTc Sestamibi at peak stress with gated-SPECT imaging performed after a 30-minute delay. The 2-day protocol differed in that subjects received 30 mCi of 99mTc Sestamibi (45 mCi in patients with a BMI>45) prior to both rest and stress imaging.
Images were acquired with a dual-head GE Infinia camera with low-energy, high-resolution collimators. Each camera head rotated through 60 projections at 30-40 seconds per projection to acquire 180° of data using a standard 99mTc energy window. The data from the 2 heads were combined to give 360° of coverage. No scatter or attenuation correction was used.
Myocardial perfusion studies were initially read clinically by experienced nuclear cardiology specialists using visual and quantitative image analysis (14). All borderline or abnormal studies were reclassified by the consensus of two additional readers blinded to additional patient information. The UVA quantification program used provides continuous measurement of relative percent tracer uptake in each of 17 standard segments. Segments were flagged as normal or abnormal, based on normal databases. Reversibility was flagged by computer-based analysis of variance derived from the normal databases. Systolic and diastolic volumes and body surface area normalized volumes were also calculated (14).
In order to compare the results more easily with other published studies, each segment was categorized into normal, mild, moderate, severe defects, and absent tracer uptake (scores 0-4). Segmental scores were categorized by each reader who chose a score based on both the quantitative perfusion data and a qualitative visual assessment. The semi-quantitative summed stress, rest, and difference values were calculated from these segmental scores. The five apical segments were weighted at 40% the value of non-apical segments to correct the standard 17 segment model so that each unit myocardial volume was given equal weight. Finally, the “percent myocardial ischemia” was obtained by dividing the difference between summed stress and summed rest scores by the maximum possible difference. This score, although misnamed by tradition, does provide a logical semi-quantitative measure, which combines both extent and severity of left ventricular inducible ischemia (11,12).
The primary outcome for our analysis was the prevalence of ≥10% LV ischemia on MPI. This value was used as the cutpoint for significant ischemia based on a prior report of revascularization benefit in patients demonstrating ≥10% LV ischemia (11). The mean %LV ischemic burden and the percentages of patients with 0%, 1-4%, 5-9%, and ≥10% LV ischemia, as categorized in the COURAGE trial nuclear substudy, were ascertained (18). The prevalence of varying degrees of LV ischemia was determined in the subgroups of patients achieving either <7 METS, 7-9 METS, or ≥10 METS. The prevalence of fixed defects in these groups was documented as well. The influence of ischemic ST-depression on this workload-ischemia relationship was also investigated.
Descriptive statistics are given as medians with 25th and 75th percentiles and compared by analysis of variance (ANOVA) with Tukey’s studentized range testing and t-tests for continuous variables and as numbers of patients with percentages and comparisons by Pearson chi-square or Fisher’s exact testing for categorical variables. The level of significance was 0.05 for all analyses.
Univariable logistic regression analyses of possible predictors of ≥10% LV ischemia (variables in Table 1) were performed. Variables with p-values <0.10 were entered into a multivariable logistic regression model predicting ≥10% LV ischemia. The c-statistic represents the discriminative power of the logistic equation (1.0 represents perfect prediction). All statistics were performed using SAS version 9.1.
Patients reaching ≥85% of their MAPHR had a 22.4% prevalence of known CAD with 132 of 974 patients (13.6%) having had a prior MI. Table 1 shows that the patients who achieved higher workloads were younger, more often male, and had significantly lower rates of diabetes and hypertension. For variables with p<0.05, all pair-wise comparisons were statistically-significant between those reaching ≥10 METS and both those attaining <7 METS and 7-9 METS except an abnormal resting ECG, which was only significant between <7 and ≥10 METS. Only age and diabetes mellitus had statistically-significant differences between all 3 groups. There were no significant differences in the proportion with prior known CAD or MI. Symptoms possibly related to ischemia (i.e. chest pain or dyspnea) were reported in 77.4% (754/974) of the overall cohort with no significant differences among groups based on exercise capacity (p=0.65).
The physiologic parameters, symptoms, and stress-ECG findings are provided in Table 2. In patients reaching ≥85% MAPHR, 117 (12%) had chest pain during the test and 93 (80%) of these had normal scans. The prevalence of exercise chest pain (40/473, 8.5%) and ST-depression (43/473, 9.1%) were both significantly lower in individuals attaining ≥10 METS than in the lower workload subgroups.
The small change in the percentage of the MAPHR achieved was not clinically-significant and was only statistically significant between <7 and ≥10 METS (93% vs. 96%). No other physiologic parameters varied by exercise workload. The median Duke Treadmill Score was significantly different across all three workload levels (<7 METS: 4.3; 7-9 METS: 7.0; ≥10 METS: 9.0, p<0.001 between each of the 3 groups). A low-risk Duke Treadmill Score is considered ≥5.0, and an intermediate score is ≥ −10.0 but <5.0 (15). In this study, the median Duke Treadmill Score fell in the low-risk range for those attaining ≥7 METS and in the intermediate risk category for those reaching <7 METS. The median Duke Treadmill Score was in the same risk category for patients achieving ≥10 METS and those reaching 7-9 METS. However, the prevalence of ≥10% LV ischemia was significantly different between the two workload groups.
The relationship between cardiac workload and SPECT imaging findings are presented in Table 3. All variables with a global p-value ≤0.05 had statistically-significant differences between those reaching ≥10 METS and both those attaining <7 METS and 7-9 METS. Individuals who achieved ≥85% of their MAPHR with higher exercise workloads had a markedly lower prevalence of perfusion abnormalities (p<0.001)(Figure 2). Subjects with ≥10 METS exercise capacity had a more than 5-fold lower prevalence of reversible ischemic defects and 2.6-fold fewer fixed perfusion defects compared with those attaining a poor workload (<7 METS).
Those who achieved ≥10 METS had a low percentage of any ischemia (19/473, 4%) and significant ischemia (2/473, 0.4%), defined as ≥10% of the left ventricle. The latter represents a more than 17-fold decrease compared to the prevalence of ≥10% LV ischemia in those attaining <7 METS (19/267, 7.1%). The percentage of subjects with significant left-ventricular dysfunction (EF <35%) was also lower in those attaining ≥10 METS (0.7% versus 3.1%, p=0.007).
Figure 3 shows that of the 430 patients who achieved ≥10 METS with no ischemic ST-depression, only 3 (0.7%) had 5-9% LV ischemia. The prevalence of ≥10% LV ischemia was 0%. Of the 43 patients who achieved ≥10 METS with ischemic ST-depression, 2 (4.7%) had 5-9% LV ischemia and 2 had ≥10% LV ischemia (p=0.016 and <0.001 respectively, compared to those without ST-depression). As shown in Figure 3, the prevalence of LV ischemia by SPECT was higher in patients failing to reach ≥10 METS. Of the 70 patients attaining <10 METS with ST-depression, 14 (20%) had ≥10% LV ischemia. For those in this group that attained <7 METS, 28.6% (10/35) had ≥10% LV ischemia.
Diabetes, hyperlipidemia, and tobacco use were not significant predictors of ≥10% LV ischemia on univariable logistic regression analysis. The remaining variables from Table 1 were entered into a multivariable logistic regression model predicting significant LV ischemia (≥10%) in subjects attaining ≥85% of their MAPHR (Table 4). The predictive accuracy of this model is very high with a C-statistic of 0.92. Lower exercise capacity (<10 METS) gave the largest increased odds of ≥10% LV ischemia when present. Pre-specified testing revealed no interactions between cardiac workload and age, male gender, decreased LVEF, and ischemic ST-depression (p=0.925, 0.921, 0.645, and 0.829 respectively).
Of all the patients in the original study cohort achieving ≥10 METS, 14.8% (82/555) reached <85% of their MAPHR. This subgroup had a higher rate of beta-blocker use on the day of testing (18.3% versus 5.1%, p<0.001) and a 2.2-fold higher prevalence of known CAD (43.9% versus 20.1%, p<0.001) compared to the 473 patients achieving ≥85% of MAPHR and ≥10 METS.
Table 5 shows that subjects attaining ≥10 METS of workload but <85% MAPHR were approximately 4 times more likely to have fixed and ischemic perfusion defects than patients achieving ≥10 METS and ≥85% of their MAPHR. Ischemia of ≥10% of the LV was also more prevalent in those reaching <85% of their MAPHR, but the difference was not statistically-significant (2.4% vs. 0.4%, p=0.11). As shown in Table 5, the <85% MAPHR group showed a higher percentage of patients with an ESVI ≥25 (25.9% vs. 8.5%, p<0.001) and a lower median LVEF (61% versus 65%, p<0.001).
Exercise workload is an important prognostic variable derived from the exercise stress test. Good exercise capacity has been associated with decreased mortality, myocardial infarction, and revascularization, even in those with ischemic ST-segment depression (6,8,9,17,19,20). Moreover, exercise duration is one of the three components of the Duke Treadmill Score. High levels of exercise workload and low risk Duke Treadmill Scores are associated with a lack of benefit with revascularization and a decreased prognostic impact of ischemia with respect to cardiac death and nonfatal MI (3,4). A high rate-pressure product without ST-depression also identifies a low-risk group (5). Exercise capacity was shown to be a better predictor of all-cause mortality than maximum exercise heart rate and even the angiographic severity of CAD (6,9).
However, these prior studies have certain limitations, including small sample sizes, inclusion of lower risk subjects with a low incidence of cardiovascular risk factors, a lack of symptom documentation, and the exclusion of patients with CAD or prior MI. Many of these analyses were retrospective, analyzed only all-cause mortality, and did not determine the value of MPI to further risk-stratify.
The study population in this report comprised individuals referred for combined exercise ECG testing and MPI at the outset, thereby reducing bias from selective referral. The majority of these patients were symptomatic and had known CAD or multiple risk factors (one-quarter had diabetes) consistent with an intermediate to high risk of CAD.
A cutpoint of 10 METS was chosen, as prior studies have shown low rates of all-cause mortality, cardiac death, nonfatal MI and revascularization in individuals reaching this level of workload (19-21). Among the patients with diagnostic exercise heart rates, there was a very low rate of myocardial ischemia (4%) in those reaching an exercise workload ≥10 METS. Only 2 of the 473 patients (0.4%) attaining ≥85% of their MAPHR and ≥10 METS had significant ischemia, which was defined as ≥10% of the left-ventricular myocardium (LV). This finding is especially important, as Hachamovitch et al. showed a survival benefit with revascularization only in patients with ischemia involving ≥10% of the LV. Although their study is subject to the limitations of a retrospective analysis, it suggests that 10% LV ischemia may be the optimal threshold for revascularization (11,12). Moreover, in the COURAGE nuclear substudy, the rate of death or MI was high (39.3%) for individuals with residual ischemia of ≥10% of the LV (18). In the present study, patients reaching <7 METS had a greater than 17-fold increase in the prevalence of ≥10% LV ischemia.
The low prevalence of ≥10% LV ischemia and decreased benefit of perfusion imaging in the group with increased workload are consistent with the outcomes in patients with a low-risk Duke Treadmill Score (4,15). Some key differences between analyzing workload alone versus the Duke Treadmill Score are worth mentioning. The prevalence of moderate to severe perfusion defects appears higher in patients with a low-risk Duke Treadmill Score (16-20%) (3,4) versus the prevalence of such defects for those reaching ≥10 METS in the present study (0.4%). This difference is not unexpected. Although individuals achieving 7-9 METS in this study had a median Duke Treadmill Score in the low-risk range, they had a higher rate of significant perfusion abnormalities. Moreover, chest pain, one of the components of the Duke Treadmill Score, is subjective and often not reflective of ischemia (22). The majority of individuals reaching ≥85% MAPHR with exercise chest pain in the present study had normal scans (80%).
No differences in LVEF or cardiac volumes were observed with decreasing exercise workload. This suggests that the degree of myocardial ischemia affects exercise capacity more than LV systolic function or volumes. This is consistent with the finding of a lesser relationship between extent of fixed defects and workload achieved. These patients achieving ≥10 METS but <85% MAPHR had more perfusion defects, a higher prevalence of significant ischemia, and higher end-systolic volumes than those attaining ≥10 METS and ≥85% of their MAPHR. Thus, the MAPHR-achieved provides important additional information to exercise capacity with respect to predicting the prevalence of significant ischemia. This is not surprising since chronotropic incompetence during a treadmill test is a marker of increased future cardiovascular mortality (13).
The model examining the predictors of ≥10% LV ischemia was highly predictive (c=0.92) and demonstrated that reduced exercise capacity is one of the two most significant markers of significant LV ischemia. Not reaching ≥10 METS was associated with a 10-fold increase in risk of having ≥10% LV ischemia on SPECT imaging. The other significant predictor was the presence of ischemic ST-depression. As mentioned previously, not one patient with achieving ≥85% of MAPHR and ≥10 METS of workload without ischemic ST-depression had ≥10% LV ischemia. It seems unlikely that any supplemental prognostic information which might influence management decisions could be expected from myocardial SPECT imaging as an adjunct to the exercise ECG in this subgroup. For example, in patients achieving a workload of ≥10 METS without exercise-induced ischemic ST-depression, optimal medical therapy would likely first be instituted according to practice guidelines.
New protocols should be explored in which patients would be referred for exercise electrocardiography with only conditional SPECT myocardial perfusion imaging. Those individuals reaching target heart rate and ≥10 METS of workload without ischemic ST-depression would not be injected with tracer. Although the appearance of significant ST-depression solely during the recovery period would complicate this approach, such an occurrence is unlikely. Very few patients achieving their target heart rate with high workloads show ST-depression only during recovery (23). Similarly, patients with an abnormal blood pressure response or non-sustained ventricular tachycardia might benefit from myocardial imaging despite reaching a high workload.
Diagnostic imaging is the fastest growing cost for Medicare and has been targeted by the Office of the Inspector General for a medical appropriateness assessment (24,25). SPECT MPI makes up a substantial portion of these costs, with an estimated $1.2 billion in allowed charges on stress nuclear SPECT in 2006 alone. This represents a 10.5% increase from 2004. In this study, 31% (430/1396) of all patients referred for exercise SPECT myocardial perfusion imaging over a 12-month period achieved ≥10 METS of exercise workload without exercise ischemic ST-depression. Assuming the mix of patients in this study is roughly representative of the national referral pattern, and these savings are projected to the more than 9.3 million SPECT studies performed each year, the cost savings could be potentially quite substantial (2,26-28).
One possible limitation is that the percentage LV ischemia, rather than hard clinical events, was used as the endpoint of the study. This may not be a major limitation since prognosis for patients with significant LV ischemia (≥10% of the LV) has been well-established. Similarly, the hard cardiac event rate for patients with normal exercise SPECT scans is very low (<1% per year). The prevalence of balanced ischemia due to left main and/or 3-vessel CAD yielding “normal” perfusion scans should rarely occur in a cohort of patients achieving ≥85% of MAPHR and ≥10 METS of workload with no ischemic ST-depression.
The low rate of ≥10% LV ischemia limits the number of variables that can be tested in the multivariable logistic regression model. Including too many predictors can lead to model over-fitting. Candidate variables were limited, and univariable logistic regression analysis was performed to minimize this risk.
In summary, this analysis suggests that the achievement of ≥10 METS is associated with a very low prevalence of ≥10% LV ischemia on MPI. No patient achieving ≥85% of MAPHR and ≥10 METS without exercise ST-depression had this degree of ischemia by SPECT. This group represented 31% of all patients undergoing exercise stress SPECT over a 12-month period. Patients attaining 7-9 METS and <7 METS had a progressively higher prevalence of ≥10% LV ischemia despite reaching their target exercise heart rate. By multivariable analysis, low exercise capacity was associated with 10-fold increased odds of having ≥10% LV ischemia. These observations in a large consecutive series of patients referred for exercise SPECT imaging suggest that additional risk stratification with MPI may be eliminated in individuals who achieve ≥85% of their maximum age-predicted heart rate and ≥10 METS without ischemic ST-depression. This would lead to substantial cost savings.
Funding: Dr. Bourque is funded by an NIH NRSA Training Grant: T32 EB003841-04
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