Clinical Cardiology
Exercise Echocardiography
or Exercise SPECT Imaging?
A Meta-analysis of Diagnostic Test Performance
Kirsten E. Fleischmann, MD, MPH; Maria G. M. Hunink, MD, PhD;
Karen M. Kuntz, ScD; Pamela S. Douglas, MD
Context.—Cardiac imaging has advanced rapidly, providing clinicians with several choices for evaluating patients with suspected coronary artery disease, but few
studies compare modalities directly.
Objectives.—To review the contemporary literature and to compare the diagnostic performance of exercise echocardiography (ECHO) and exercise singlephoton emission computed tomography (SPECT) imaging in the diagnosis of
coronary artery disease.
Data Sources.—Studies published between January 1990 and October 1997
identified from MEDLINE search; bibliographies of reviews and original articles; and
suggestions from experts in each area.
Study Selection.—Articles were included if they discussed exercise ECHO
and/or exercise SPECT imaging with thallous chloride TI 201 (thallium) or technetium Tc 99m sestamibi for detection and/or evaluation of coronary artery disease,
if data on coronary angiography were presented as the reference test, and if the
absolute numbers of true-positive, false-negative, true-negative, and false-positive
observations were available or derivable from the data presented. Studies
performed exclusively in patients after myocardial infarction, after percutaneous
transluminal coronary angioplasty, after coronary artery bypass grafting, or with recent unstable coronary syndromes were excluded.
Data Extraction.—Clinical variables, technical factors, and test performance
were independently extracted by 2 reviewers on a standardized spreadsheet. Discrepancies were resolved by consensus.
Results.—Forty-four articles met inclusion criteria. In pooled data weighted by
the sample size of each study, exercise ECHO had a sensitivity of 85% (95% confidence interval [CI], 83%-87%) with a specificity of 77% (95% CI, 74%-80%). Exercise SPECT yielded a similar sensitivity of 87% (95% CI, 86%-88%) but a lower
specificity of 64% (95% CI, 60%-68%). In a summary receiver operating characteristic model comparing exercise ECHO performance to exercise SPECT, exercise ECHO was associated with significantly better discriminatory power (parameter estimate, 1.18; 95% CI, 0.71-1.65), when adjusted for age, publication year,
and a setting including known coronary artery disease for SPECT studies. In models
comparing the discriminatory abilities of exercise ECHO and exercise SPECT vs
exercise testing without imaging, both ECHO and SPECT performed significantly
better than exercise testing. The incremental improvement in performance
was greater for ECHO (3.43; 95% CI, 2.74-4.11) than for SPECT (1.49; 95% CI,
0.91-2.08).
Conclusions.—Exercise ECHO and exercise SPECT have similar sensitivities
for the detection of coronary artery disease, but exercise ECHO has better specificity and, therefore, higher overall discriminatory capabilities as used in contemporary practice.
JAMA. 1998;280:913-920
JAMA, September 9, 1998—Vol 280, No. 10
CORONARY ARTERY disease is the
leading cause of death in men and women in the United States.1 Methods of detecting and assessing the presence and
extent of disease have become increasingly important in applying therapies to
decrease morbidity and mortality.2 Exercise electrocardiography (ECG) is
widely used for noninvasive detection of
coronary artery disease due to its ready
availability and relatively low cost, but
imaging techniques such as myocardial
perfusion scintigraphy or echocardiography (ECHO) are often added to improve detection and/or localization of exercise-induced ischemia or in patients in
whom the ECG is uninterpretable.
The choice between these 2 imaging
modalities should rest in large part with a
comparison of their diagnostic accuracy
based on an aggregate of the available
experience. Limited data are available
comparing the performance of exercise
single-photon emission computed tomography (SPECT) imaging and exercise
ECHO directly,3-8 in that studies evaluated modest numbers of patients or were
conducted by physicians and centers
more expert in one technique than the
other. Interpretation of the literature
From the Cardiology Division, University of California,
San Francisco, Medical Center, San Francisco (Dr
Fleischmann); and the Section for Clinical Epidemiology (Dr Kuntz), Brigham and Women’s Hospital, and the
Cardiovascular Division (Dr Douglas), Beth Israel Deaconess Medical Center, Harvard Medical School, and
the Department of Health Policy and Management (Drs
Hunink and Kuntz), Harvard School of Public Health,
Boston, Mass; and the Departments of Epidemiology
and Biostatistics and Radiology, Erasmus University,
Rotterdam, the Netherlands (Dr Hunink).
Corresponding author: Kirsten E. Fleischmann, MD,
MPH, Cardiovascular Division, University of California,
San Francisco, Medical Center, 505 Parnassus Ave,
San Francisco, CA 94143-0214 (e-mail: Fleischm@
cardio.ucsf.edu).
Meta-analysis of Exercise SPECT vs Exercise ECHO—Fleischmann et al
©1998 American Medical Association. All rights reserved.
913
overall has been hampered by significant
variability in case mix and pretest probability of disease, differences in the positivity criteria used, and the lack of reliable techniques to combine reports on the
performance of diagnostic tests.9 Therefore, we undertook a meta-analysis of the
contemporary literature on exercise
SPECT imaging and exercise ECHO using a new methodologic tool, summary receiver operating characteristic (SROC)
analysis.10-12
METHODS
Data Extraction
A literature review was performed to
identify articles published from January
1990 to October 1997 in the English-language literature on exercise SPECT imaging and exercise ECHO.12 We focused
on this period because both exercise
ECHO and exercise SPECT were in
widespread clinical use. Also, these
years postdated several potentially important developments in myocardial
perfusion imaging, such as SPECT techniques and the introduction of technetium Tc 99m sestamibi as an imaging
agent. Articles were obtained through a
MEDLINE search using the key words
coronary disease and exercise test in conjunction with either echocardiography,
thallium or thallium radioisotopes, or
sestamibi and restricted by the term human; from bibliographies of original and
review articles; and in response to suggestions by experts in each area.
Articles3-8,14-51 were included in the
analysis if (1) exercise ECHO and/or exercise SPECT imaging were performed
with thallous chloride Tl 201 (thallium) or
technetium Tc 99m sestamibi to detect
and/or evaluate coronary artery disease
(if data on exercise ECG results in the
same patient population were also presented, these data were extracted, although a comprehensive search of the literature concerning standard exercise
testing was not performed); (2) data on
coronary angiography were presented as
the reference test; and (3) the absolute
numbers of true-positive, false-negative,
true-negative,andfalse-positiveobservations were available or derivable from the
data presented. Studies performed exclusively in patients after myocardial infarction (MI), after percutaneous transluminal coronary angioplasty, after coronary
artery bypass grafting (CABG), or with
unstable coronary syndromes were excluded. One stress ECHO article was excluded because of its substantially different positivity criterion,13 namely displacement of the atrioventricular plane. In
cases in which authors had published several reports in quick succession, we were
able to contact them and to determine
914 JAMA, September 9, 1998—Vol 280, No. 10
whether multiple analyses were reported
on a substantially overlapping patient
population. If this was the case, only 1 report was used in the analysis to avoid undue influence by results in one cohort of
patients. A radiologist (M.G.M.H.) and
cardiologist (K.E.F.) independently extracted data on clinical variables, technical factors, and test performance by
meansofastandardizedspreadsheet.Discrepancies were resolved by consensus.
Variables extracted included identifying
information (first author, journal, city,
and institution), publication year, mean
age, percentage of male patients, clinical
indication or setting and percentage of
patients with previous MI, percutaneous
transluminal coronary angioplasty, or
CABG surgery. In addition, we recorded
such test factors as the test used, the type
of exercise performed, type of radionuclide used (if applicable), the positivity criterion used, the reference test used, how
authors defined significant coronary artery disease (eg, $50% stenosis or $70%
stenosis), and the presence of possible
verification bias. The number of patients
with and without disease, number of true
positives and false positives, and percentage of diagnostic tests (patients reached
at least 85% of their predicted maximal
heart rate) were extracted as well as the
percentage of uninterpretable tests and
morbidity and mortality associated with
each test, if provided.
If the article reported sensitivity and
specificity data for important patient subsets, such as patients with multivessel
disease, these data were extracted separately. If several types of tests were assessed in the same report (ie, exercise
ECG, exercise ECHO, and exercise
SPECT), data on test performance were
extracted for each. An assessment of the
likelihood of verification bias52 was made
by noting whether the decision to proceed to the reference test, in this case contrast angiography, was in part dependent
on the results of the noninvasive test.
Since positive noninvasive test results
are more likely to be followed up by an
invasive test, this tends to increase the
chance of detecting a true positive relative to a false negative and tends to
increase the chance of detecting a false
positive relative to a true negative.
Therefore, sensitivity may appear falsely
elevated and specificity falsely depressed
in the verified sample.
Weighted Pooled Analysis
In our analysis, pooled results weighted
by the sample size of each study were first
calculated using a fixed-effects model.53
Pooled weighted results were also generated for important patient subsets, such
as patients without prior MI and patients with severe coronary artery dis-
ease as defined in each report. We also explored the effect of varying positivity
criteria on pooled results. For the analysis, positivity criteria were grouped according to whether an abnormal test
result required that an abnormality manifested after exercise vs either at rest or
after exercise. If not fully specified, a less
stringent criterion of abnormality at rest
or after exercise was used. In addition, exercise ECHO studies were grouped as requiring either new regional wall motion
abnormalities (RWMAs) or new or worse
RWMAs. All results are presented as percentage sensitivity and specificity with
95% confidence intervals (CIs).
SROC Analysis
for Each Diagnostic Test
Receiver operating characteristic
curves graphically represent the truepositive and false-positive ratios for a diagnostic test when the threshold for a positive test result is varied.54 The area under
the curve summarizes the overall diagnostic performance of the test, with larger
areas corresponding to a more discriminating test. An area of 0.5 corresponds to
a test whose results are no better than
chance, while an area of 1.0 denotes a perfect test. SROC analysis assumes that part
of the variability in test performance reported in the literature is due to the use
of different cut points or positivity criteria and adjusts for these differences. For
example, a study of exercise ECHO may
use a more stringent criterion such as development of a new RWMA to signal an
abnormal test result or a more lenient criterion such as the absence of a hyperkinetic contractile response to exercise resulting in a different reported sensitivity
and specificity. SROC analysis also allows adjustment for important clinical covariates and for comparison between different types of tests.55 In this last case, a
variable corresponding to the type of exercise testing used (eg, exercise ECHO or
exercise SPECT) is entered into the regression equation. The b-coefficients for
the variable give a measure of the difference in diagnostic performance of the 2
tests, with positive coefficients indicating better discriminatory power and negative coefficients corresponding to reduced discriminatory ability.
SROC curves were generated separately for each test. We assessed the influence of variables including publication year; proportion of patients with
prior MI; indication or setting for the
test; mean age; proportion of men in the
study population; presence of verification bias; the angiographic definition of
disease (50% stenosis vs 70% or 75%);
type of exercise (treadmill vs other);
positivity criterion; and in the case of exercise SPECT, type of nuclide (thallium
Meta-analysis of Exercise SPECT vs Exercise ECHO—Fleischmann et al
©1998 American Medical Association. All rights reserved.
vs technetium Tc 99m sestamibi) and
type of analysis (visual vs quantitative)
on test performance. We used a significance level of P,.05, implying that b regression coefficients whose 95% CIs do
not cross zero are statistically significant. Since multiple variables were
tested, one would normally adjust P values for multiple comparisons, eg, with a
Bonferroni correction. However, to
minimize the chance of missing potential
confounding factors, all explanatory
variables with P ,.05 were included in
subsequent multivariate analyses. The
Bonferroni-adjusted P values in our
analyses were approximately .005;
therefore, explanatory variables with
.005 , P , .05 should be interpreted with
caution.
Data for some explanatory variables
were not specified in all articles. For example, the proportion of prior percutaneous transluminal coronary angioplasty and CABG and the percentage of
uninterpretable tests were excluded
from all analyses due to missing data.
Also, in the 1 article in which mean age
was not given, in the 1 case in which the
proportion of men was absent, in the 1
article in which the clinical setting for
testing was not fully specified, and in the
2 articles in which the proportion of patients with MI was not specified, we used
estimates for these variables based on a
best subset regression analysis, so the
widest range of literature could be included. Sensitivity analyses using
weighted mean values for the missing
data or excluding these articles from the
analysis did not change the results substantively. Therefore, the base case including all articles is presented.
We then assessed which explanatory
variables were significant in multivariate analysis for each test using stepwise
forward regression analysis with backward elimination including all variables.
All variables with a P,.05 were kept in
the model. Variables with .05,P,.10
were kept in the model if they substantially increased the explanatory power
of the model.
Comparison SROC Analyses
Between Diagnostic Tests
SROC curves were performed comparing exercise ECHO to exercise SPECT,
exercise ECHO to exercise ECG, and exercise SPECT to exercise ECG. In each
case, all explanatory variables were once
again tested along with the variable indicating the test comparison. We then performed multivariate stepwise forward
regression with backward elimination including all variables with P,.05 in the
step above as well as all variables significant in multivariate analysis for each individual test. To develop a parsimonious
JAMA, September 9, 1998—Vol 280, No. 10
model with similar explanatory variables
across all comparisons, we included in the
final models significant variables with
similar effects for all tests as well as interaction terms to account for significant
variables with effects specific to a particular diagnostic test. Final models were
tested for heterogeneity by comparing
the values predicted by the model to the
95% CI of the actual values for each article. Similar SROC analyses were also
performed in the following important
subsets: studies comparing exercise
ECHO and exercise SPECT directly in
the same patients, patients without prior
MI, and patients with severe disease as
defined in each report.
RESULTS
Overview of Studies
A total of 902 citations published between January 1990 and October 1997
were screened, and 44 articles met inclusion criteria.3-8,14-51 The clinical characteristics of the studies analyzed are
outlined in Table 1. Overall, 24 studies
reported exercise ECHO results in 2637
patients with a weighted mean age of 59
years. The patients were predominantly
men (69%). Significant coronary artery
disease, as defined in each report, was
present in 66% of patients and prior MI
was present in 20% of patients. Twentyseven studies reported exercise SPECT
data on 3237 patients, of whom 70% were
male, with a mean age of 59 years. Significant coronary artery disease was
present in 78%, with past MI in 33%. In
24 articles on exercise ECHO and/or exercise SPECT, data on results of the exercise ECG in the same patient population were also given. These encompassed
2456 patients with a mean age of 59
years, of whom 66% were men. The
prevalence of coronary artery disease
was 69% with past MI in 20%.
Weighted Pooled Results
Diagnostic test performance for individual studies is outlined in Table 1. In
pooled data weighted by the number of
patients with and without disease in each
study, exercise ECHO had a sensitivity
(true-positive ratio) of 85% (95% CI, 83%87%) with a specificity (1 − false-positive
ratio) of 77% (95% CI, 74%-80%). The
SPECT analyses yielded a similar sensitivity of 87% (95% CI, 86%-88%) but a
lower specificity of 64% (95% CI, 60%68%). Weighted pooled data for exercise
ECG revealed a significantly lower sensitivity of 52% (95% CI, 50%-55%) and a
specificity of 71% (95% CI, 68%-74%).
When only patients without prior MI
were considered, the sensitivity and
specificity for exercise ECHO were similar to those of the cohort overall at 87%
(95% CI, 84%-89%) and 84% (95% CI,
81%-88%). Weighted pooled results for
SPECT in this subset were also similar to
overall results with a sensitivity of 86%
(95% CI, 83%-88%) and a specificity of
62% (95% CI, 55%-70%).
The criterion for severe disease varied
from article to article but generally denoted multivessel disease. In patients
with severe disease, the sensitivity for
exercise ECHO rose to 92% (95% CI,
90%-94%) when any abnormal test result
was considered positive, but the specificity also dropped significantly to 54% (95%
CI, 50%-58%). In contrast, when only abnormalities in multiple coronary distributions were considered an abnormal test
result, the sensitivity fell to 60% (95% CI,
53%-67%) while specificity rose to 88%
(95% CI, 85%-92%). Similar trends were
seen for exercise SPECT with a sensitivity of 92% (95% CI, 90%-94%) and a specificity of 21% (95% CI, 19%-24%) when any
abnormality was considered a positive
test result, but a sensitivity of 44% (95%
CI, 38%-49%) and a specificity of 87%
(95% CI, 85%-89%) when only abnormalities in multiple distributions were considered positive.
Pooled results were analyzed by positivity criteria as outlined in the “Methods” section and compared with the
overall results. No significant differences in sensitivity were detected for
either exercise ECHO or exercise
SPECT. However, specificity in reports
requiring an abnormality seen only after exercise rather than at rest or after
exercise was significantly higher for exercise SPECT (76% [95% CI, 69%-83%]
vs 61% [95% CI, 57%-65%]) and for exercise ECHO (84% [95% CI, 81%-87%] vs
70% [95% CI, 66%-74%]). Specificity was
also higher for exercise ECHO reports
requiring a new RWMA than for those
using a new or worsened RWMA as a
positivity criterion (93% [95% CI, 88%98%) vs 75% [95% CI, 72%-78%]).
SROC Analysis
for Each Diagnostic Test
In univariate analysis for exercise
ECHO, age and publication year were
significant predictors. The discriminatory power of the test diminished slightly
with increasing mean age (b-coefficient,
−0.22 per year; 95% CI, −0.31 to −0.12)
and with later publication year ( −0.41 per
year; 95% CI, −0.58 to −0.24). Performance was better in reports requiring an
abnormality seen only after exercise
rather than at rest or after exercise (0.87;
95% CI, 0.005-1.74). Sex was not a significant predictor (0.40; 95% CI, −0.99 to
1.79). Similarly, increasing age (−0.15;
95% CI, −0.24 to −0.06) was a significant
predictor of SPECT performance. Unlike exercise ECHO, settings that in-
Meta-analysis of Exercise SPECT vs Exercise ECHO—Fleischmann et al
©1998 American Medical Association. All rights reserved.
915
Table 1.—Clinical Characteristics of the Studies Included in the Meta-analysis*
Age,
Mean, Men, Previous
y
%
MI, %
Reference
ECHO only
Beleslin et al35
Exercise
Used
Exercise
Radionuclide Verification
ECG
Used
Bias
Results
Positivity Criterion
True
False
True
False
Positive Negative Negative Positive
50
85
57
Treadmill
No
Yes
New or worse RWMA after
exercise
105
14
14
3
Bjornstad et al36
58
81
59
Upright
bicycle
No
Yes
New or worse RWMA after
exercise
26
5
4
2
Cohen et al37
63
98
25
Supine
ergometry
No
Yes
New or worse RWMA after
exercise
29
8
13
2
Crouse et al38
62
67
0
Treadmill
Yes
Yes
Absence of hyperkinesis
with exercise
170
5
34
19
Dagianti et al39
54
79
39
Supine
ergometry
No
Yes
New or worse RWMA after
exercise
19
6
33
2
Galanti et al40
54
87
0
Bicycle
Likely
Yes
New RWMA after exercise
25
2
25
1
Jun et al41
54
83
17
Treadmill
Likely
Yes
Absence of hyperdynamic
response after exercise
28
4
14
1
Luotolahti et al
55
85
48
Bicycle
No
Yes
New or worse RWMA after
exercise
101
7
7
3
Marangelli et al43
58
84
0
Treadmill
No
No
New RWMA after exercise
42
5
30
3
Marwick et al44
57
79
37
Treadmill
Yes
Yes
RWMA after exercise
or at rest
96
18
31
5
Marwick et al45
60
0
0
Treadmill and
bicycle
Yes
Yes
RWMA after exercise
or at rest
47
12
83
19
Marwick et al46
58
59
0
Treadmill
No
No
Failure to augment or
worsening wall motion
44
18
77
8
Roger et al47
64
77
26
Treadmill
...
Yes
No
Absence of hyperdynamic
response after exercise
50
10
56
34
Roger et al48
64
100
0
Treadmill
...
Yes
Yes
RWMA at rest or after
exercise
151
43
22
28
Roger et al48
66
0
0
Treadmill
...
Yes
Yes
RWMA at rest or after
exercise
46
12
14
24
Ryan et al49
57
75
43
Bicycle
Yes
Yes
New or worse RWMA after
exercise or at rest
RWMA
193
18
76
22
Tawa et al50
58
70
45
Treadmill
Yes
Yes
Fixed or reversible RWMA
31
2
10
2
Williams et al51
60
0
0
Bicycle
No
Yes
New or worse RWMA after
exercise
29
4
31
6
SPECT only
Berman et al14
64
73
0
Treadmill
MIBI/TI
Yes
No
Fixed or reversible PD
involving 2 or more
segments
50
5
6
2
Chae et al15
62
0
42
Treadmill
TI
Yes
Yes
PD at rest or after exercise
116
47
52
28
Christian et al16
63
77
42
Treadmill
TI
Likely
No
Fixed or reversible PD
527
51
30
80
Fleming et al17
55
60
43
Treadmill
MIBI
Likely
No
PD with stress
16
1
6
2
Gupta et al18
58
83
40
Treadmill
TI
Likely
No
Fixed or reversible PD
62
14
14
3
Hambye et al19
60
70
0
Bicycle
MIBI
No
Yes
Fixed or reversible PD
75
16
28
9
Heiba et al20
50
64
31
Treadmill
MIBI
Yes
No
PD not otherwise specified
28
2
2
2
Ho et al21
56
76
33
Bicycle
TI
No
No
Fixed or reversible PD
29
9
10
3
Kiat et al22
56
74
45
Treadmill
MIBI
Likely
No
Fixed or reversible PD
45
3
4
1
Mahmarian et al23
56
74
43
Treadmill
TI
Likely
No
Fixed or reversible PD
192
29
65
10
Minoves et al24
57
...
42
Treadmill
MIBI/TI
Likely
No
PD not otherwise specified
27
3
22
2
Nguyen et al25
62
65
37
Treadmill
TI
No
No
Fixed or reversible PD
19
6
5
0
Oguzhan et al26
51
84
30
Treadmill
MIBI
No
Yes
Reversible PD
47
2
15
6
Palmas et al27
60
81
30
Treadmill
MIBI
Likely
No
PD after exercise
or at rest
60
6
3
1
Rubello et al28
51
88
57
Bicycle
MIBI
Likely
No
PD after exercise
100
7
8
5
Solot et al29
61
62
...
Bicycle
MIBI
Likely
No
PD not otherwise specified
87
3
27
11
Sylven et al30
58
63
37
Bicycle
MIBI
Yes
Yes
Persistent or transient PD
41
16
5
5
Taillefer et al31
58
0
17
Treadmill
MIBI
No
No
Reduced uptake at rest
or after exercise
23
9
13
3
Van Train et al32
56
76
19
Treadmill
MIBI
Yes
No
PD after exercise
91
11
8
14
Van Train et al33
60
83
16
Treadmill
MIBI
Likely
No
PD at rest or after exercise
28
1
4
5
Van Train et al34
...
86
35
Treadmill
TI
Likely
No
PD at rest or after exercise
290
17
32
32
42
cluded known coronary artery disease vs
suspected coronary artery disease only
were associated with better discriminatory performance (1.14; 95% CI, 0.59-1.70)
as were higher proportions of men in the
916 JAMA, September 9, 1998—Vol 280, No. 10
study population (1.89; 95% CI, 0.72-3.07).
No predictors were significant for exercise ECG.
In multivariate analysis, increasing
age (−0.16; 95% CI, −0.23 to −0.09) re-
mained a significant predictor of performance for exercise ECHO, as did a setting including known coronary artery
disease (−0.56; 95% CI, −1.00 to −0.12).
For exercise SPECT, a setting including
Meta-analysis of Exercise SPECT vs Exercise ECHO—Fleischmann et al
©1998 American Medical Association. All rights reserved.
Table 1.—Clinical Characteristics of the Studies Included in the Meta-analysis* (cont)
Reference
ECHO and SPECT
Hecht et al3
Hoffmann et al4
Marwick et al5
Pozzoli et al6
Quinones et al7
Salustri et al8
Mean Men, Previous
Age, y %
MI, %
58
57
59
52
57
59
86
24
77
0
70
87
67
80
0
19
...
36
Exercise
Used
Treadmill/
bicycle
Bicycle
Bicycle
Bicycle
Treadmill
Bicycle
Radionuclide Verification
Used
Bias
Exercise
ECG
Results
TI
Yes
MIBI
MIBI
MIBI
TI
MIBI/TI
No
No
Yes
No
Yes
Yes
Yes
Likely
Yes
No
Yes
Positivity Criterion
True
False
True
False
Positive Negative Negative Positive
New or worsening
RWMA or severe
RWMA at rest
46
5
16
4
SPECT PD on exercise
or rest images
47
4
13
7
ECHO new RWMA after
exercise
40
10
14
2
SPECT PD not
otherwise specified
37
5
9
4
ECHO RWMA at rest
or after exercise
49
7
24
6
SPECT fixed or
reversible PD
41
15
21
9
ECHO new RWMA after
exercise
35
14
25
1
SPECT partially or
completely reversible
PD after exercise
41
8
23
3
ECHO new or worse
RWMA after exercise
or RWMA at rest
64
22
23
3
SPECT fixed or
reversible PD
65
21
21
5
ECHO new or worse
RWMA after exercise
or RWMA at rest
26
4
12
2
SPECT transient PD
or PD at rest
25
5
9
5
*ECHO indicates echocardiography; SPECT, single-photon emission computed tomography; ECG, electrocardiography; MI, myocardial infarction; MIBI, technetium Tc 99m
sestamibi; TI, thallous chloride TI 201 (thallium); RWMA, regional wall motion abnormality; and PD, perfusion defect. Ellipses indicate that data is not available.
known or suspected coronary artery disease (1.19; 95% CI, 0.67-1.70) in the study
population was associated with improved performance. For both tests,
performance diminished with later publication year with a parameter estimate
of −0.27 (95% CI, −0.40 to −0.14) for
ECHO and −0.15 (95% CI, −0.28 to
−0.012) for SPECT. No explanatory
variables were significant for exercise
ECG in multivariate analysis.
Table 2.—Comparison SROC Analyses Between Diagnostic Tests*
Exercise SPECT vs exercise ECG
P
,.001
Age, per year
−0.12 (−0.17 to −0.06)
,.001
Publication year
−0.21 (−0.30 to −0.11)
,.001
0.77 (0.26 to 1.29)
1.49 (0.91 to 2.08)
.004
,.001
SPECT mixed setting
SPECT vs ETT
Age, per year
SPECT publication year
Exercise ECHO vs exercise ECG
Comparison SROC Analyses
Between Diagnostic Tests
b-Coefficient†
(95% CI)
1.18 (0.71 to 1.65)
Comparison
Variable
Exercise ECHO vs exercise SPECT ECHO vs SPECT
SPECT mixed setting
ECHO vs ETT
Age, per year
JAMA, September 9, 1998—Vol 280, No. 10
.05
−0.15 (−0.27 to −0.029)
.02
1.01 (0.52 to 1.50)
3.43 (2.74 to 4.11)
−0.066 (−0.11 to −0.021)
ECHO publication year
In a model comparing exercise ECHO
performance to SPECT, exercise ECHO
displayed significantly better discriminatory power (parameter estimate for incremental improvement, 1.18; 95% CI,
0.71-1.65), when adjusted for age, publication year, and a setting including known
coronary artery disease for SPECT studies (Table 2). In models comparing the performance of exercise ECHO vs exercise
ECG and exercise SPECT vs exercise
ECG, both ECHO and SPECT performed significantly better than exercise ECG (Table 2). The incremental improvement was greater for ECHO than
for SPECT. These results are presented graphically in Figures 1 and 2. In the
subset of reports (n=6) comparing exercise ECHO and exercise SPECT directly in the same patients, exercise
−0.047 (−0.093 to −0.0004)
−0.35 (−0.50 to −0.21)
Adjusted
r2
0.64
0.67
,.001
,.001
.005
0.78
,.001
*CI indicates confidence interval; ECHO, echocardiography; SPECT, single-photon emission computed tomography; ECG, electrocardiography; and ETT, exercise treadmill testing
†The b-coefficient for the variable gives a measure of the difference in diagnostic performance of the 2 tests, with
positive coefficients indicating better discriminatory power and negative coefficients corresponding to reduced
discriminatory ability.
ECHO also displayed better discriminatory performance parameter estimate
(1.06; 95% CI, 0.77-1.36) in a model adjusted for age.
In patients without prior MI, results
were qualitatively similar to the overall
analysis. When exercise ECHO and exercise SPECT were compared in this
subgroup, exercise ECHO had better
discriminatory power (1.21; 95% CI,
0.57-1.85). Both exercise SPECT and exercise ECHO performed significantly
better than exercise ECG in patients
without prior MI, but the incremental
improvement for exercise ECHO was
larger (2.35; 95% CI, 1.79-2.91) than
for exercise SPECT (1.36; 95% CI, 0.582.15). Results were also similar for models assessing diagnostic performance in
patients with severe coronary artery
disease as defined by each report. Exercise ECHO performed significantly better than exercise SPECT (parameter
estimate, 0.91; 95% CI, 0.26-1.56). This
result should be interpreted with caution, however, given the varying definitions of severe coronary artery disease
from study to study and the relatively
few studies in which these data were
reported.
Meta-analysis of Exercise SPECT vs Exercise ECHO—Fleischmann et al
©1998 American Medical Association. All rights reserved.
917
Base Case
Worst Case
Best Case
True-Positive Ratio
A
Studies With >100 Patients
B
C
1.0
1.0
1.0
0.8
0.8
0.8
0.6
0.6
0.6
0.4
0.4
0.4
0.2
0.2
0.2
0.0
0.2
0.4
0.6
0.8
1.0
False-Positive Ratio
0.0
Studies With <100 Patients
0.2
0.4
0.6
0.8
1.0
0.0
False-Positive Ratio
0.2
0.4
0.6
0.8
1.0
False-Positive Ratio
Figure 1.—Panel A shows summary receiver operating characteristic (SROC) curves for exercise single-photon emission computed tomography (SPECT) based
on a model comparing exercise echocardiography (ECHO) and exercise SPECT. Panel B shows SROC curves for exercise ECHO based on model comparing exercise ECHO and exercise SPECT. Panel C shows SROC curves for exercise testing without adjunct imaging based on a model comparing exercise ECHO and
exercise electrocardiography. In all panels, the horizontal axis represents the false-positive ratio (1 − specificity) and the vertical axis the true-positive ratio (sensitivity). The base case is adjusted to a population aged 59 years, publication year 1993, and a setting including known or suspected coronary artery disease (CAD)
in half of the cases. Additional SROC curves represent the best case, which is adjusted to age 55 years, publication year 1990, and a setting including known or
suspected CAD in all cases, and worst case, which is adjusted to age 65 years, publication year 1995, and a setting with suspected CAD only in all cases.
1.0
True-Positive Ratio
0.8
0.6
0.4
ECHO
SPECT
No Imaging
0.2
0.0
0.2
0.4
0.6
0.8
1.0
False-Positive Ratio
Figure 2.—Comparative summary receiver operating characteristic curves are shown for exercise
echocardiography (ECHO), exercise single-photon
emission computed tomography (SPECT), and exercise testing without adjunct imaging. The horizontal axis represents the false-positive ratio
(1 − specificity) and the vertical axis the truepositive ratio (sensitivity).
Testing for Heterogeneity
Final models were tested for heterogeneity by comparing the model predicted discriminatory power to the 95%
CIs of the actual discriminatory power
for each study. Analyses were homogeneous with the exception of the following
data. In the models comparing exercise
SPECT with either exercise ECHO or
exercise ECG in the overall cohort,
SPECT data from Solot et al29 fell outside
the predicted parameters, likely related
to the very high sensitivity (97%) reported in this cohort with one specific
918 JAMA, September 9, 1998—Vol 280, No. 10
SPECT imaging filter. In addition, in the
comparison of exercise ECHO to exercise SPECT, ECHO data from Crouse et
al38 and SPECT data from Van Train et
al32 showing very high sensitivity fell outside predicted values. In models comparing exercise ECG with either exercise
ECHO or exercise SPECT, exercise
ECG data from Sylven et al30 fell outside
the predicted parameters, due primarily
to a very high false-positive ratio (90%)
associated with the cutoff used. In models concerning diagnostic performance
for severe disease, these reports also fell
outside predicted values, as did exercise
ECHO data from Ryan et al49 and Roger
et al48 and SPECT data from Oguzhan et
al.26 Models in the subset of patients without prior MI were all homogeneous.
COMMENT
The current study presents a metaanalysis of the contemporary literature
on exercise ECHO and exercise SPECT
imaging. Our analysis suggests that both
exercise ECHO and exercise SPECT
imaging have similar sensitivities but
that exercise ECHO has lower falsepositive ratios and, thus, higher specificity. As a result, the discriminatory ability of exercise ECHO was significantly
higher than that of exercise SPECT.
Our data also show that both exercise
SPECT imaging and exercise ECHO
have significantly better discriminatory
capabilities than exercise ECG in these
patient populations, although the incremental improvement in performance is
greater for exercise ECHO. Detrano et
al56 have suggested in previous metaanalyses of exercise testing that the in-
cremental value of imaging may be overestimated when data on exercise ECG are
drawn from reports in which exercise
ECG is compared to a “better” test. This
may, in part, be related to study of cohorts
enriched for patients with baseline echocardiographic abnormalities or other conditions affecting accuracy of the exercise
ECG. In addition, the data on exercise
ECG in reports focusing on an imaging
modality may not include detailed information on important variables such as exercise duration, symptoms, or degree of
ST-segment changes. They do, however,
represent contemporaneous data on exercise ECG results in the same clinical cohorts. Our estimates of the performance
of exercise ECG lie within the 95% CIs
generated in the meta-analysis by Detrano et al and are unlikely to give qualitatively varying results. In actual clinical
practice, the performance of an imaging
test such as SPECT or ECHO with exercise is not pitted against the performance
of standard exercise testing but, rather, is
used in conjunction with information from
the exercise test to enhance its diagnostic
and prognostic capabilities.57
Performance for exercise ECHO and
exercise SPECT in the subset of patients
without evidence of prior MI was similar
to that for each test in the cohort overall.
Interestingly, however, in multivariate
analysis, a setting with known or suspected coronary artery disease (a proxy
for pretest probability of disease) was associated with somewhat lower discriminatory power for exercise ECHO but led
to improved discrimination for exercise
SPECT. These findings may be related to
the differing nature of exercise ECHO,
Meta-analysis of Exercise SPECT vs Exercise ECHO—Fleischmann et al
©1998 American Medical Association. All rights reserved.
which relies on the functional response of
the myocardium to exercise, and exercise
SPECT, in which perfusion is gauged as
normal or abnormal. For example, the
baseline RWMA associated with prior infarction may make interpretation of exercise ECHO more difficult if a positivity
criterion requiring development of new
or worsening RWMA after exercise is
used but may not influence interpretation
of perfusion in an identical fashion. The
findings may also relate to differences in
positivity criteria, although the SROC
methods used should adjust for this in
large part.
Although these data suggest that exercise ECHO performs as well or better
than exercise myocardial perfusion scintigraphy with SPECT imaging, an alternative interpretation should be considered. Several studies have reported that
the specificity of diagnostic tests decreases with time as the test is used more
widely in clinical decision making and is
applied to a wider spectrum of patient
populations.58-60 This is consistent with
our finding that publication year is a significant predictor of the performance of
each test and that discriminatory power
decreases in more recent reports. Since
myocardial perfusion scintigraphy has
been in widespread clinical use since the
early 1980s and as exercise ECHO has
become popular more recently, the difference in specificity seen could be a function of this different experience. However, in the subset of studies comparing
the 2 modalities directly in the same patients, exercise ECHO performed significantly better, mitigating against this possibility. These direct comparisons may
still be influenced by verification bias
(also known as posttest referral bias) and
the tendency to confirm noninvasive test
findings more frequently in patients with
abnormal test results, but the degree of
bias should be similar for the 2 tests.
Several technical factors related to test
performance were not significant predictors of discriminatory ability, although
pairs of sensitivity and specificity can still
be different in that they may be shifted
along the same receiver operating characteristic curve. For example, the distinction between bicycle and treadmill exercise was not a significant predictor of
exercise ECHO performance, suggesting that both can give similar results. Similarly, variables comparing thallium stress
test with technetium Tc 99m sestamibi or
distinguishing visual from quantitative or
computer-based interpretation of exercise SPECT were also not significant in
the current analysis.
Some limitations of the literature reviewed deserve note. Information on the
incidence of uninterpretable test results
for either imaging modality was often
JAMA, September 9, 1998—Vol 280, No. 10
sketchy or absent. In some reports, patients with inadequate imaging were excluded from the analysis, inflating diagnostic test performance and obviating
meaningful adjustment for this parameter. Some insight may be gained from
the large series comparing the 2 modalities head to head in the same patients
by Quinones et al.7 In this series of 292
patients, 99% of ECHO and 100% of
SPECT studies were adequate for interpretation. Information on other potentially important factors such as test performance in relation to sex or body size
was also rarely given. Verification bias
remains a concern since recent studies60
suggest substantial effects on reported
sensitivities and specificities, although
the likely presence or absence of verification bias was not a significant predictor for the comparison of exercise
SPECT and exercise ECHO. Ongoing
technological developments for both
tests may also affect test performance.
For example, recent reports using gated
SPECT imaging suggest this technique
can enhance specificity for the diagnosis
of coronary artery disease,61,62 particularly in patient subsets prone to artifact,
such as women.63 Despite these limitations, an aggregate of the contemporary
literature likely represents the best factual information available regarding exercise imaging.
Our conclusions should also be viewed
in light of study design considerations
that could influence results. Meta-analysis of diagnostic tests may be subject to
publication bias. That is, reports that
present the diagnostic test under study
in a favorable light may more likely be
submitted and published than those
showing little or no benefit. However,
this bias affects the literature for both
exercise SPECT and exercise ECHO
and visual inspection of a plot of study
size vs discriminatory power for each
test indicated little systematic bias. Our
analysis uses partially dependent data
in that multiple tests were performed in
some patients, but a sensitivity analysis
randomly selecting 1 test per study
yielded similar results. The analysis focuses on diagnostic test performance for
coronary artery disease and does not incorporate potential differences in prognostic capabilities. Finally, these results
cannot be fully generalized to a number
of important subgroups, such as patients
undergoing pharmacologic stress testing with adjunctive imaging or those undergoing exercise ECHO or exercise
SPECT for other indications, such as
risk stratification after recent angioplasty or MI. Because our search was
conducted in English-language literature and reports were retrieved primarily from the United States and Canada,
our conclusions may also be applicable
primarily to practice in those countries.
Our analysis of the current literature
shows that exercise ECHO and exercise
SPECT have similar sensitivities for the
detection of coronary artery disease;
however, that exercise ECHO has better
specificity and higher overall discriminatory capabilities as used in contemporary
practice. Previous individual studies
have had limited power to detect differences in the performance of the 2 tests,
but in aggregate, these differences become significant. While exercise ECHO
may, therefore, be preferable in most instances, the clinician’s ultimate choice of
imaging modality must take into account
other important factors such as local expertise and experience with each test,
availability, and cost.
Kirsten E. Fleischmann, MD, MPH, is the recipient of a Clinical Investigator Development Award
(1K08HL02964-01) from the National Heart, Lung
and Blood Institute, Bethesda, Md. Dr Fleischmann
and Ms Kuntz were also supported by a project
grant from the American Society of Echocardiography. Dr Hunink was supported by a Persoongerichte Impuls voor Onderzoeksgroepen met Nieuwe
Ideeen voor Excellente Research (PIONIER) award
from the Netherlands Organization for Scientific Research, the Hague, Netherlands.
The authors thank Finn Mannting, MD, for his
thoughtful comments.
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Meta-analysis of Exercise SPECT vs Exercise ECHO—Fleischmann et al
©1998 American Medical Association. All rights reserved.