Symptom-limited exercise combined with dipyridamole stress: Prognostic value in assessment of known or suspected coronary artery disease by use of gated SPECT imaging

Symptom-limited exercise combined with dipyridamole stress: Prognostic value in assessment of known or suspected coronary artery disease by use of gated SPECT imaging Alan W. Ahlberg, MA, Sarkis B. Baghdasarian, MD, Haris Athar, MD, Jeffrey P. Thompsen, MD, Deborah M. Katten, RN, MPH, Gavin L. Noble, MD, Igor Mamkin, MD, Anuj R. Shah, MD, Ivette A. Leka, BS, and Gary V. Heller, MD, PhD, FACC Background. Combining vasodilator and exercise stress reduces noncardiac side effects, improves image quality, and enhances the detection of ischemia, compared with suboptimal exercise or vasodilator stress alone. However, prognostic data with combined protocols are limited. Methods and Results. Consecutive patients (n ⴝ 2064) who underwent symptom-limited exercise and dipyridamole stress with gated single-photon emission computed tomography (SPECT) imaging, without early revascularization, were studied. Subsequent cardiac death or nonfatal myocardial infarction was related to exercise and gated SPECT variables. Cox proportional hazards regression modeling was performed to identify predictors of adverse outcome. Annualized event rates in patients with normal and abnormal images were 0.96% and 2.71%, respectively (P < .001). With abnormal imaging, annualized event rates were 0.86% and 3.13% in patients with average to high and fair or poor functional capacity, respectively (P ⴝ .019). Abnormal imaging, a severely reduced post-stress ejection fraction, transient ischemic dilation, and fair or poor functional capacity emerged as predictors of adverse outcome. Accordingly, patients were stratified into low-risk, intermediate-risk, and high-risk cohorts with annualized event rates of 0.94%, 2.24%, and 8.19%, respectively (P < .001 in any two-way comparison). Conclusions. A protocol that combines symptom-limited exercise and dipyridamole stress with gated SPECT imaging provides highly effective risk stratification for adverse outcomes. (J Nucl Cardiol 2008;15:42-56.) Key Words: Symptom-limited exercise • dipyridamole • gated SPECT • risk stratification

See related article on p. 3 Stress-gated single-photon emission computed tomography (SPECT) imaging is highly effective in risk stratification, with multiple components providing both

From the Nuclear Cardiology Laboratory, Henry Low Heart Center, Division of Cardiology, Hartford Hospital, Hartford, Conn, and the University of Connecticut School of Medicine, Farmington, Conn. This study was supported in part by a grant from Bristol-Myers Squibb Medical Imaging, Billerica, Mass. Financial disclosure: G.V.H. receives grant support and is on the speaking board of Bristol-Myers Squibb Medical Imaging. Received for publication April 3, 2007; final revision accepted Sept 10, 2007. Reprint requests: Gary V. Heller, MD, PhD, FACC, Nuclear Cardiology Laboratory, Henry Low Heart Center, Division of Cardiology, Hartford Hospital, 80 Seymour St, Hartford, CT 06102; gheller@ harthosp.org. 1071-3581/$34.00 Copyright © 2008 by the American Society of Nuclear Cardiology. doi:10.1016/j.nuclcard.2007.09.025 42

independent and incremental prognostic information.1-9 Exercise is the preferred stress modality because it provides additional prognostic information, such as functional capacity.10-13 However, inadequate exercise testing negatively affects the identification of coronary artery disease (CAD) and the quantification of ischemia by perfusion imaging.14,15 In patients unable to perform adequate exercise, vasodilator stress (using either dipyridamole or adenosine) perfusion imaging has been utilized successfully as a diagnostic16-21 and prognostic22-29 alternative. A protocol that combines vasodilator and exercise stress has advantages compared with suboptimal exercise or vasodilator stress alone in terms of reducing noncardiac side effects, improving image quality, and enhancing the detection of ischemia.30-45 However, data on the prognostic value of combined stress protocols are limited.4 Our laboratory uses a protocol in selected patients that combines symptom-limited exercise with dipyridamole stress. Such a protocol, if safe, maximizes the assessment of ischemia and permits a determination of functional capacity.34 To our

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knowledge, there are no published data on the prognostic value of a protocol that combines symptom-limited exercise with vasodilator stress. Accordingly, this study investigated the prognostic value of symptom-limited exercise combined with dipyridamole stress in selected patients referred for noninvasive assessment of known or suspected CAD. METHODS Patient Selection This study was approved by, and conducted within, the guidelines of the Institutional Review Board at Hartford Hospital. From the Nuclear Cardiology Laboratory clinical database at Hartford Hospital, consecutive patients who underwent a combined protocol of symptom-limited exercise and dipyridamole stress with gated SPECT imaging from January 2, 1996 through December 31, 2003 were identified. The decision for a patient to undergo vasodilator-exercise stress was made by the referring physician, and was generally based on a patient’s perceived inability to perform optimal exercise because of physical limitations or coexisting conditions that would not safely allow for the discontinuation of antianginal medications. A combined stress protocol was also chosen over vasodilator stress alone on the assumption that the patient could perform some level of exercise. Of 2437 patients who underwent standard dipyridamole infusion and performed some level of exercise, follow-up was 92.4% complete over 2.4 ⫾ 1.5 (mean ⫾ standard deviation) years. Of these 2252 patients, 188 (8.3%) underwent a revascularization procedure (coronary artery bypass grafting [CABG] or percutaneous coronary intervention [PCI]) ⱕ60 days (early) after testing. Patients who had undergone early revascularization were excluded from the prognostic portion of the analysis.

Figure 1. Schematic representation of protocol that combines symptom-limited exercise and dipyridamole stress with gated SPECT imaging.

Stress-Testing Variables Stress-induced ECG changes were interpreted independent of imaging results. An ECG response was considered positive for ischemia if there was ST-segment elevation, ⱖ1 mm of horizontal or downsloping or 1.5 mm of up-sloping ST-segment depression 80 ms beyond the J-point, or if there was a change of ⬎1 mm in a segment with ⬍0.5 mm deviation from the isoelectric line at baseline. Functional capacity was estimated from exercise workload achieved (see Appendix I-A for formula), and was expressed in metabolic equivalents (METs), wherein 1 MET equals oxygen consumption at rest (approximately 3.5 mL/kg/min). Using an age-based and sexbased classification system,47 in addition to findings in previous work,12,13 functional capacity was subcategorized as average to high versus fair or poor (see Appendix I-B for classification system). The maximum predicted heart rate (MPHR) achieved was calculated based on the formula 220 minus age (in years).

Radiopharmaceutical Injection and Image Acquisition Dipyridamole-Exercise Stress Protocol Patients were instructed to fast ⱖ8 hours and to refrain from caffeine-containing food and drugs as well as oral dipyridamole for 24 to 48 hours before testing. Vital signs and a 12-lead electrocardiogram (ECG) were monitored before, during, and after the termination of testing. As shown in Figure 1, and consistent with the protocol described by Ignaszewski et al,34 patients underwent a 4-minute infusion of dipyridamole (0.56 mg/kg), immediately followed by symptom-limited treadmill exercise according to the standard (88.3%) or modified (11.7%) Bruce protocol. The exercise was performed within the guidelines of the American College of Cardiology/American Heart Association.46 Approximately 1 minute before the termination of exercise or between 7 and 9 minutes after the initiation of dipyridamole infusion (in patients performing extremely limited exercise), patients were injected with 30 to 45 mCi of Tc-99m sestamibi. Aminophylline (50 to 125 mg) was injected prophylactically ⱖ2 minutes after tracer injection, and thus always occurred after the completion of exercise, with additional doses if indicated.

Radiopharmaceutical dosing, image acquisition, and processing were performed within the guidelines of the American Society of Nuclear Cardiology.48 A 1-day rest and stress-imaging protocol was utilized in 81.5% of patients, whereas the remaining patients underwent a 2-day protocol. Some patients (3.4%) with normal perfusion and function on stress imaging did not undergo rest imaging. Attenuation correction data were not used.

Gated SPECT Image Interpretation Images were interpreted during daily clinical reading sessions by a consensus of two or more experienced readers, using a 17-segment model and scoring system.49 Left-ventricular (LV) cavity size at stress and rest was assessed visually and scored on a scale of 0 to 3 (0 ⫽ normal, 1 ⫽ mild, 2 ⫽ moderate, and 3 ⫽ severe dilation). If the LV cavity size was dilated at stress, it was further classified as fixed (score at stress equal to the score at rest) or as transient ischemic dilation (TID) (score at stress greater than the score at rest27). In the visual assessment of LV perfusion, each segment was scored on a

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Table 1. Comparison of gated SPECT imaging data between patients who had undergone early coronary revascularization ⱕ60 days after dipyridamole-exercise stress, and those who did not

Variable Gated SPECT image Normal (%) Abnormal (%) LV cavity size Normal (%) Fixed dilation (%) TID (%) SSS Normal (%) Mildly to moderately abnormal (%) Severely abnormal (%) SDS No ischemia (%) Mild to moderate ischemia (%) Severe ischemia (%) Post-stress EF Normal (%) Mildly to moderately reduced (%) Severely reduced (%)

Early revasc (n ⴝ 188)

Non-early revasc (n ⴝ 2,064)

P value

16 (8.5) 172 (91.5)

1337 (64.8) 727 (35.2)

⬍.001 ⬍.001

131 (69.7) 20 (10.6) 37 (19.7)

1857 (90) 181 (8.8) 26 (1.3)

⬍.001 .39 ⬍.001

22 (11.7) 98 (52.1) 68 (36.2)

1477 (71.6) 405 (19.6) 182 (8.8)

⬍.001 ⬍.001 ⬍.001

25 (13.3) 77 (41) 86 (45.7)

1647 (79.8) 327 (15.8) 90 (4.4)

⬍.001 ⬍.001 ⬍.001

133 (70.7) 45 (23.9) 10 (5.3)

1789 (86.7) 203 (9.8) 72 (3.5)

⬍.001 ⬍.001 .2

Numbers in parentheses refer to percentage of patients in column who have the particular variable. Revasc, Revascularization; LV, left ventricular; TID, transient ischemic dilation; SSS, summed stress score; SDS, summed difference score; EF, ejection fraction; SPECT, single-photon emission computed tomographic.

scale of 0 to 4 (0 ⫽ normal; 4 ⫽ absent photon activity). A summed stress score (SSS) and a summed rest score (SRS) were calculated by adding the segment scores at stress and at rest, respectively. In the classification of the presence and severity of perfusion defects, SSS ⱕ3 was considered normal, 4 to 13 was considered mildly to moderately abnormal, and ⬎13 was considered severely abnormal.1,5,6 A summed difference score (SDS) was calculated by subtracting the SRS from the SSS. In the classification of the presence and severity of ischemia, SDS ⱕ1 was considered to indicate no ischemia, 2 to 7 was considered to indicate mild to moderate ischemia, and ⬎7 was considered to indicate severe ischemia.2,5,6 The poststress ejection fraction (EF), reflecting global LV systolic function, was derived using QGS software50 and confirmed visually. A post-stress EF ⱖ51% in women and ⱖ43% in men was considered normal, 35% to 50% in women and 30% to 42% in men was considered mildly to moderately reduced, and ⬍35% in women and ⬍30% in men was considered severely reduced.8 An image was classified as abnormal if one or more of the following findings were present on gated SPECT: LV cavity dilation at stress, SSS ⱖ4, SDS ⱖ2, or post-stress EF ⱕ50% in women and ⱕ42% in men.

Follow-Up Patient follow-up was achieved through scripted telephone interviews and mailed questionnaires. An investigator unaware

of clinical, stress testing, and gated SPECT data confirmed events by reviewing hospital admission records, the public Social Security database, and death certificates. The endpoint for this study was cardiac death or nonfatal myocardial infarction (MI). Patients were followed up to 6 years after testing, and were censored at the first cardiac event.

Statistical Analysis Clinical, stress, and gated SPECT imaging characteristics were expressed as mean ⫾ standard deviation or as proportions. Intergroup and intragroup comparisons were performed using two-tailed t tests (independent or paired samples, respectively) for continuous variables, and the chi-square or Fisher exact test for categorical variables. Annual cardiac event rates were calculated as the number of events divided by the sum of each individual follow-up period in years. Cumulative cardiac eventfree survival curves were obtained using the Kaplan-Meier procedure, and were compared by means of the log-rank test. Significant parameters evaluated in univariate analysis were entered into Cox proportional hazards regression modeling. A forward stepwise selection procedure, based on the Wald statistic probability, was performed, with a threshold of P ⱕ .05 and P ⱖ .1 for variable entry and removal, respectively. Stress-testing and gated SPECT variables were entered into a multivariable analysis as categorical covariates. In all statistical

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Table 2. Clinical, dipyridamole-exercise stress, and gated SPECT imaging variables in relation to cardiac events

Variable Clinical Age (y) Male gender (%) Previous MI (%) Previous PCI (%) Previous CABG (%) Diabetes mellitus (%) Hypertension (%) Elevated cholesterol (%) History of smoking (%) Abnormal resting ECG (%) Dipyridamole-exercise stress Positive ECG response (%) METs Fair or poor functional capacity (%) Gated SPECT imaging Abnormal image (%) Fixed cavity dilation (%) Transient ischemic dilation (%) SSS Abnormal SSS (%) Severely abnormal SSS (%) SDS Ischemia by SDS (%) Severe ischemia by SDS (%) Post-stress EF Reduced post-stress EF (%) Severely reduced post-stress EF (%)

Cardiac event-free (n ⴝ 1982)

Cardiac event (n ⴝ 82)

P value

63 ⫾ 12 907 (45.8) 382 (19.3) 289 (14.6) 279 (14.1) 524 (26.5) 1307 (65.9) 1047 (52.8) 636 (32.1) 1008 (50.9)

64 ⫾ 13 55 (67.1) 33 (40.2) 28 (34.1) 20 (24.4) 41 (50) 61 (74.4) 48 (58.5) 33 (40.2) 56 (68.3)

.326 ⬍.001 ⬍.001 ⬍.001 .009 ⬍.001 .113 .31 .122 .002

423 (21.3) 5.9 ⫾ 2.9 1468 (74.1)

19 (23.2) 4.9 ⫾ 2.3 74 (90.2)

.692 ⬍.001 .001

676 (34.1) 160 (8.1) 21 (1.1) 3.2 ⫾ 6.1 542 (27.3) 162 (8.2) 1.1 ⫾ 2.6 393 (19.8) 86 (4.3) 58.7% ⫾ 11.6% 247 (12.5) 57 (2.9)

51 (62.2) 21 (25.6) 5 (6.1) 6.9 ⫾ 8.3 45 (54.9) 20 (24.4) 1.6 ⫾ 3.1 24 (29.3) 4 (4.9) 48.9% ⫾ 15.3% 28 (34.1) 15 (18.3)

⬍.001 ⬍.001 .003 ⬍.001 ⬍.001 ⬍.001 .118 .037 .78 ⬍.001 ⬍.001 ⬍.001

Numbers in parentheses refer to the percentage of patients in the column who have the particular variable. MI, Myocardial infarction; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; ECG, electrocardiogram; MPHR, maximum predicted heart rate; METs, metabolic equivalents; SPECT, single-photon emission computed tomographic; SSS, summed stress score; SDS, summed difference score; EF, ejection fraction.

analyses, P ⬍ .05 was considered significant, using SPSS version 15.0 (2006, Chicago, Ill).

(39.9% vs 28.1% respectively, P ⫽ .002). For all other clinical, stress, and gated SPECT variables, no significant differences were observed.

RESULTS Patients With Complete Versus Incomplete Follow-up

Clinical, Stress, and Gated SPECT Imaging Characteristics

Compared with the 2252 patients in whom follow-up was complete, the 185 with incomplete data were younger (63 ⫾ 12 vs 57 ⫾ 13 years, respectively, P ⬍ .001) and had less often manifested a previous PCI (16.2% vs 10.3% respectively, P ⫽ .033), a stress ECG that was positive for ischemia (23.3% vs 15.7% respectively, P ⫽ .018), or an abnormal gated SPECT image

Patients with a complete follow-up ranged in age from 19 to 94 years, 52.1% were female, and 52.6% had known CAD or diabetes mellitus. The most common indication for stress-gated SPECT imaging was assessment of chest pain (86.2% of patients), whereas the most common reasons for termination of exercise were fatigue, chest pain/dyspnea, or muscu-

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Table 3. Unadjusted 6-year cumulative cardiac event-free survival in relation to gated SPECT variables

Variable LV cavity size Normal Fixed dilation Transient ischemic dilation SSS Normal Mildly to moderately abnormal Severely abnormal SDS No ischemia Mild to moderate ischemia Severe ischemia Post-stress EF Normal Mildly to moderately reduced Severely reduced

Unadjusted 6-year cumulative cardiac event-free P survival (%) value ⬍.001 89.8 71.7 73.5 ⬍.001 92.7 84.2 64.1

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patients exhibited an ECG response that was positive for ischemia. Gated SPECT images were normal in 1353 (60.1%) patients, and abnormal in 899 (39.9%). Of patients who underwent early revascularization, 91.5% had abnormal images, compared with 35.2% of those who did not undergo an early interventional procedure (Table 1). With the exception of fixed LV cavity dilation or a severely reduced post-stress EF, patients who underwent early revascularization more often had severe abnormalities, particularly with respect to SSS, SDS, and the presence of TID. Of 16 patients with normal images who underwent early revascularization (1.2% of those with normal images), 12 had stress-induced chest pain, and five had an ECG response that was positive for ischemia. Notably, nine of those patients were receiving beta-blocker therapy at time of testing.

.207 87.6 86.0

Variables Associated With Adverse Cardiac Outcomes

85.9

Among 2064 patients comprising the prognostic analysis, 82 (4%) had an adverse cardiac event during follow-up (40 suffered cardiac death, and 42 sustained a nonfatal MI). Patients with adverse outcomes were more likely to be male and more often had a previous MI, PCI, or CABG, diabetes mellitus, or an abnormal resting ECG (Table 2). In addition, patients with a cardiac event were more likely to achieve a lower exercise workload (METs) and to demonstrate fair or poor functional capacity. Patients with adverse outcomes also more often had an abnormal gated SPECT image, which consisted of fixed or transient ischemic dilation, higher SSS or SDS, or a lower post-stress EF.

⬍.001 90.8 77.3 51.3

LV, Left ventricular; SSS, summed stress score; SDS, summed difference score; EF, ejection fraction; SPECT, single-photon emission computed tomographic.

loskeletal pain/claudication (70.8%, 17.2%, and 6.5% of patients, respectively). The exercise workload achieved by patients ranged from 1 to 17.2 METs, with 1092 (48.5%), 608 (27%), 329 (14.6%), 211 (9.4%), and 12 (0.5%) demonstrating poor, fair, average, good, and high functional capacity, respectively. Five-hundred eighty-five (25.9%) patients exercised ⬎6 minutes (a common threshold with low-level exercise augmentation protocols), whereas 785 (34.9%) achieved ⱖ85% of their MPHR. Of 552 patients demonstrating average to high functional capacity (24.5% of the cohort), 242 (43.8%) achieved ⬍85% of their MPHR, of whom 159 (65.7%) were receiving beta-blocker therapy at time of testing. Concomitant beta-blocker therapy was marginally associated with METs, but was highly associated with percent MPHR achieved (5.7 ⫾ 2.7 vs 5.9 ⫾ 2.9, P ⫽ .043, and 74% ⫾ 13% vs 82% ⫾ 12%, P ⬍ .001, in patients receiving and not receiving beta-blocker therapy, respectively). Five-hundred twenty-four (23.3%)

Stress and Gated SPECT Variables in Relation to Adverse Cardiac Outcomes The annualized rate of cardiac death or nonfatal MI in patients with normal gated SPECT images (0.96%, 31/1337) was significantly lower than in those with abnormal images (2.71%, 51/727, odds ratio [OR] ⫽ 2.86, 95% confidence interval [CI] ⫽ 1.83 to 4.49, P ⬍ .001). In general, the presence and severity of abnormalities on gated SPECT imaging were associated with a significantly lower 6-year cumulative cardiac event-free survival (Table 3). In patients with a normal, mildly to moderately abnormal, or severely abnormal SSS, the annualized event rate was 1.04% (37/1,477), 2.34% (25/405, P ⫽ .001 vs normal), and 4.26% (20/182, P ⬍ .001 vs normal, P ⫽ .04 vs mildly to moderately abnormal), respectively. Similarly, patients with a normal, mildly to moderately reduced, or severely reduced

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Figure 2. Kaplan-Meier 6-year cumulative cardiac event-free survival in relation to functional capacity (average to high vs fair or poor).

post-stress EF had an annualized event rate of 1.23% (54/1789), 2.4% (13/203, P ⫽ .027 vs normal), and 8.77% (15/72, P ⬍ .001 vs normal or mildly to moderately reduced), respectively. The 6-year unadjusted cumulative cardiac event-free survival in patients with average to high functional capacity (97.4%) was significantly higher than in those with fair or poor functional capacity (85%, P ⫽ .004, Figure 2). Functional capacity was significantly related to the gated SPECT result (38.6% [595/1542] of patients demonstrating fair or poor functional capacity had abnormal images, compared with 25.3% [132/522] of those demonstrating average to high functional capacity; P ⬍ .001). However, in patients with abnormal images, a significantly lower annualized event rate was observed in those with average to high versus fair or poor functional capacity (Figure 3). Similarly, in patients with fair or poor functional capacity, those with normal images had a significantly lower annualized event

rate than those with abnormal images (P ⬍ .001). Notably, mean LV cavity, perfusion, and function scores/values in patients with abnormal images were not significantly different between those with average to high versus fair or poor functional capacity. Stress and Gated SPECT Predictors of Adverse Cardiac Outcomes Initial Cox proportional hazards regression modeling, which included the significant clinical and stress variables listed in Table 2, showed that abnormal gated SPECT imaging predicted cardiac death or nonfatal MI (Wald chi-square ⫽ 5.86, OR ⫽ 1.78, 95% CI ⫽ 1.11 to 2.86, P ⫽ .015). In subsequent modeling, stress and gated SPECT variables that emerged as independent predictors of adverse outcome were, in order of significance, severely reduced post-stress EF (Wald chi-

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Ahlberg et al Symptom-limited exercise combined with dipyridamole stress

Figure 3. Annualized cardiac event rate in relation to gated SPECT imaging result (normal or abnormal) and functional capacity (average to high vs fair or poor).

Figure 4. Risk-stratification algorithm for adverse cardiac outcomes, using a protocol that combines symptom-limited exercise and dipyridamole stress with gated SPECT imaging.

square ⫽ 12.08, OR ⫽ 4.42, 95% CI ⫽ 1.91 to 10.24, P ⫽ .0005), TID (Wald chi-square ⫽ 11.03, OR ⫽ 4.87, 95% CI ⫽ 1.91 to 12.42, P ⫽ .0009), and fair or poor functional capacity (Wald chi-square ⫽ 5.54, OR ⫽ 2.43, 95% CI ⫽ 1.16 to 5.09, P ⫽ .019). Risk Stratification for Adverse Cardiac Outcomes In accordance with the findings in Cox proportional hazards regression modeling, risk stratification by integration of gated SPECT imaging and functional capacity data was explored (Figure 4). Of 631 patients with abnormal images who did not fulfill the criteria for high-risk categorization, 119 (18.9%) were categorized as low-risk, based on functional capacity. Clinical and

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stress variables, the severity of abnormalities on gated SPECT imaging, and adverse outcomes all were associated with risk category (Table 4). The annualized event rate in low-risk, intermediate-risk, and high-risk cohorts was 0.94% (33/1456), 2.24% (30/512, OR ⫽ 2.42, 95% CI ⫽ 1.47 to 3.99 vs low-risk), and 8.19% (19/96, OR ⫽ 9.43, 95% CI ⫽ 5.27 to 16.87 versus low-risk; OR ⫽ 3.88, 95% CI ⫽ 2.15 to 7.03 vs intermediate-risk), respectively (P ⬍ .001 in any two-way comparison). Similarly, the 6-year unadjusted cumulative cardiac event-free survival was 93.2%, 80.7%, and 56.4% in low-risk, intermediate-risk, and high-risk patients, respectively (P ⬍ .001 in any two-way comparison, Figure 5). The 3-year unadjusted cumulative event-free survival in low-risk, intermediate-risk, and high-risk categories was 97.3%, 95.2%, (P ⫽ .028 vs low-risk), and 78.7% (P ⬍0.001 vs low-risk or intermediate-risk), respectively. The final Cox proportional hazards regression modeling showed that the high-risk categorization was the most significant predictor of cardiac death or nonfatal MI (Table 5). Concomitant beta-blocker therapy in relation to gated SPECT results and adverse cardiac outcomes. Concomitant beta-blocker therapy in relation to gated SPECT results and adverse cardiac outcomes was examined. Compared with patients not receiving betablocker therapy, those who did receive beta-blocker therapy were more likely to have a history of CAD or hypertension, more often had abnormalities on gated SPECT imaging, and had a higher incidence of cardiac death and non-fatal MI (Table 6). In patients with normal images, the 6-year unadjusted cumulative cardiac eventfree survival in those not receiving beta-blocker therapy (96.1%) was higher than in those receiving beta-blocker therapy (88.4%), although the difference was not statistically significant (Figure 6). The 3-year unadjusted cumulative event-free survival was similar between patient groups (97.9% and 96.4% in those not receiving and receiving beta-blocker therapy, respectively, P ⫽ .292). In patients receiving beta-blocker therapy at time of testing, gated SPECT results and functional capacity in relation to adverse cardiac outcome were examined. The annualized event rate in those with normal images (1.35%, 18/553) was significantly lower than in those with abnormal images (3.56%, 39/426, OR ⫽ 2.69, 95% CI ⫽ 1.53 to 4.73, P ⬍ .001). In patients with normal images, no significant difference in the annualized event rate was observed between those demonstrating average to high versus fair or poor functional capacity (Figure 7). However, the event rate in the former group suggests a low-risk cohort. In patients with abnormal images, a 2.7-fold higher annualized event rate was observed in those with fair or poor versus average to high functional

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Table 4. Comparison of clinical, dipyridamole-exercise stress, gated SPECT imaging, and adverse cardiac outcome variables between risk categories

Variable Clinical Age (y) Male gender (%) Previous MI (%) Previous PCI (%) Previous CABG (%) Diabetes mellitus (%) Abnormal resting ECG (%) Dipyridamole-exercise stress Positive ECG response % MPHR METs Gated SPECT imaging LV cavity size at stress LV cavity size at rest SSS Severely abnormal SSS SRS SDS Severe ischemia by SDS Post-stress EF (%) Adverse cardiac outcome Nonfatal MI (%) Cardiac death (%) Cardiac death or nonfatal MI (%)

Low-risk (n ⴝ 1456)

Intermediate-risk (n ⴝ 512)

High-risk (n ⴝ 96)

62 ⫾ 12 579 (39.8) 182 (12.5) 183 (12.6) 145 (10) 334 (23) 639 (43.9)

64 ⫾ 12† 314 (61.3)† 186 (36.3)† 113 (22.1)† 127 (24.8)† 191 (37.3)† 344 (67.2)†

65 ⫾ 12* 69 (71.9)†‡ 47 (49)†‡ 21 (21.9)* 27 (28.1)† 40 (41.7)† 81 (84.4)†£

314 (21.6) 80.5 ⫾ 12.7 6.3 ⫾ 3

105 (20.5) 73.4 ⫾ 13.1† 4.6 ⫾ 1.8†

23 (24) 72.9 ⫾ 11.5† 4.6 ⫾ 2.5†

0.02 ⫾ 0.19 0.02 ⫾ 0.19 0.8 ⫾ 3.4 30 (2.1) 0.6 ⫾ 2.9 0.2 ⫾ 1.2 12 (0.8) 62.5 ⫾ 8

0.25 ⫾ 0.55† 0.25 ⫾ 0.55† 8.6 ⫾ 6.2† 100 (19.5)† 5.4 ⫾ 6.5† 3.1 ⫾ 3.4† 57 (11.1)† 51.5 ⫾ 10.9†

1.44 ⫾ 0.86†£ 1.17 ⫾ 1.04†£ 13.8 ⫾ 9.4†£ 52 (54.2)†£ 10.1 ⫾ 9.9†£ 3.6 ⫾ 5† 21 (21.9)†£ 30.3 ⫾ 13.2†£

20 (1.4) 13 (0.9) 33 (2.3)

17 (3.3)* 13 (2.5)* 30 (5.9)†

5 (5.2)* 14 (14.6)†£ 19 (19.8)†£

Numbers in parentheses refer to percentage of patients in column who have the particular variable. MI, Myocardial infarction; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; ECG, electrocardiogram; MPHR, maximum predicted heart rate; METs, metabolic equivalents; SSS, summed stress score; SDS, summed difference score; EF, ejection fraction; MI, myocardial infarction; SPECT, single-photon emission computed tomographic. *P ⬍ .01 vs low-risk. † P ⬍ .001 vs low-risk. ‡ P ⬍ .05 vs intermediate-risk. £ P ⬍ .001 vs intermediate-risk.

capacity, with a statistical trend achieved likely because of low patient numbers. DISCUSSION This study investigated the prognostic value of a protocol in selected patients that combined symptomlimited exercise and dipyridamole stress with gated SPECT imaging. Our results indicate that this combined stress protocol is highly effective in the identification of clinically significant CAD as well as risk stratification for adverse outcomes. These findings have potentially important implications in patients undergoing noninvasive assessment of known or suspected CAD.

Rationale for Combining Vasodilator and Exercise Stress With Gated SPECT Imaging Not infrequently, a clinician is faced with uncertainty regarding the ability of a patient to perform adequate exercise in conjunction with gated SPECT imaging. Protocols which combine vasodilator and exercise stress are well-suited for such patients, and were shown to be safe while reducing noncardiac side effects and improving image quality compared with vasodilator stress alone, as well as enhancing the detection of ischemia compared with suboptimal exercise or vasodilator stress alone.30-45 Combined stress protocols, particularly those that allow performance of

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Figure 5. Kaplan-Meier 6-year cumulative cardiac event-free survival in relation to risk categorization (low vs intermediate vs high), using a protocol that combines symptom-limited exercise and dipyridamole stress with gated SPECT imaging (*P ⬍ .001 in any two-way comparison).

Table 5. Cox proportional hazards regression analysis: final model in prediction of cardiac death or nonfatal MI in patients undergoing dipyridamole-exercise gated SPECT imaging

Predictors

Wald chi-square

OR

95% CI

P value

High-risk categorization Diabetes mellitus Prior PCI Male gender Intermediate-risk categorization

36.82 11.93 8.98 6.83 4.17

6.14 2.17 2.03 1.88 1.7

3.41–11.04 1.4–3.38 1.27–3.23 1.17–3.04 1.02–2.84

⬍.0001 .0006 .003 .009 .041

OR, odds ratio; CI, confidence interval; PCI, percutaneous coronary intervention; SPECT, single-photon emission computed tomographic.

symptom-limited exercise, also have the potential to provide additional prognostic information.34,44,45 Our findings confirm this, insofar as functional-capacity data provided a further point of risk stratification beyond gated SPECT imaging alone.

Prognostic Value of Vasodilator-Exercise Gated SPECT Imaging Protocols Thomas et al4 demonstrated the prognostic value of adenosine with simultaneous low-level exercise. In that

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51

Table 6. Comparison of clinical, dipyridamole-exercise stress, gated SPECT imaging, and adverse cardiac outcome variables between patients not receiving and receiving beta-blocker therapy at time of testing

Variable Clinical Age (y) Male gender (%) Previous MI (%) Previous PCI (%) Previous CABG (%) Hypertension (%) Dipyridamole-exercise stress Pre-HR (beats/min) Pre-SBP (mm Hg) Pre-RPP (HR ⫻ SBP) Peak HR (beats/min) % MPHR Peak SBP (mm Hg) Peak RPP (HR ⫻ SBP) Exercise time (min) METs Positive ECG response (%) Gated SPECT imaging Abnormal image (%) Fixed cavity dilation (%) Transient ischemic dilation (%) SSS Abnormal SSS (%) Severely abnormal SSS (%) SDS Ischemia by SDS (%) Severe ischemia by SDS (%) Post-stress EF Reduced post-stress EF (%) Severely reduced post-stress EF (%) Adverse cardiac outcome Nonfatal MI (%) Cardiac death (%) Cardiac death or nonfatal MI (%)

BBⴚ (n ⴝ 1084)

BBⴙ (n ⴝ 978)

P value

61 ⫾ 12 449 (41.4) 135 (12.5) 91 (8.4) 88 (8.1) 574 (53)

64 ⫾ 11 513 (52.5) 279 (28.5) 226 (23.1) 211 (21.6) 794 (81.2)

⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001

71 ⫾ 11 131 ⫾ 19 9374 ⫾ 2,192 131 ⫾ 21* 82 ⫾ 12 154 ⫾ 24* 20,336 ⫾ 5189* 5 ⫾ 2.7 5.9 ⫾ 2.9 218 (20.1)

66 ⫾ 11 133 ⫾ 19 8826 ⫾ 2,092 115 ⫾ 21* 74 ⫾ 12 148 ⫾ 25* 17,265 ⫾ 4971* 4.9 ⫾ 2.6 5.7 ⫾ 2.7 224 (22.9)

⬍.001 .017 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 .228 .047 .123

300 (27.7) 73 (6.7) 7 (0.6) 2.1 ⫾ 4.8 219 (20.2) 54 (5) 0.8 ⫾ 2.2 181 (16.7) 31 (2.9) 60 ⫾ 11 113 (10.4) 25 (2.3)

426 (43.6) 107 (10.9) 19 (1.9) 4.7 ⫾ 7.2 367 (37.5) 128 (13.1) 1.4 ⫾ 3 236 (24.1) 59 (6) 56 ⫾ 12 161 (16.5) 46 (4.7)

⬍.001 .001 .008 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 .003

12 (1.1) 13 (1.2) 25 (2.3)

30 (3.1) 27 (2.8) 57 (5.8)

.002 .01 ⬍.001

Numbers in parentheses refer to the percentage of patients in the column who have the particular variable. Two patients had missing data regarding beta-blocker therapy. MI, Myocardial infarction; BB⫹, receiving beta-blocker therapy; BB⫺, not receiving beta-blocker therapy; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; HR, heart rate; SBP, systolic blood pressure; RPP, rate pressure product; MPHR, maximum predicted heart rate; METs, metabolic equivalents; ECG, electrocardiogram; SSS, summed stress score; SDS, summed difference score; EF, ejection fraction; SPECT, single-photon emission computed tomographic. *P ⬍ .001 vs resting HR, SBP, or RPP.

study, relative risks with abnormal imaging or transient ischemic dilation were significantly higher in patients who had received adenosine with low-level exercise compared with those who had received adenosine stress alone. Based on these findings, the authors theorized that

adenosine-gated SPECT imaging can be enhanced by the addition of low-level exercise. A theoretic advantage of dipyridamole over adenosine is its longer hyperemic phase (minutes vs seconds), allowing a patient to exercise to the point of fatigue or a

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Ahlberg et al Symptom-limited exercise combined with dipyridamole stress

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Figure 6. Kaplan-Meier 6-year cumulative cardiac event-free survival in patients with normal gated SPECT images who either did not receive or received beta-blocker therapy (BB⫺ and BB⫹, respectively) at time of testing.

clinical endpoint before the injection of a radiopharmaceutical.51 In our study, patients with normal gated SPECT images had a low incidence of cardiac death or nonfatal MI (⬍1% per year). In addition, effective risk stratification was achieved by the use of stress perfusion data, while severely reduced post-stress EF and transient ischemic dilation emerged as powerful predictors of adverse outcome. Among our patient population, fair or poor functional capacity predicted adverse outcome, a finding consistent with reports of exercise SPECT imaging,12,13 and was associated with a twofold and fourfold higher event rate with normal and abnormal gated SPECT imaging, respectively. In patients with abnormal images, those demonstrating average to high functional capacity had a low event rate, and thus noninvasive approaches to management may be appropriate.52 The integration of gated SPECT imaging and functional capacity data proved highly effective in the stratification of patients into low-risk, intermediate-risk, and high-risk

cohorts. It is noteworthy that stratification was favorably altered in 19% of patients who otherwise would have been categorized as intermediate-risk by gated SPECT imaging alone. Utility of Dipyridamole-Exercise Gated SPECT Imaging There are some fundamental differences between the combined stress protocol our laboratory utilizes and those pioneered by others.31,35,39,45 In the United States, simultaneous low-level treadmill exercise as an adjunct to standard dipyridamole stress31 or standard adenosine stress39 presumably are the most commonly used combination protocols, and appear to be most appropriate in patients with limited functional capacity who otherwise would undergo vasodilator stress alone. Conversely, the protocol examined in the Both Exercise and Adenosine Stress Test Trial45 used a 4-minute adenosine infusion as

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Figure 7. Annualized cardiac event rate in relation to gated SPECT imaging result (normal or abnormal) and functional capacity (average to high vs fair or poor) in patients who received concomitant beta-blocker therapy at time of testing.

an adjunct to symptom-limited treadmill exercise in patients who might not achieve the target heart rate because of concomitant antianginal drug therapy or other confounding factors. With adenosine-exercise protocols, the injection of a radiopharmaceutical is targeted during the peak hyperemic phase of adenosine, and not at the patient’s peak exercise tolerance. A protocol that combines symptom-limited exercise with dipyridamole stress is unique and well-suited for patients in whom there is uncertainty regarding the ability to undergo standard treadmill testing, or for those referred for standard vasodilator stress with the ability to perform some level of exercise. The low incidence of early revascularization in patients with normal images (1.2%) and favorable prognostic findings, coupled with the wide range in achieved exercise workload and low percentage demonstrating an adequate heart-rate response, reinforces the utility of the protocol.34 From a practical standpoint, the routine utilization of dipyridamole-exercise stress in our laboratory has substantially reduced the incidence of inadequate exercise testing, because physicians realize that the combined protocol will provide information regarding functional capacity while optimizing identification of clinically significant CAD on perfusion imaging.44 All three selective A2A agents are bolus injections, similar to dipyridamole, with much longer hyperemic phases than with adenosine.53 To our knowledge, there are no published data on the value of combining exercise with these agents. Potential impact of concomitant beta-blocker therapy on identification of clinically significant CAD with dipyridamole-exercise gated SPECT imaging. Concomitant beta-blocker therapy was shown to negatively affect the sensitivity of perfusion imaging for the detection of CAD with exercise54,55 and dipyridam-

Ahlberg et al Symptom-limited exercise combined with dipyridamole stress

53

ole stress.56 Our findings suggest that concomitant betablocker therapy may negatively affect the identification of clinically significant CAD with dipyridamole-exercise stress, and hence may negatively affect the prognostic value of normal gated SPECT imaging. However, the progression of CAD is an alternative explanation, because the 3-year cumulative event-free survival with normal imaging was very high (⬎95%) and similar between patients not receiving and receiving betablocker therapy at time of testing. Brown and Rowen57 found that concurrent antianginal therapy at time of exercise testing did not affect the prognostic value of normal imaging. Conversely, Burns et al58 concluded that the prognostic value of normal exercise imaging was negatively affected in patients tested while taking antianginal medications. Nonetheless, clinicians should consider instructing patients to discontinue beta-blocker therapy 36 to 48 hours before testing to optimize results, particularly if the purpose of stress-perfusion imaging is for the diagnosis of CAD.59 For patients in whom discontinuation of beta-blocker therapy is not advisable because of a risk, albeit low, of potentially life-threatening complications,60-63 our findings indicate that effective risk stratification can be achieved with dipyridamole-exercise stress, particularly with the integration of gated SPECT imaging and functional capacity data. The event rate in patients with normal images who also demonstrate average to high functional capacity (1.1% per year) is indicative of a low-risk cohort. Limitations This was a retrospective analysis of prospectively collected data. Complete follow-up data were obtained in a high percentage of patients, although the exclusion of those who had undergone early revascularization and with incomplete follow-up may have altered the risk profile of our cohort. However, an analysis of patients comprising the latter group suggested a lower-risk population. Ejection fractions were obtained during poststress gated acquisition, and thus we were unable to examine the prognostic value of reversible dysfunction. Attenuation-corrected gated SPECT data were not included in this analysis (because the technique was not available when the majority of patients were undergoing evaluation), and may have enhanced risk stratification. The number of patients and events did not allow a thorough examination of risk stratification in key subsets or for cardiac death and non-fatal MI as separate endpoints. Various factors may have affected our findings in patients receiving beta-blocker therapy at time of testing, including type, duration of action, and the inability to determine which patients, if any, discontinued therapy

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Ahlberg et al Symptom-limited exercise combined with dipyridamole stress

for at least 36 hours before testing. However, the vast majority of patients were evaluated before the emergence of data demonstrating the negative impact of betablockade on the sensitivity of dipyridamole SPECT imaging,56 while pre-stress and peak-stress hemodynamics suggest that therapy was not discontinued for a significant time before testing (Table 6). There was no comparison with a matched group of patients who had undergone either suboptimal exercise or dipyridamole stress alone; thus it is unknown whether a combined stress protocol significantly enhances risk stratification.

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9.

10.

11.

CONCLUSIONS 12.

In selected patients, a protocol that combines symptomlimited exercise and dipyridamole stress with gated SPECT imaging is highly effective in the identification of clinically significant CAD as well as risk stratification for adverse outcome.

13.

References 1. Sharir T, Germano G, Kavanaugh PB, Lai Shenhan, Cohen I, Lewin HC, et al. Incremental prognostic value of post-stress left ventricular ejection fraction and volume by gated myocardial perfusion single photon emission computed tomography. Circulation 1999;100:1035-42. 2. Sharir T, Germano G, Kang X, Lewin HC, Miranda R, Cohen I, et al. Prediction of myocardial infarction versus cardiac death by gated myocardial perfusion SPECT: risk stratification by the amount of stress-induced ischemia and the post-stress ejection fraction. J Nucl Med 2001;42:831-7. 3. Travin MI, Heller GV, Johnson LL, Katten D, Ahlberg AW, Isasi CR, et al. The prognostic value of ECG-gated SPECT imaging in patients undergoing stress Tc-99m sestamibi myocardial perfusion imaging. J Nucl Cardiol 2004;11:253-62. 4. Thomas GS, Miyamoto MI, Morello AP, Majmundar H, Thomas JJ, Sampson CH, et al. Technetium-99m sestamibi myocardial perfusion imaging predicts clinical outcome in the community outpatient setting: the Nuclear Utility in the Community (NUC) Study. J Am Coll Cardiol 2004;43:213-23. 5. Petix NR, Sestini S, Marcucci G, Coppola A, Arena A, Nassi F, et al. Can the reversible regional wall motion abnormalities on stress gated Tc-99m sestamibi SPECT predict a future cardiac event? J Nucl Cardiol 2005;12:20-31. 6. Petix NR, Sestini S, Coppola A, Marcucci G, Nassi F, Taiti A, et al. Prognostic value of combined perfusion and function by stress technetium-99m sestamibi gated SPECT myocardial perfusion imaging in patients with suspected or known coronary artery disease. Am J Cardiol 2005;95:1351-7. 7. Navare SM, Katten D, Johnson LL, Mather JF, Fowler MS, Ahlberg AW, et al. Risk stratification with electrocardiographicgated dobutamine stress technetium-99m sestamibi single-photon emission tomographic imaging: value of heart rate response and assessment of left ventricular function. J Am Coll Cardiol 2006; 47:781-8. 8. Sharir T, Kang X, Germano G, Bax JJ, Shaw LJ, Gransar H, et al. Prognostic value of poststress left ventricular volume and ejection fraction by gated myocardial perfusion SPECT in women and men:

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23. Miller DD, Stratmann HG, Shaw L, Tamesis BR, Wittry MD, Younis LT, et al. Dipyridamole technetium 99m sestamibi myocardial tomography as an independent predictor of cardiac eventfree survival after acute ischemic events. J Nucl Cardiol 1994;1: 72-82. 24. Heller GV, Herman SD, Travin MI, Baron JI, Santos-Ocampo C, McClellan JR. Independent prognostic value of intravenous dipyridamole with technetium-99m sestamibi tomographic imaging in predicting cardiac events and cardiac-related hospital admissions. J Am Coll Cardiol 1995;26:1202-8. 25. Stratmann HG, Tamesis BR, Younis LT, Wittry MD, Amato M, Miller DD. Prognostic value of predischarge dipyridamole technetium 99m sestamibi myocardial tomography in medically treated patients with unstable angina. Am Heart J 1995;130: 734-40. 26. Stratmann HG, Younis LT, Wittry MD, Amato M, Miller DD. Dipyridamole technetium-99m sestamibi myocardial tomography in patients evaluated for elective vascular surgery: prognostic value of perioperative and late cardiac events. Am Heart J 1996;131: 923-9. 27. McClellan JR, Travin MI, Herman SD, Baron JI, Golub RJ, Gallagher JJ, et al. Prognostic importance of scintigraphic left ventricular cavity dilation during intravenous dipyridamole technetium-99m sestamibi myocardial tomographic imaging in predicting coronary events. Am J Cardiol 1997;79:600-5. 28. Hachamovitch R, Berman DS, Kiat H, Cohen I, Lewin H, Amanullah A, et al. Incremental prognostic value of adenosine stress myocardial perfusion single-photon emission computed tomography and impact on subsequent management in patients with or suspected of having myocardial ischemia. Am J Cardiol 1997;80:426-33. 29. Hachamovitch R, Hayes SW, Friedman JD, Cohen I, Berman DS. A progressive score for prediction of cardiac mortality risk after adenosine stress myocardial perfusion scintigraphy. J Am Coll Cardiol 2005;45:722-9. 30. Laarman GJ, Bruschke AVG, Verzijlbergen JF, Bal ET, van der Wall EE, Ascoop CA. Efficacy of intravenous dipyridamole with exercise thallium-201 myocardial perfusion scintigraphy. Eur Heart J 1988;1206-14. 31. Casale PN, Guiney TE, Strauss HW, Boucher CA. Simultaneous low level treadmill exercise and intravenous dipyridamole stress thallium imaging. Am J Cardiol 1988;62:799-802. 32. Laarman GJ, Bruschke AVG, Verzijibergen JF, Go TL, Bal ET, Van Der Wall EE, et al. Thallium-201 scintigraphy after dipyridamole infusion with low-level exercise. II. Quantitative analysis vs. visual analysis. Eur Heart J 1990;11:162-72. 33. Laarman GJ, Serruys PW, Verzijlbergen JF, Ascoop CA. Thallium-201 scintigraphy after dipyridamole infusion with lowlevel exercise. III. Clinical significance and additional diagnostic value of ST segment depression and angina pectoris during the test. Eur Heart J 1990;11:705-11. 34. Ignaszewski AP, McCormick LX, Heslip PG, McEwan AJ, Humen DP. Safety and clinical utility of combined intravenous dipyridamole/symptom-limited exercise stress test with thallium-201 imaging in patients with known or suspected coronary artery disease. J Nucl Med 1993;34:2053-61. 35. Pennell DJ, Mavrogeni SI, Forbat SM, Karwatowski SP, Underwood SR. Adenosine combined with dynamic exercise for myocardial perfusion imaging. J Am Coll Cardiol 1995;25:1300-9. 36. Stein L, Burt R, Oppenheim B, Schauwecker D, Fineberg N. Symptom-limited arm exercise increases detection of ischemia during dipyridamole tomographic thallium stress testing in patients with coronary artery disease. Am J Cardiol 1995;75: 568-72.

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37. Daou D, Le Guiudec D, Faraggi M, Foult JM, Lebtahi R, Cohen-Solal A, et al. Nonlimited exercise test combined with high-dose dipyridamole for thallium-201 myocardial single-photon emission computed tomography in coronary artery disease. Am J Cardiol 1995;76:753-8. 38. Elliott MD, Holly TA, Leonard SM, Hendel RC. Impact of an abbreviated adenosine protocol incorporating adjunctive treadmill exercise on adverse effects and image quality in patients undergoing stress myocardial perfusion imaging. J Nucl Cardiol 2000;7: 584-9. 39. Thomas GS, Prill NV, Majmundar H, Fabrizi RR, Thomas JJ, Hayashida C, et al. Treadmill exercise during adenosine infusion is safe, results in fewer adverse reactions, and improves myocardial perfusion image quality. J Nucl Cardiol 2000;7:439-46. 40. Vitola JV, Brambatti JC, Caligaris F, Lesse CR, Nogueira PR, Joaquim AI, et al. Exercise supplementation to dipyridamole prevents hypotension, improves electrocardiogram sensitivity, and increases heart-to-liver activity ratio on Tc-99m sestamibi imaging. J Nucl Cardiol 2001;8:652-9. 41. Samady H, Wackers FJ, Joska TM, Zaret BL, Jain D. Pharmacologic stress perfusion imaging with adenosine: role of simultaneous low-level treadmill exercise. J Nucl Cardiol 2002;9: 188-96. 42. Verzijibergen JF, Vermeersch PH, Laarman GJ, Ascoop CA. Inadequate exercise leads to suboptimal imaging. Thallium-201 myocardial perfusion imaging after dipyridamole combined with low-level exercise unmasks ischemia in symptomatic patients with non-diagnostic thallium-201 scans who exercise submaximally. J Nucl Med 1991;32:2071-8. 43. Pennell DJ, Mavrogeni S, Anagnostopoulos C, Ell PJ, Underwood SR. Thallium myocardial perfusion tomography using intravenous dipyridamole combined with maximal dynamic exercise. Nucl Med Commun 1993;14:939-45. 44. Candell-Riera J, Santana-Boado C, Castell-Conesa J, AguadeBruix S, Olona M, Palet J, et al. Simultaneous dipyridamole/ maximal subjective exercise with 99mTc-MIBI SPECT: improved diagnostic yield in coronary artery disease. J Am Coll Cardiol 1997;29:531-6. 45. Holly TA, Satran A, Bromet DS, Mieres JH, Frey MJ, Elliott MD, et al. The impact of adjunctive adenosine infusion during exercise myocardial perfusion imaging: results of the Both Exercise and Adenosine Stress Test (BEAST) Trial. J Nucl Cardiol 2003;10: 291-6. 46. Gibbons RJ, Balady GJ, Beasley JW, Bricker JT, Duvernoy WF, Froelicher VF, et al. ACC/AHA guidelines for exercise testing: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee on Exercise Testing). J Am Coll Cardiol 1997;30: 260-315. 47. McArdle WD, Katch FI, Katch WL. Essentials of exercise physiology. Philadelphia: Lea & Febiger, 1994:354. 48. American Society of Nuclear Cardiology. Imaging guidelines for nuclear cardiology procedures, part 2. J Nucl Cardiol 1999; 6:G47-84. 49. Cerqueria MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart: a statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation 2002;105:539-42. 50. Germano G, Kiat H, Kavanaugh PB, Moriel M, Mazzanti M, Hsiao-Te S. Automatic quantification of ejection fraction from gated myocardial perfusion SPECT. J Nucl Med 1995;36: 2138-47.

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51. Brown KA. Exercise-dipryidamole myocardial perfusion imaging: the circle is now complete— editorial. J Nucl Med 1993; 34:2053-61. 52. Boden WE, O’Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk WJ. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1-14. 53. Udelson JE, Heller GV, Wackers FJT, Chair A, Hinchman D, Coleman PS. Randomized, controlled dose-ranging study of the selective adenosine A2A receptor agonist binodenoson for pharmacological stress as an adjunct to myocardial perfusion imaging. Circulation 2004;109:457-65. 54. Hockings B, Saltissi S, Croft DN, Webb-Peploe MM. Effect of beta adrenergic blockade on thallium-201 myocardial perfusion imaging. Br Heart J 1983;48:83-9. 55. Martin GJ, Henkin RE, Scanlon PJ. Beta blockers and the sensitivity of the thallium treadmill test. Chest 1987;92:486-7. 56. Taillefer R, Ahlberg AW, Masood Y, White CM, Lamargese I, Mather JP, et al. Acute beta-blockade reduces the extent and severity of myocardial perfusion defects with dipyridamole Tc-99m sestamibi SPECT imaging. J Am Coll Cardiol 2003; 42:1475-83. 57. Brown KA, Rowen MA. Impact of antianginal medications, peak heart rate, and stress level on the prognostic value of a normal exercise myocardial perfusion imaging study. J Nucl Med 1993;34:1467-71. 58. Burns RJ, Kruzyk GC, Armitage DL, Druck MN. Effect of antianginal medications on the prognostic value of exercise thallium scintigraphy. Can J Cardiol 1989;5:29-32. 59. Gerson MC. Reduction in dipyridamole-induced single-photon emission computed tomography myocardial defect size by betablockers— editorial. J Am Coll Cardiol 2003;42:1484-6. 60. Alderman EL, Coltart DJ, Wettach GE, Harrison DC. Coronary artery syndromes after sudden propranolol withdrawal. Ann Intern Med 1974;81:625-7. 61. Miller RR, Olson HG, Amsterdam EA, Mason DT. Propranololwithdrawal rebound phenomenon. Exacerbation of coronary events after abrupt cessation of antianginal therapy. N Engl J Med 1975;293:416-8. 62. Myers MG, Wisenberg G. Sudden withdrawal of propranolol in patients with angina pectoris. Chest 1977;71:24-6. 63. Lindenfield J, Crawford MH, O’Rourke RA, Levine SP, Montiel MM, Horowitz LD. Adrenergic responsiveness after abrupt propranolol withdrawal in normal subjects and in patients with angina pectoris. Circulation 1980;62:704-11.

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APPENDIX I-A Formula for calculation of METs achieved with dipyridamole-exercise stress (Speed ⫻ 26.8 ⫻ 0.1) ⫹ (Grade ⁄ 100 ⫻ 1.8 ⫻ Speed ⫻ 26.8) 3.5 Speed ⫽ miles per hour. Grade ⫽ percent.

Between two stages, metabolic equivalent (MET) values were interpolated. The correct MET value of a stage is reached after a stage time of 2 minutes.

APPENDIX I-B Classification of estimated functional capacity (expressed in metabolic equivalents) according to age and sex

Estimated functional capacity (METs) Age (y) Poor Women ⱕ29 30–39 40–49 50–59 ⱖ60 Men ⱕ29 30–39 40–49 50–59 ⱖ60

Fair

Average

⬍7.5 7.5–10 ⬍7 7–9 ⬍6 6–8 ⬍5 5–7 ⬍4.5 4.5–6

10–13 9–11 8–10 7–9 6–8

⬍8 8–11 ⬍7.5 7.5–10 ⬍7 7–8.5 ⬍6 6–8 ⬍5.5 5.5–7

11–14 10–12.5 8.5–11.5 8–11 7–9.5

METS, Metabolic equivalents.

Good

High

13–16 11–15 10–14 9–13 8–11.5

⬎16 ⬎15 ⬎14 ⬎13 ⬎11.5

14–17 12.5–16 11.5–15 11–14 9.5–13

⬎17 ⬎16 ⬎15 ⬎14 ⬎13