- Email: [email protected]
Prognostic value of myocardial perfusion SPECT versus exercise electrocardiography in patients with ST-segment depression on resting electrocardiography
Prognostic value of myocardial perfusion SPECT versus exercise electrocardiography in patients with ST-segment depression on resting electrocardiography Andrea De Lorenzo, MD, PhD,a Rory Hachamovitch, MD, MSc,c Xingping Kang, MD,a Heidi Gransar, MS,a Maria G. Sciammarella, MD,a,b Sean W. Hayes, MD,a,b John D. Friedman, MD,a,b Ishac Cohen, PhD,a Guido Germano, PhD,a and Daniel S. Berman, MDa,b Background. The value of exercise-induced ST-segment depression for the prognostic evaluation of patients with 1 mm of ST depression or greater on the resting electrocardiogram is controversial. Methods and Results. Patients who underwent exercise myocardial perfusion single photon emission computed tomography (MPS) and had resting ST depression of 1 mm or greater with a nondiagnostic exercise electrocardiographic response (n ⴝ 1122) were followed up for 3.4 ⴞ 2.3 years. Those with paced rhythm, pre-excitation, left bundle branch block, or myocardial revascularization within the first 60 days after MPS were excluded. Additional exercise-induced ST-segment depression was considered significant if >2 mm MPS was scored semiquantitatively by use of a 20-segment model of the left ventricle; the percentage of myocardium involved with stress defects (% myo) was derived by normalizing to the maximal possible score of 80. Hard events were defined as nonfatal myocardial infarction or cardiac death. A Cox analysis was used to determine independent predictors of hard events among clinical, exercise, and nuclear variables. Hard event rates increased as a function of % myo for either patients with exercise-induced ST depression (1.4%/y for normal MPS vs 4.1%/y for % myo >10%, P < .03) or those without it (0.7%/y for normal MPS vs 3.0%/y for % myo >10%, P ⴝ .0001). Age, diabetes mellitus, shortness of breath as the presenting symptom, and % myo were independent predictors of hard events. Exercise-induced ST depression was predictive of hard events only when it was 3 mm or greater. The presence and extent of perfusion defects, reflected in the % myo, had incremental prognostic value over clinical variables and also over all degrees of exercise-induced ST depression. Conclusions. Although MPS effectively risk-stratifies patients with resting ST depression of 1 mm or greater, the prognostic value of exercise-induced ST depression is limited in these patients, with a small added risk when severe (>3 mm). (J Nucl Cardiol 2005;12:655-61.) Key Words: Myocardial perfusion single photon emission computed tomography • abnormal electrocardiogram • prognosis The presence of ST-segment depression on the resting electrocardiogram (ECG) has been associated with increased cardiac risk1-3 and often results in further noninvasive testing. Assessment of ST-segment change with exercise ECG in patients with resting ST-segment depression has been questioned, because in these patients From the Department of Imaging, Division of Nuclear Medicine,a and Department of Medicine, Division of Cardiology,b Cedars-Sinai Medical Center , and Department of Medicine, Division of Cardiology, Keck School of Medicine, University of Southern California,c Los Angeles, Calif. This work was supported in part by a grant from Bristol-Myers Squibb Medical Imaging, Inc, Billerica, Mass. Andrea De Lorenzo is the recipient of a scholarship granted by CAPES (Coordenacao de Auxilio de Pessoal de Nivel Superior), Brazil.
the specificity of exercise-induced ST depression for the diagnosis of coronary artery disease (CAD) is reduced4,5 and its usefulness as a prognostic indicator may be also limited.6 A recent study found that the exercise treadmill test (ETT), in conjunction with the clinical evaluation, was able to risk-stratify most patients with nonspecific ST-T abnormalities on the resting ECG and that myocardial Received for publication Jan 12, 2005; final revision accepted Aug 8, 2005. Reprint requests: Daniel S. Berman, MD, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Room 1258, Los Angeles, CA 90048; bermand@ cshs.org. 1071-3581/$30.00 Copyright © 2005 by the American Society of Nuclear Cardiology. doi:10.1016/j.nuclcard.2005.08.005 655
656
De Lorenzo et al Myocardial perfusion SPECT in patients with resting ST-segment depression
perfusion single photon emission computed tomography (SPECT) (MPS) should be reserved for patients at intermediate risk determined by clinical and exercise data.7 However, in that study resting ST depression was in general 1 mm. Current guidelines still recommend ETT for the prognostic evaluation of patients with a normal resting ECG or mild (⬍1 mm) ST depression, whereas stress imaging is suggested as the initial test for the diagnosis or risk stratification of patients with suspected or known CAD and resting ST depression of 1 mm or greater.6 Whereas stress MPS has been shown to effectively risk-stratify a wide variety of patient subsets,8-10 the prognostic value of MPS in those with 1 mm of resting ST depression or greater remains to be fully defined. In addition, whether exercise-induced ST depression adds to the prognostic evaluation in these patients is unknown. Therefore the objective of this study was to determine and compare the prognostic values of exercise-induced ST depression and of MPS in patients with 1 mm of ST depression or greater on the resting ECG. METHODS Patient Population We identified 1763 consecutive patients who underwent same-day rest thallium 201/exercise technetium 99m sestamibi MPS at Cedars-Sinai Medical Center, Los Angeles, Calif, and had 1 mm of ST depression or greater in 1 or more leads on the resting ECG (with or without concomitant T-wave abnormalities), a finding for which exercise electrocardiographic responses are considered nondiagnostic for the evaluation of exercise-induced ischemia in our laboratory. Patients with known valvular heart disease or nonischemic cardiomyopathy or with resting ST depression due to left bundle branch block, paced rhythm, or pre-excitation were excluded. Patients with early coronary revascularization (within the first 60 days after MPS) were censored as previously described (n ⫽ 166).11 Patients taking digitalis (n ⫽ 389) were also excluded from the primary analysis, because digitalis use might be related to the presence of left ventricular dysfunction, which might by itself determine a worse prognosis. However, in a secondary analysis these patients were added to the study population to evaluate the influence of digitalis on the previously determined predictors of risk. Of the initial population, 86 patients (4.9%) were lost to follow-up. The final population consisted of 1122 patients (61% with nonspecific ST depression and 39% with ST depression due to left ventricular hypertrophy).
Resting/Exercise MPS Protocol All patients underwent same-day rest Tl-201/exercise Tc-99m sestamibi dual-isotope MPS.12 For the rest study, Tl-201 (3.0-4.5 mCi) was injected intravenously and image acquisition was started 10 minutes later. A symptom-limited ETT was then performed according to a standard Bruce
Journal of Nuclear Cardiology November/December 2005
protocol. Patients were instructed to discontinue -blockers and calcium channel blockers for 48 hours and long-acting nitrates for 6 hours before exercise whenever possible. During ETT, leads V1, V5, and aVF were continuously monitored, and a 12-lead ECG was recorded at 1-minute intervals. At nearmaximal exercise, Tc-99m sestamibi (25-40 mCi) was injected intravenously. Patients continued to exercise for at least 1 minute after injection. Blood pressure was measured and recorded at rest, at the end of each stage of exercise, at peak stress, and during recovery. Exercise endpoints were exhaustion, severe angina, exertional hypotension, or sustained ventricular arrhythmia. Although in this study all patients had exercise electrocardiographic responses interpreted as nondiagnostic as a result of the baseline ST abnormality, additional, exercise-induced ST depression in any lead except aVR was measured and recorded. For the purposes of the study, significant ST depression during ETT was defined as 2 mm of additional ST depression or greater (upsloping, horizontal, or downsloping) occurring at 80 milliseconds after the J point of the ECG. This cutoff was chosen because of evidence indicating that 2 mm of additional ST depression or greater is a more specific marker of CAD than the usual criterion of 1 mm.2 We also defined severe additional ST depression if 3 mm of additional ST-segment depression or greater was present during exercise. Postexercise MPS acquisition was started 15 to 30 minutes after the isotope injection.
MPS Acquisition Protocol A large–field-of-view gamma camera with a high-resolution collimator was used to obtain 60 to 64 projections at 20 seconds per projection over a 180° semicircular arc, as previously described.12 For Tl-201, 2 energy windows were used, a 30% window centered on the 68- to 80-keV peak and a 10% window centered on the 167-keV peak. For Tc-99m sestamibi, a 15% window centered on the 140-keV peak was used. After filtered backprojection and transaxial reconstruction, short-axis and vertical and horizontal long-axis tomograms of the left ventricle were extracted. No attenuation or scatter correction was used.
Image Interpretation Semiquantitative visual interpretation was performed for resting and stress perfusion images with short-axis and vertical long-axis myocardial tomograms by use of a 20-segment model of the left ventricle, as previously described.13 Each segment was scored by expert observers with a 5-point scoring system (0, normal; 1, mild reduction of radiotracer uptake; 2, moderate reduction; 3, severe reduction; and 4, absent uptake). The summed stress score was calculated by adding the scores of the 20 segments in the stress images. This score was then converted to percentage myocardium with stress perfusion defect (% myo) by dividing the summed score by 80, the maximum possible score (4 ⫻ 20), and multiplying by 100.14 MPS was considered normal, mildly abnormal, and moderately to severely abnormal with % myo values of less than 5%, 5% to
Journal of Nuclear Cardiology Volume 12, Number 6;655-61
De Lorenzo et al Myocardial perfusion SPECT in patients with resting ST-segment depression
10%, and greater than 10%, respectively, in accordance with our previous observations.8
Table 1. Baseline characteristics
Follow-up Patients were followed up by scripted telephone interview performed by individuals blinded to MPS results. Hard events were defined as either cardiac death, as noted and confirmed by review of death certificates and medical records, or nonfatal myocardial infarction, as evidenced by the appropriate combination of symptoms, ECGs, and cardiac enzyme changes. Patients were followed up for 3.4 ⫾ 2.3 years (ⱖ2 years in all patients).
Prescan Likelihood of CAD The prescan likelihood of CAD was calculated for each patient by CADENZA computer program (Advanced Heuristics, Bainbridge Island, Wash)15 by use of a Bayesian analysis of age, sex, risk factors, symptoms, resting ECG, and ETT results.
Statistical Analysis SPSS software (version 10.0; SPSS Inc, Chicago, Ill) was used for all analyses. P ⬍ .05 was considered statistically significant. Continuous variables were described as mean ⫾ SD; those that were normally distributed were compared by use of the Student t test. The Wilcoxon rank-sum test was used for comparison of continuous variables if a normal distribution was not present. Categorical variables were compared by use of 2. A Cox proportional hazards analysis was used to measure the association between clinical, exercise, and nuclear variables and hard events. Incremental prognostic value was defined as an increase in prognostic information, reflected in the 2 value, after the stepwise addition of clinical, exercise, and nuclear variables to the Cox models. On the basis of this model, risk-adjusted cumulative curves were constructed to compare patients with and without severe additional ST depression (ⱖ3 mm).
RESULTS Baseline Characteristics During the ETT, additional ST depression developed in 313 patients (28%). Table 1 shows baseline clinical, exercise, and MPS variables for patients with and without exercise-induced ST depression. Patients in whom additional ST depression developed were more frequently men, had a greater exercise tolerance and higher rest and peak heart rate, and more often had exertional angina than those without exercise-induced ST depression (P ⬍ .05). There were no significant differences in prevalence of risk factors or history of CAD, symptoms, and overall prescan likelihood of CAD.
657
Age (y) Male gender Diabetes mellitus Hypertension Hypercholesterolemia Smoking Prior myocardial infarction Prior coronary revascularization Typical angina Shortness of breath Prescan likelihood of CAD Exercise duration (min) Resting heart rate (beats/min) Peak heart rate (beats/min) Exertional angina % myo
Additional ST depression (n ⴝ 313)
No additional ST depression (n ⴝ 809)
64 ⫾ 13 215 (69%) 42 (13%) 187 (60%) 136 (43%) 35 (11%)
66 ⫾ 12 473 (58%)* 142 (18%) 470 (58%) 378 (47%) 124 (15%)
69 (22%)
217 (27%)
82 (26%) 122 (39%) 15 (5%)
222 (27%) 333 (41%) 43 (5%)
0.39 ⫾ 0.23
0.42 ⫾ 0.23
7.1 ⫾ 2.9
6.2 ⫾ 2.5*
69 ⫾ 14
72 ⫾ 14*
147 ⫾ 18 50 (16%) 8.2 ⫾ 11.7
142 ⫾ 17* 90 (11%)* 8.2 ⫾ 12.2
*P ⬍ .05.
With respect to MPS findings, there was no significant difference in % myo between the two groups. Outcome Results During follow-up, 66 hard events (5.9%) occurred (32 nonfatal myocardial infarctions and 34 cardiac deaths). The development of exercise-induced ST depression was not associated with a significantly higher annualized hard event rate (P ⬎. 05) (Figure 1). In contrast, hard event rates increased as a function of % myo: in both patients with additional ST depression and those without additional ST depression, increasing values of % myo were associated with higher event rates (Figure 2). Table 2 shows annual event rates and hazard ratios associated with each of the clinical, exercise, and nuclear variables. Diabetes mellitus, prior myocardial infarction, and prior revascularization, shortness of breath as the presenting symptom, and an overall higher pretest likelihood of CAD determined the highest event rates and hazard ratios.
658
De Lorenzo et al Myocardial perfusion SPECT in patients with resting ST-segment depression
2.3 (1.5-3.5)
HE rate (%/year)
2.5 2
1.6 (1.2-2.2) No additional ST depression With additional ST depression
1.5 1 0.5 0
809
313
Figure 1. Annualized hard event (HE) rates as a function of the development of exercise-induced additional ST depression. P ⬎ .05. White bar, No exercise-induced additional ST depression developed; black bar, additional ST depression (ⱖ2 mm) developed during exercise. †
Hard event rate (%/year)
5
*
4
3.0 (2.0-4.4)
<5%
92
Influence of Digitalis When patients taking digitalis were added to the study population and the survival analysis was adjusted for this factor, it did not have independent prognostic value. Age, shortness of breath, and % myo remained independent predictors of hard events (P ⬍ .003), but diabetes did not. Additional exercise-induced ST depression (of any degree) was not a significant predictor.
>10%
1.4 (0.7-2.7)
DISCUSSION
0.7 (0.4-1.3)
492
increase in the global 2 (from 39 to 44, P ⫽ .03), whereas with the inclusion of % myo, the global 2 increase was substantial (from 44 to 57, P ⫽ .0002), thus indicating the presence of incremental prognostic value (Figure 3). Figure 4 demonstrates that patients with severe additional ST depression (ⱖ3 mm) had a significantly lower event-free survival rate than patients with ST depression of less than 3 mm (P ⬍ .05).
5-10%
2
0
2.8 (0.9-8.8)
2.6 (1.4-5.0)
3
1
4.1 (2.3-7.2)
Journal of Nuclear Cardiology November/December 2005
225
no additional ST depression
187
33
93
with additional ST depresion
Figure 2. Annualized hard event rates according to additional ST depression ⱖ2 mm and % myo categories. Asterisk, P ⫽ .0001 across MPS categories in group with no additional ST depression. Dagger, P ⬍ .03 across % myo categories in group with additional ST depression. Bars represent % myo categories (white, ⬍5%; gray, 5%-10%; black, ⬎10%).
This study aimed to investigate the roles of exerciseinduced ST depression and of MPS for the risk stratification of patients with ST depression on the resting ECG. Our findings demonstrated that MPS had independent and incremental prognostic value over clinical variables and exercise-induced ST depression and could further risk-stratify patients both with and without exerciseinduced ST depression. In contrast, only severe (ⱖ3 mm) exercise-induced additional ST depression was predictive of hard events.
Multivariate Survival Analysis Two models were generated from the Cox proportional hazards analysis. In model 1, with 2 mm of additional ST depression or greater used as the criterion to define significant ST-segment depression during exercise, % myo was the strongest independent predictor of hard events, followed by age, shortness of breath, and diabetes. Additional exercise-induced ST depression did not show statistically significant prognostic value (P ⫽ .07) (Table 3). Model 2 considered severe (ⱖ3 mm) additional exercise-induced ST-segment depression, instead of 2 mm or greater as in model 1. In this model % myo remained the strongest predictor of hard events. History of coronary artery bypass grafting and history of hypertension were also significant predictors, but diabetes was not. Of note, additional ST depression of 3 mm or greater was an independent predictor of hard events (P ⬍ .05) (Table 4). On the basis of model 2 (Table 4), after consideration of the most predictive clinical variables, additional ST depression of 3 mm or greater demonstrated a modest
Prognostic Implications of Resting ST Depression and Methods for Risk Stratification Resting ST depression has been identified as a marker for adverse prognosis. In a prospective study of elderly patients, those with 1 mm of ST depression or greater on the resting ECG were 3 times more likely to develop new cardiac events than those without resting ST depression.1 In a large cohort study of men without overt CAD, Sigurdsson et al3 demonstrated an independent contribution of resting ST-T changes to prognosis, with a 2-fold increase in relative risk of death from coronary heart disease even after adjustment for the presence of hypertension and other risk factors. The usefulness of the ETT for CAD assessment in patients with resting ST depression has been a matter of debate. In these patients the development of additional ST depression during exercise has reduced specificity for the diagnosis of CAD.4,5 Because these abnormalities affect the diagnostic performance of the ETT, American College of Cardiology/American Heart Association guide-
Journal of Nuclear Cardiology Volume 12, Number 6;655-61
De Lorenzo et al Myocardial perfusion SPECT in patients with resting ST-segment depression
659
Table 2. Annual hard event rates and hazard ratios associated with clinical, exercise, and nuclear variables
Event rate per year (95% CI) Present (95% CI) Absent (95% CI) Age (years) Male gender Diabetes mellitus Hypertension Hypercholesterolemia Smoking Prior myocardial infarction Prior coronary revascularization Typical angina Shortness of breath Prescan likelihood of CAD Exercise duration (min) Resting heart rate (beats/min) Peak heart rate (beats/min) Metabolic equivalents Additional ST depression (ⱖ2 mm) Exertional angina % myo
1.9 (1.4-2.5) 3.2 (2.1-5.0)* 2.1 (1.6-2.8) 1.8 (1.2-2.5) 1.7 (0.9-3.3) 2.8 (1.9-4.0)* 2.7 (1.9-3.9)* 2.0 (1.4-2.8) 5.6 (3.0-10.5)*
1.7 (1.1-2.5) 1.5 (1.1-2.0) 1.4 (0.9-2.1) 1.8 (1.3-2.5) 1.8 (1.4-2.3) 1.4 (1.0-2.0) 1.4 (1.1-1.9) 1.7 (1.2-2.3) 1.6 (1.2-2.1)
2.3 (1.5-3.5) 2.3 (1.3-4.2)
1.6 (1.2-2.2) 1.7 (1.3-2.2)
Hazard ratio (95% CI) 1.05 (1.02-1.08) 1.14 (0.69-1.90) 2.16 (1.28-3.65) 1.56 (0.93-2.61) 0.99 (0.61-1.60) 0.96 (0.47-1.93) 2.04 (1.25-3.33) 2.03 (1.25-3.30) 1.19 (0.73-1.93) 3.48 (1.77-6.85) 3.77 (1.27-11.17) 0.87 (0.78-0.96) 1.01 (0.99-1.02) 0.98 (0.96-0.99) 0.88 (0.79-0.98) 1.44 (0.87-2.38) 1.37 (0.71-2.61) 1.04 (1.03-1.06)
CI, Confidence interval. *P ⬍ .05 versus absence of events by use of log rank test.
Table 3. Multivariate predictors of hard events with model 1
% myo Age Shortness of breath Diabetes Additional ST depression (ⱖ2 mm)
2
HR
95% CI
P value
18.9 8.8 6.4 5.3
1.04 1.04 2.43 1.88
1.02-1.05 1.01-1.07 1.22-4.83 1.10-3.21
.000 .003 .011 .021
3.2
1.60
0.96-2.68
.074
HR, Hazard ratio; CI, confidence interval.
lines for exercise testing consider ETT as class III (inadequate) for the diagnosis of CAD in patients with 1 mm of resting ST depression or greater.6 For prognostic assessment of these patients, in the presence of cardiac symptoms or a history of CAD, the ETT is considered class IIb (possibly useful). To overcome the limitations of STsegment interpretation in this patient population, other exercise-based prognostic markers have been investigated. The Duke treadmill score, which incorporates exercise capacity (exercise duration) and exercise-induced ischemia (exercise-induced ST depression and
Table 4. Multivariate predictors of hard events with model 2
% myo Age Shortness of breath CABG Hypertension Additional ST depression (ⱖ3 mm) Diabetes
2
HR
95% CI
P value
15.2 7.7 7.7 4.8 4.7
1.03 1.04 2.66 1.81 1.81
1.02-1.05 1.01-1.06 1.33-5.31 1.06-3.08 1.06-3.10
.000 .005 .005 .028 .030
4.6 3.5
2.21 1.67
1.07-4.55 0.98-2.85
.032 .061
HR, Hazard ratio; CI, confidence interval; CABG, coronary artery bypass grafting.
angina), has been shown to be a useful prognostic indicator, not only for patients with normal resting ECG16,17 but also for those with nonspecific resting electrocardiographic abnormalities.18 However, only patients with mildly abnormal resting ECGs (⬍1 mm ST depression) were included in the last study. Thus, imaging modalities have been generally recommended for the subset of patients addressed by this study.
660
De Lorenzo et al Myocardial perfusion SPECT in patients with resting ST-segment depression
(p=0.0002)
70
(p=0.03)
60 50
χ2
44
39
40
57
30 20 10 0
Clinical
Clinical+Exer
Clinical+Exer+%myo
Figure 3. Models for hard events. Bars represent 2 values for prediction of hard events via Cox hazards analysis, based on clinical data alone, clinical data plus exercise (Exer) data (ST depression ⱖ3 mm), and clinical data plus exercise data plus % myo. 1.00
MI-free Survival
.98
ST ↓ <3 mm .96 .94
ST ↓ ≥3 mm
.92 .90 .88 0
ST<3mm (n) 1019 ST≥3mm (n) 103
400
800
1200
1600
999 97
981 95
974 94
969 94
Time(days) (days) Time
Figure 4. Risk-adjusted myocardial infarction (MI)–free survival curves for patients with and without severe additional ST depression (ⱖ3 mm) during exercise testing. P ⬍ .05 between groups.
Prognostic Value of ETT and MPS MPS has been shown to have incremental prognostic value over the exercise ECG in different subsets of patients, including those with electrocardiographically defined left ventricular hypertrophy.10 In this study we chose to assess patients with resting ST depression, either nonspecific or due to left ventricular hypertrophy, thus obtaining results more widely applicable and useful for a broader patient population. In our study only additional exercise-induced ST depression of 3 mm or greater was associated with the occurrence of hard events, and only in patients not taking digoxin. An additional ST depression of 2 mm or greater predicted a borderline increased risk of hard event, as the estimated hazard ratio was 1.6 with a wide confidence interval (P ⫽ .074). Therefore exercise-induced ST depression provided limited value as a prognostic indicator in patients with 1 mm of ST depression or greater at rest. In patients taking digoxin, it has been suggested
Journal of Nuclear Cardiology November/December 2005
before (by Sketch et al19) that exercise-induced ST depression is unlikely to have any prognostic value; in these patients exercise-induced ST depression may be caused by the effects of the medication itself on the ECG.20 Recently, Kwok et al,7 in a study with 939 patients with resting ST-T abnormalities who underwent exercise thallium SPECT, found that 76% of patients could be effectively risk-stratified with clinical and exercise data alone. However, their population included patients with isolated T-wave abnormalities, and even when resting ST depression was present, it was mostly 1 mm or less. In the presence of less severe baseline electrocardiographic abnormalities, the prognostic value of ETT may indeed be higher, compared with our population, composed of patients with resting ST depression of 1 mm or greater. In addition, they considered exercise data as the Duke treadmill score, including other exercise variables, which may have strengthened the prognostic value of exercise, whereas in this study we focused on exercise-induced ST depression alone. We decided to focus on this variable because it is promptly and easily assessed (and perhaps the most traditionally assessed) when a patient undergoing ETT is evaluated. Interestingly, the presence of shortness of breath as the presenting symptom also contributed significantly to prognosis. Most likely, this was related to the presence of systolic or diastolic ventricular dysfunction. In this population, in which almost 50% of patients had left ventricular hypertrophy, underlying diastolic dysfunction, which has been shown to be related to cardiac events,21,22 may be an important factor in this relationship. Nonetheless, after stratification by clinical and exercise variables, MPS still provided the greatest amount of prognostic information and, even in a population whose characteristics point to a high risk of cardiac events, was able to identify a subgroup with a low incidence of hard events (⬍1%/y). In conclusion, our study demonstrated that in patients with resting ST depression of 1 mm or greater and nondiagnostic exercise ECG, MPS provided significant incremental prognostic information over clinical and exercise variables. Exercise-induced additional ST depression was an independent predictor of hard events only if it was 3 mm or greater. Considering the gain in risk stratification provided by MPS in this population, testing with MPS in patients with resting ST depression of 1 mm or greater appears to be appropriate when CAD is suspected. These results may impact current recommendations for the prognostic use of exercise testing. Subsequent studies with larger populations may be useful to fully define the prognostic value of exerciseinduced ST-segment depression in patients with these characteristics.
Journal of Nuclear Cardiology Volume 12, Number 6;655-61
De Lorenzo et al Myocardial perfusion SPECT in patients with resting ST-segment depression
Acknowledgment The authors have indicated they have no financial conflicts of interest.
References 1. Aronow WS. Correlation of ischemic ST-segment depression on the resting electrocardiogram with new cardiac events in 1,106 patients over 62 years of age. Am J Cardiol 1989;64:232-3. 2. Miranda CP, Lehmann KG, Froelicher VF. Correlation between resting ST segment depression, exercise testing, coronary angiography, and long-term prognosis. Am Heart J 1991;122:1617-28. 3. Sigurdsson E, Sigfusson N, Sigvaldason H, Thorgeirsson G. Silent ST-T changes in an epidemiologic cohort study—a marker of hypertension or coronary heart disease, or both: the Reykjavik Study. J Am Coll Cardiol 1996;27:1140-7. 4. Botvinick EH, Taradash MR, Shames DM, Parmley WW. Thallium201 myocardial perfusion scintigraphy for the clinical clarification of normal, abnormal and equivocal electrocardiographic stress tests. Am J Cardiol 1978;41:43-51. 5. Meyers DG, Bendon KA, Hankins JH, Stratbucker RA. The effect of baseline electrocardiographic abnormalities on the diagnostic accuracy of exercise-induced ST segment changes. Am Heart J 1990;119:272-6. 6. Gibbons RJ, Balady GJ, Beasley JW, Bricker JT, Duvernoy WF, Froelicher VF, et al. ACC/AHA guidelines for exercise testing: executive summary: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee on Exercise Testing). Circulation 1997;96:345-54. 7. Kwok JMF, Christian TF, Miller TD, Hodge DO, Gibbons RJ. Incremental prognostic value of exercise single-photon emission computed tomography (SPECT) thallium 201 imaging in patients with ST-T abnormalities on their resting electrocardiograms. Am Heart J 2005;149:145-51. 8. Hachamovitch R, Berman DS, Kiat H, Cohen I, Cabico A, Friedman JD, et al. Exercise myocardial perfusion SPECT in patients with known or suspected coronary artery disease. Incremental prognostic value and use in risk stratification. Circulation 1996;93:905-14. 9. Hachamovitch R, Berman DS, Shaw LJ, Kiat H, Cohen I, Cabico A, et al. Incremental prognostic value of myocardial perfusion single photon emission computed tomography for the prediction of cardiac death. Differential stratification for risk of cardiac death and myocardial infarction. Circulation 1998;97:535-43. 10. Amanullah AM, Berman DS, Kang X, Cohen I, Germano G, Friedman JD. Enhanced prognostic stratification of patients with left ventricular hypertrophy with the use of single-photon emission computed tomography. Am Heart J 2000;140:456-62.
661
11. Staniloff HM, Forrestinger JS, Berman DS, Swan HJC. Prediction of death, myocardial infarction, and worsening chest pain using thallium scintigraphy and exercise electrocardiography. J Nucl Med 1986;27:1842-8. 12. Berman DS, Kiat H, Friedman JD, Wang FR, Van Train K, Matzer L, et al. Separate acquisition resting thallium-201/stress technetium-99m sestamibi myocardial perfusion single photon emission computed tomography: a clinical validation study. J Am Coll Cardiol 1993;22:1455-64. 13. Berman DS, Hachamovitch R, Kiat H, Cohen I, Cabico A, Wang FP, et al. Incremental value of prognostic testing in patients with known or suspected ischemic heart disease: a basis for optimal utilization of exercise technetium-99m sestamibi myocardial perfusion single photon emission computed tomography. J Am Coll Cardiol 1995;26:639-47. 14. Hachamovitch R, Hayes SW, Friedman JD, Cohen I, Berman DS. Comparison of the short-term survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation 2003;107:2900-7. 15. Diamond GA, Staniloff HM, Forrester JS, Pollock BH, Swan HJC. Computer assisted diagnosis in the noninvasive evaluation of patients with suspected coronary artery disease. J Am Coll Cardiol 1983;1:444-55. 16. Mark DB, Shaw L, Harrell FE, Hlatky MA, Lee KL, Bengtson JR, et al. Prognostic value of a treadmill exercise score in outpatients with suspected coronary artery disease. N Engl J Med 1991;325:849-53. 17. Shaw LJ, Peterson ED, Shaw LK, Kesler KL, DeLong ER, Harrell FE, et al. Use of a prognostic treadmill score in identifying diagnostic coronary disease subgroups. Circulation 1998;98:1622-30. 18. Kwok JMF, Miller TD, Christian TF, Hodge DO, Gibbons RJ. Prognostic value of a treadmill exercise score in symptomatic patients with nonspecific ST-T abnormalities on resting ECG. JAMA 1999;282:1047-53. 19. Sketch MH, Mooss AN, Butler ML, Nair CK, Mohiuddin SM. Digoxin-induced positive exercise tests: their clinical and prognostic significance. Am J Cardiol 1981;48:655-9. 20. Le Winter MM, Crawford MH, O’Rourke RA, Karliner JS. The effects of oral propranolol, digoxin and combination therapy on the resting and exercise electrocardiogram. Am Heart J 1977;93:202-9. 21. O’Connor CM, Gattis WA, Shaw L, Cuffe MS, Califf RM. Clinical characteristics and long-term outcomes of patients with heart failure and preserved systolic function. Am J Cardiol 2000;86: 863-7. 22. Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure: part I: diagnosis, prognosis, and measurements of diastolic function. Circulation 2002;105:1387-93.
the specificity of exercise-induced ST depression for the diagnosis of coronary artery disease (CAD) is reduced4,5 and its usefulness as a prognostic indicator may be also limited.6 A recent study found that the exercise treadmill test (ETT), in conjunction with the clinical evaluation, was able to risk-stratify most patients with nonspecific ST-T abnormalities on the resting ECG and that myocardial Received for publication Jan 12, 2005; final revision accepted Aug 8, 2005. Reprint requests: Daniel S. Berman, MD, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Room 1258, Los Angeles, CA 90048; bermand@ cshs.org. 1071-3581/$30.00 Copyright © 2005 by the American Society of Nuclear Cardiology. doi:10.1016/j.nuclcard.2005.08.005 655
656
De Lorenzo et al Myocardial perfusion SPECT in patients with resting ST-segment depression
perfusion single photon emission computed tomography (SPECT) (MPS) should be reserved for patients at intermediate risk determined by clinical and exercise data.7 However, in that study resting ST depression was in general 1 mm. Current guidelines still recommend ETT for the prognostic evaluation of patients with a normal resting ECG or mild (⬍1 mm) ST depression, whereas stress imaging is suggested as the initial test for the diagnosis or risk stratification of patients with suspected or known CAD and resting ST depression of 1 mm or greater.6 Whereas stress MPS has been shown to effectively risk-stratify a wide variety of patient subsets,8-10 the prognostic value of MPS in those with 1 mm of resting ST depression or greater remains to be fully defined. In addition, whether exercise-induced ST depression adds to the prognostic evaluation in these patients is unknown. Therefore the objective of this study was to determine and compare the prognostic values of exercise-induced ST depression and of MPS in patients with 1 mm of ST depression or greater on the resting ECG. METHODS Patient Population We identified 1763 consecutive patients who underwent same-day rest thallium 201/exercise technetium 99m sestamibi MPS at Cedars-Sinai Medical Center, Los Angeles, Calif, and had 1 mm of ST depression or greater in 1 or more leads on the resting ECG (with or without concomitant T-wave abnormalities), a finding for which exercise electrocardiographic responses are considered nondiagnostic for the evaluation of exercise-induced ischemia in our laboratory. Patients with known valvular heart disease or nonischemic cardiomyopathy or with resting ST depression due to left bundle branch block, paced rhythm, or pre-excitation were excluded. Patients with early coronary revascularization (within the first 60 days after MPS) were censored as previously described (n ⫽ 166).11 Patients taking digitalis (n ⫽ 389) were also excluded from the primary analysis, because digitalis use might be related to the presence of left ventricular dysfunction, which might by itself determine a worse prognosis. However, in a secondary analysis these patients were added to the study population to evaluate the influence of digitalis on the previously determined predictors of risk. Of the initial population, 86 patients (4.9%) were lost to follow-up. The final population consisted of 1122 patients (61% with nonspecific ST depression and 39% with ST depression due to left ventricular hypertrophy).
Resting/Exercise MPS Protocol All patients underwent same-day rest Tl-201/exercise Tc-99m sestamibi dual-isotope MPS.12 For the rest study, Tl-201 (3.0-4.5 mCi) was injected intravenously and image acquisition was started 10 minutes later. A symptom-limited ETT was then performed according to a standard Bruce
Journal of Nuclear Cardiology November/December 2005
protocol. Patients were instructed to discontinue -blockers and calcium channel blockers for 48 hours and long-acting nitrates for 6 hours before exercise whenever possible. During ETT, leads V1, V5, and aVF were continuously monitored, and a 12-lead ECG was recorded at 1-minute intervals. At nearmaximal exercise, Tc-99m sestamibi (25-40 mCi) was injected intravenously. Patients continued to exercise for at least 1 minute after injection. Blood pressure was measured and recorded at rest, at the end of each stage of exercise, at peak stress, and during recovery. Exercise endpoints were exhaustion, severe angina, exertional hypotension, or sustained ventricular arrhythmia. Although in this study all patients had exercise electrocardiographic responses interpreted as nondiagnostic as a result of the baseline ST abnormality, additional, exercise-induced ST depression in any lead except aVR was measured and recorded. For the purposes of the study, significant ST depression during ETT was defined as 2 mm of additional ST depression or greater (upsloping, horizontal, or downsloping) occurring at 80 milliseconds after the J point of the ECG. This cutoff was chosen because of evidence indicating that 2 mm of additional ST depression or greater is a more specific marker of CAD than the usual criterion of 1 mm.2 We also defined severe additional ST depression if 3 mm of additional ST-segment depression or greater was present during exercise. Postexercise MPS acquisition was started 15 to 30 minutes after the isotope injection.
MPS Acquisition Protocol A large–field-of-view gamma camera with a high-resolution collimator was used to obtain 60 to 64 projections at 20 seconds per projection over a 180° semicircular arc, as previously described.12 For Tl-201, 2 energy windows were used, a 30% window centered on the 68- to 80-keV peak and a 10% window centered on the 167-keV peak. For Tc-99m sestamibi, a 15% window centered on the 140-keV peak was used. After filtered backprojection and transaxial reconstruction, short-axis and vertical and horizontal long-axis tomograms of the left ventricle were extracted. No attenuation or scatter correction was used.
Image Interpretation Semiquantitative visual interpretation was performed for resting and stress perfusion images with short-axis and vertical long-axis myocardial tomograms by use of a 20-segment model of the left ventricle, as previously described.13 Each segment was scored by expert observers with a 5-point scoring system (0, normal; 1, mild reduction of radiotracer uptake; 2, moderate reduction; 3, severe reduction; and 4, absent uptake). The summed stress score was calculated by adding the scores of the 20 segments in the stress images. This score was then converted to percentage myocardium with stress perfusion defect (% myo) by dividing the summed score by 80, the maximum possible score (4 ⫻ 20), and multiplying by 100.14 MPS was considered normal, mildly abnormal, and moderately to severely abnormal with % myo values of less than 5%, 5% to
Journal of Nuclear Cardiology Volume 12, Number 6;655-61
De Lorenzo et al Myocardial perfusion SPECT in patients with resting ST-segment depression
10%, and greater than 10%, respectively, in accordance with our previous observations.8
Table 1. Baseline characteristics
Follow-up Patients were followed up by scripted telephone interview performed by individuals blinded to MPS results. Hard events were defined as either cardiac death, as noted and confirmed by review of death certificates and medical records, or nonfatal myocardial infarction, as evidenced by the appropriate combination of symptoms, ECGs, and cardiac enzyme changes. Patients were followed up for 3.4 ⫾ 2.3 years (ⱖ2 years in all patients).
Prescan Likelihood of CAD The prescan likelihood of CAD was calculated for each patient by CADENZA computer program (Advanced Heuristics, Bainbridge Island, Wash)15 by use of a Bayesian analysis of age, sex, risk factors, symptoms, resting ECG, and ETT results.
Statistical Analysis SPSS software (version 10.0; SPSS Inc, Chicago, Ill) was used for all analyses. P ⬍ .05 was considered statistically significant. Continuous variables were described as mean ⫾ SD; those that were normally distributed were compared by use of the Student t test. The Wilcoxon rank-sum test was used for comparison of continuous variables if a normal distribution was not present. Categorical variables were compared by use of 2. A Cox proportional hazards analysis was used to measure the association between clinical, exercise, and nuclear variables and hard events. Incremental prognostic value was defined as an increase in prognostic information, reflected in the 2 value, after the stepwise addition of clinical, exercise, and nuclear variables to the Cox models. On the basis of this model, risk-adjusted cumulative curves were constructed to compare patients with and without severe additional ST depression (ⱖ3 mm).
RESULTS Baseline Characteristics During the ETT, additional ST depression developed in 313 patients (28%). Table 1 shows baseline clinical, exercise, and MPS variables for patients with and without exercise-induced ST depression. Patients in whom additional ST depression developed were more frequently men, had a greater exercise tolerance and higher rest and peak heart rate, and more often had exertional angina than those without exercise-induced ST depression (P ⬍ .05). There were no significant differences in prevalence of risk factors or history of CAD, symptoms, and overall prescan likelihood of CAD.
657
Age (y) Male gender Diabetes mellitus Hypertension Hypercholesterolemia Smoking Prior myocardial infarction Prior coronary revascularization Typical angina Shortness of breath Prescan likelihood of CAD Exercise duration (min) Resting heart rate (beats/min) Peak heart rate (beats/min) Exertional angina % myo
Additional ST depression (n ⴝ 313)
No additional ST depression (n ⴝ 809)
64 ⫾ 13 215 (69%) 42 (13%) 187 (60%) 136 (43%) 35 (11%)
66 ⫾ 12 473 (58%)* 142 (18%) 470 (58%) 378 (47%) 124 (15%)
69 (22%)
217 (27%)
82 (26%) 122 (39%) 15 (5%)
222 (27%) 333 (41%) 43 (5%)
0.39 ⫾ 0.23
0.42 ⫾ 0.23
7.1 ⫾ 2.9
6.2 ⫾ 2.5*
69 ⫾ 14
72 ⫾ 14*
147 ⫾ 18 50 (16%) 8.2 ⫾ 11.7
142 ⫾ 17* 90 (11%)* 8.2 ⫾ 12.2
*P ⬍ .05.
With respect to MPS findings, there was no significant difference in % myo between the two groups. Outcome Results During follow-up, 66 hard events (5.9%) occurred (32 nonfatal myocardial infarctions and 34 cardiac deaths). The development of exercise-induced ST depression was not associated with a significantly higher annualized hard event rate (P ⬎. 05) (Figure 1). In contrast, hard event rates increased as a function of % myo: in both patients with additional ST depression and those without additional ST depression, increasing values of % myo were associated with higher event rates (Figure 2). Table 2 shows annual event rates and hazard ratios associated with each of the clinical, exercise, and nuclear variables. Diabetes mellitus, prior myocardial infarction, and prior revascularization, shortness of breath as the presenting symptom, and an overall higher pretest likelihood of CAD determined the highest event rates and hazard ratios.
658
De Lorenzo et al Myocardial perfusion SPECT in patients with resting ST-segment depression
2.3 (1.5-3.5)
HE rate (%/year)
2.5 2
1.6 (1.2-2.2) No additional ST depression With additional ST depression
1.5 1 0.5 0
809
313
Figure 1. Annualized hard event (HE) rates as a function of the development of exercise-induced additional ST depression. P ⬎ .05. White bar, No exercise-induced additional ST depression developed; black bar, additional ST depression (ⱖ2 mm) developed during exercise. †
Hard event rate (%/year)
5
*
4
3.0 (2.0-4.4)
<5%
92
Influence of Digitalis When patients taking digitalis were added to the study population and the survival analysis was adjusted for this factor, it did not have independent prognostic value. Age, shortness of breath, and % myo remained independent predictors of hard events (P ⬍ .003), but diabetes did not. Additional exercise-induced ST depression (of any degree) was not a significant predictor.
>10%
1.4 (0.7-2.7)
DISCUSSION
0.7 (0.4-1.3)
492
increase in the global 2 (from 39 to 44, P ⫽ .03), whereas with the inclusion of % myo, the global 2 increase was substantial (from 44 to 57, P ⫽ .0002), thus indicating the presence of incremental prognostic value (Figure 3). Figure 4 demonstrates that patients with severe additional ST depression (ⱖ3 mm) had a significantly lower event-free survival rate than patients with ST depression of less than 3 mm (P ⬍ .05).
5-10%
2
0
2.8 (0.9-8.8)
2.6 (1.4-5.0)
3
1
4.1 (2.3-7.2)
Journal of Nuclear Cardiology November/December 2005
225
no additional ST depression
187
33
93
with additional ST depresion
Figure 2. Annualized hard event rates according to additional ST depression ⱖ2 mm and % myo categories. Asterisk, P ⫽ .0001 across MPS categories in group with no additional ST depression. Dagger, P ⬍ .03 across % myo categories in group with additional ST depression. Bars represent % myo categories (white, ⬍5%; gray, 5%-10%; black, ⬎10%).
This study aimed to investigate the roles of exerciseinduced ST depression and of MPS for the risk stratification of patients with ST depression on the resting ECG. Our findings demonstrated that MPS had independent and incremental prognostic value over clinical variables and exercise-induced ST depression and could further risk-stratify patients both with and without exerciseinduced ST depression. In contrast, only severe (ⱖ3 mm) exercise-induced additional ST depression was predictive of hard events.
Multivariate Survival Analysis Two models were generated from the Cox proportional hazards analysis. In model 1, with 2 mm of additional ST depression or greater used as the criterion to define significant ST-segment depression during exercise, % myo was the strongest independent predictor of hard events, followed by age, shortness of breath, and diabetes. Additional exercise-induced ST depression did not show statistically significant prognostic value (P ⫽ .07) (Table 3). Model 2 considered severe (ⱖ3 mm) additional exercise-induced ST-segment depression, instead of 2 mm or greater as in model 1. In this model % myo remained the strongest predictor of hard events. History of coronary artery bypass grafting and history of hypertension were also significant predictors, but diabetes was not. Of note, additional ST depression of 3 mm or greater was an independent predictor of hard events (P ⬍ .05) (Table 4). On the basis of model 2 (Table 4), after consideration of the most predictive clinical variables, additional ST depression of 3 mm or greater demonstrated a modest
Prognostic Implications of Resting ST Depression and Methods for Risk Stratification Resting ST depression has been identified as a marker for adverse prognosis. In a prospective study of elderly patients, those with 1 mm of ST depression or greater on the resting ECG were 3 times more likely to develop new cardiac events than those without resting ST depression.1 In a large cohort study of men without overt CAD, Sigurdsson et al3 demonstrated an independent contribution of resting ST-T changes to prognosis, with a 2-fold increase in relative risk of death from coronary heart disease even after adjustment for the presence of hypertension and other risk factors. The usefulness of the ETT for CAD assessment in patients with resting ST depression has been a matter of debate. In these patients the development of additional ST depression during exercise has reduced specificity for the diagnosis of CAD.4,5 Because these abnormalities affect the diagnostic performance of the ETT, American College of Cardiology/American Heart Association guide-
Journal of Nuclear Cardiology Volume 12, Number 6;655-61
De Lorenzo et al Myocardial perfusion SPECT in patients with resting ST-segment depression
659
Table 2. Annual hard event rates and hazard ratios associated with clinical, exercise, and nuclear variables
Event rate per year (95% CI) Present (95% CI) Absent (95% CI) Age (years) Male gender Diabetes mellitus Hypertension Hypercholesterolemia Smoking Prior myocardial infarction Prior coronary revascularization Typical angina Shortness of breath Prescan likelihood of CAD Exercise duration (min) Resting heart rate (beats/min) Peak heart rate (beats/min) Metabolic equivalents Additional ST depression (ⱖ2 mm) Exertional angina % myo
1.9 (1.4-2.5) 3.2 (2.1-5.0)* 2.1 (1.6-2.8) 1.8 (1.2-2.5) 1.7 (0.9-3.3) 2.8 (1.9-4.0)* 2.7 (1.9-3.9)* 2.0 (1.4-2.8) 5.6 (3.0-10.5)*
1.7 (1.1-2.5) 1.5 (1.1-2.0) 1.4 (0.9-2.1) 1.8 (1.3-2.5) 1.8 (1.4-2.3) 1.4 (1.0-2.0) 1.4 (1.1-1.9) 1.7 (1.2-2.3) 1.6 (1.2-2.1)
2.3 (1.5-3.5) 2.3 (1.3-4.2)
1.6 (1.2-2.2) 1.7 (1.3-2.2)
Hazard ratio (95% CI) 1.05 (1.02-1.08) 1.14 (0.69-1.90) 2.16 (1.28-3.65) 1.56 (0.93-2.61) 0.99 (0.61-1.60) 0.96 (0.47-1.93) 2.04 (1.25-3.33) 2.03 (1.25-3.30) 1.19 (0.73-1.93) 3.48 (1.77-6.85) 3.77 (1.27-11.17) 0.87 (0.78-0.96) 1.01 (0.99-1.02) 0.98 (0.96-0.99) 0.88 (0.79-0.98) 1.44 (0.87-2.38) 1.37 (0.71-2.61) 1.04 (1.03-1.06)
CI, Confidence interval. *P ⬍ .05 versus absence of events by use of log rank test.
Table 3. Multivariate predictors of hard events with model 1
% myo Age Shortness of breath Diabetes Additional ST depression (ⱖ2 mm)
2
HR
95% CI
P value
18.9 8.8 6.4 5.3
1.04 1.04 2.43 1.88
1.02-1.05 1.01-1.07 1.22-4.83 1.10-3.21
.000 .003 .011 .021
3.2
1.60
0.96-2.68
.074
HR, Hazard ratio; CI, confidence interval.
lines for exercise testing consider ETT as class III (inadequate) for the diagnosis of CAD in patients with 1 mm of resting ST depression or greater.6 For prognostic assessment of these patients, in the presence of cardiac symptoms or a history of CAD, the ETT is considered class IIb (possibly useful). To overcome the limitations of STsegment interpretation in this patient population, other exercise-based prognostic markers have been investigated. The Duke treadmill score, which incorporates exercise capacity (exercise duration) and exercise-induced ischemia (exercise-induced ST depression and
Table 4. Multivariate predictors of hard events with model 2
% myo Age Shortness of breath CABG Hypertension Additional ST depression (ⱖ3 mm) Diabetes
2
HR
95% CI
P value
15.2 7.7 7.7 4.8 4.7
1.03 1.04 2.66 1.81 1.81
1.02-1.05 1.01-1.06 1.33-5.31 1.06-3.08 1.06-3.10
.000 .005 .005 .028 .030
4.6 3.5
2.21 1.67
1.07-4.55 0.98-2.85
.032 .061
HR, Hazard ratio; CI, confidence interval; CABG, coronary artery bypass grafting.
angina), has been shown to be a useful prognostic indicator, not only for patients with normal resting ECG16,17 but also for those with nonspecific resting electrocardiographic abnormalities.18 However, only patients with mildly abnormal resting ECGs (⬍1 mm ST depression) were included in the last study. Thus, imaging modalities have been generally recommended for the subset of patients addressed by this study.
660
De Lorenzo et al Myocardial perfusion SPECT in patients with resting ST-segment depression
(p=0.0002)
70
(p=0.03)
60 50
χ2
44
39
40
57
30 20 10 0
Clinical
Clinical+Exer
Clinical+Exer+%myo
Figure 3. Models for hard events. Bars represent 2 values for prediction of hard events via Cox hazards analysis, based on clinical data alone, clinical data plus exercise (Exer) data (ST depression ⱖ3 mm), and clinical data plus exercise data plus % myo. 1.00
MI-free Survival
.98
ST ↓ <3 mm .96 .94
ST ↓ ≥3 mm
.92 .90 .88 0
ST<3mm (n) 1019 ST≥3mm (n) 103
400
800
1200
1600
999 97
981 95
974 94
969 94
Time(days) (days) Time
Figure 4. Risk-adjusted myocardial infarction (MI)–free survival curves for patients with and without severe additional ST depression (ⱖ3 mm) during exercise testing. P ⬍ .05 between groups.
Prognostic Value of ETT and MPS MPS has been shown to have incremental prognostic value over the exercise ECG in different subsets of patients, including those with electrocardiographically defined left ventricular hypertrophy.10 In this study we chose to assess patients with resting ST depression, either nonspecific or due to left ventricular hypertrophy, thus obtaining results more widely applicable and useful for a broader patient population. In our study only additional exercise-induced ST depression of 3 mm or greater was associated with the occurrence of hard events, and only in patients not taking digoxin. An additional ST depression of 2 mm or greater predicted a borderline increased risk of hard event, as the estimated hazard ratio was 1.6 with a wide confidence interval (P ⫽ .074). Therefore exercise-induced ST depression provided limited value as a prognostic indicator in patients with 1 mm of ST depression or greater at rest. In patients taking digoxin, it has been suggested
Journal of Nuclear Cardiology November/December 2005
before (by Sketch et al19) that exercise-induced ST depression is unlikely to have any prognostic value; in these patients exercise-induced ST depression may be caused by the effects of the medication itself on the ECG.20 Recently, Kwok et al,7 in a study with 939 patients with resting ST-T abnormalities who underwent exercise thallium SPECT, found that 76% of patients could be effectively risk-stratified with clinical and exercise data alone. However, their population included patients with isolated T-wave abnormalities, and even when resting ST depression was present, it was mostly 1 mm or less. In the presence of less severe baseline electrocardiographic abnormalities, the prognostic value of ETT may indeed be higher, compared with our population, composed of patients with resting ST depression of 1 mm or greater. In addition, they considered exercise data as the Duke treadmill score, including other exercise variables, which may have strengthened the prognostic value of exercise, whereas in this study we focused on exercise-induced ST depression alone. We decided to focus on this variable because it is promptly and easily assessed (and perhaps the most traditionally assessed) when a patient undergoing ETT is evaluated. Interestingly, the presence of shortness of breath as the presenting symptom also contributed significantly to prognosis. Most likely, this was related to the presence of systolic or diastolic ventricular dysfunction. In this population, in which almost 50% of patients had left ventricular hypertrophy, underlying diastolic dysfunction, which has been shown to be related to cardiac events,21,22 may be an important factor in this relationship. Nonetheless, after stratification by clinical and exercise variables, MPS still provided the greatest amount of prognostic information and, even in a population whose characteristics point to a high risk of cardiac events, was able to identify a subgroup with a low incidence of hard events (⬍1%/y). In conclusion, our study demonstrated that in patients with resting ST depression of 1 mm or greater and nondiagnostic exercise ECG, MPS provided significant incremental prognostic information over clinical and exercise variables. Exercise-induced additional ST depression was an independent predictor of hard events only if it was 3 mm or greater. Considering the gain in risk stratification provided by MPS in this population, testing with MPS in patients with resting ST depression of 1 mm or greater appears to be appropriate when CAD is suspected. These results may impact current recommendations for the prognostic use of exercise testing. Subsequent studies with larger populations may be useful to fully define the prognostic value of exerciseinduced ST-segment depression in patients with these characteristics.
Journal of Nuclear Cardiology Volume 12, Number 6;655-61
De Lorenzo et al Myocardial perfusion SPECT in patients with resting ST-segment depression
Acknowledgment The authors have indicated they have no financial conflicts of interest.
References 1. Aronow WS. Correlation of ischemic ST-segment depression on the resting electrocardiogram with new cardiac events in 1,106 patients over 62 years of age. Am J Cardiol 1989;64:232-3. 2. Miranda CP, Lehmann KG, Froelicher VF. Correlation between resting ST segment depression, exercise testing, coronary angiography, and long-term prognosis. Am Heart J 1991;122:1617-28. 3. Sigurdsson E, Sigfusson N, Sigvaldason H, Thorgeirsson G. Silent ST-T changes in an epidemiologic cohort study—a marker of hypertension or coronary heart disease, or both: the Reykjavik Study. J Am Coll Cardiol 1996;27:1140-7. 4. Botvinick EH, Taradash MR, Shames DM, Parmley WW. Thallium201 myocardial perfusion scintigraphy for the clinical clarification of normal, abnormal and equivocal electrocardiographic stress tests. Am J Cardiol 1978;41:43-51. 5. Meyers DG, Bendon KA, Hankins JH, Stratbucker RA. The effect of baseline electrocardiographic abnormalities on the diagnostic accuracy of exercise-induced ST segment changes. Am Heart J 1990;119:272-6. 6. Gibbons RJ, Balady GJ, Beasley JW, Bricker JT, Duvernoy WF, Froelicher VF, et al. ACC/AHA guidelines for exercise testing: executive summary: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee on Exercise Testing). Circulation 1997;96:345-54. 7. Kwok JMF, Christian TF, Miller TD, Hodge DO, Gibbons RJ. Incremental prognostic value of exercise single-photon emission computed tomography (SPECT) thallium 201 imaging in patients with ST-T abnormalities on their resting electrocardiograms. Am Heart J 2005;149:145-51. 8. Hachamovitch R, Berman DS, Kiat H, Cohen I, Cabico A, Friedman JD, et al. Exercise myocardial perfusion SPECT in patients with known or suspected coronary artery disease. Incremental prognostic value and use in risk stratification. Circulation 1996;93:905-14. 9. Hachamovitch R, Berman DS, Shaw LJ, Kiat H, Cohen I, Cabico A, et al. Incremental prognostic value of myocardial perfusion single photon emission computed tomography for the prediction of cardiac death. Differential stratification for risk of cardiac death and myocardial infarction. Circulation 1998;97:535-43. 10. Amanullah AM, Berman DS, Kang X, Cohen I, Germano G, Friedman JD. Enhanced prognostic stratification of patients with left ventricular hypertrophy with the use of single-photon emission computed tomography. Am Heart J 2000;140:456-62.
661
11. Staniloff HM, Forrestinger JS, Berman DS, Swan HJC. Prediction of death, myocardial infarction, and worsening chest pain using thallium scintigraphy and exercise electrocardiography. J Nucl Med 1986;27:1842-8. 12. Berman DS, Kiat H, Friedman JD, Wang FR, Van Train K, Matzer L, et al. Separate acquisition resting thallium-201/stress technetium-99m sestamibi myocardial perfusion single photon emission computed tomography: a clinical validation study. J Am Coll Cardiol 1993;22:1455-64. 13. Berman DS, Hachamovitch R, Kiat H, Cohen I, Cabico A, Wang FP, et al. Incremental value of prognostic testing in patients with known or suspected ischemic heart disease: a basis for optimal utilization of exercise technetium-99m sestamibi myocardial perfusion single photon emission computed tomography. J Am Coll Cardiol 1995;26:639-47. 14. Hachamovitch R, Hayes SW, Friedman JD, Cohen I, Berman DS. Comparison of the short-term survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation 2003;107:2900-7. 15. Diamond GA, Staniloff HM, Forrester JS, Pollock BH, Swan HJC. Computer assisted diagnosis in the noninvasive evaluation of patients with suspected coronary artery disease. J Am Coll Cardiol 1983;1:444-55. 16. Mark DB, Shaw L, Harrell FE, Hlatky MA, Lee KL, Bengtson JR, et al. Prognostic value of a treadmill exercise score in outpatients with suspected coronary artery disease. N Engl J Med 1991;325:849-53. 17. Shaw LJ, Peterson ED, Shaw LK, Kesler KL, DeLong ER, Harrell FE, et al. Use of a prognostic treadmill score in identifying diagnostic coronary disease subgroups. Circulation 1998;98:1622-30. 18. Kwok JMF, Miller TD, Christian TF, Hodge DO, Gibbons RJ. Prognostic value of a treadmill exercise score in symptomatic patients with nonspecific ST-T abnormalities on resting ECG. JAMA 1999;282:1047-53. 19. Sketch MH, Mooss AN, Butler ML, Nair CK, Mohiuddin SM. Digoxin-induced positive exercise tests: their clinical and prognostic significance. Am J Cardiol 1981;48:655-9. 20. Le Winter MM, Crawford MH, O’Rourke RA, Karliner JS. The effects of oral propranolol, digoxin and combination therapy on the resting and exercise electrocardiogram. Am Heart J 1977;93:202-9. 21. O’Connor CM, Gattis WA, Shaw L, Cuffe MS, Califf RM. Clinical characteristics and long-term outcomes of patients with heart failure and preserved systolic function. Am J Cardiol 2000;86: 863-7. 22. Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure: part I: diagnosis, prognosis, and measurements of diastolic function. Circulation 2002;105:1387-93.