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(Circulation. 1996;93:905-914.)
© 1996 American Heart Association, Inc.
Articles |
Exercise Myocardial Perfusion SPECT in Patients Without Known Coronary Artery Disease
Incremental Prognostic Value and Use in Risk Stratification
Presented in part at the 41st annual meeting of the Society of Nuclear Medicine, Orlando, Fla, June 1994.
From the Departments of Imaging (Division of Nuclear Medicine) and Medicine (Division of Cardiology), Cedars-Sinai Medical Center, and the Department of Medicine, UCLA School of Medicine, Los Angeles, Calif.
Correspondence to Daniel S. Berman, MD, Co-Chairman, Department of Imaging, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background We evaluated the incremental prognostic value, the role in risk stratification, and the impact on patient management of myocardial perfusion single-photon emission computed tomography (SPECT) in a population of patients without prior myocardial infarction, catheterization, or revascularization.
Methods and Results We examined 2200 consecutive patients
who at the time of their dual-isotope SPECT had not undergone
catheterization, coronary artery bypass
surgery, or percutaneous transluminal coronary
angioplasty and had no known history of previous myocardial infarction.
Follow-up was performed at a mean of 566±142 days (97% complete)
for hard events (cardiac death and myocardial infarction) and for
referral to cardiac catheterization or
revascularization within 60 days after nuclear
testing. Examination of clinical, exercise, and nuclear models by use
of pre–exercise tolerance test (ETT), post-ETT, and nuclear
information using a stepwise Cox proportional hazards model and
receiver-operating characteristic curve analysis revealed
that nuclear testing added incremental prognostic value after inclusion
of the most predictive clinical and exercise variables (global
2=12 for clinical variables; 31 for
clinical+exercise variables; 169 for nuclear variables; gain in
2, P<.0001 for all;
receiver-operating characteristic areas: 0.66±0.04 for clinical,
0.73±0.04 for clinical+ exercise variables, 0.87±0.03 for
nuclear
variables, P=.03 for gain in area with exercise
variables; P<.001 for increase with nuclear
variables). Multiple logistic regression analysis revealed
that scan information contributed 95% of the information regarding
referral to catheterization with further additional
information provided by presenting symptoms and
exercise-induced ischemia. Referral rates to early
catheterization and
revascularization paralleled the hard event
rates in all scan categories-very low referral rates in patients
with normal scans and significant increases in referral rates as a
function of worsening scan results. Even after stratification by
clinical and exercise variables such as the Duke treadmill score,
pre- and post-ETT likelihood of coronary artery disease,
presenting symptoms, sex, and age, the nuclear scan results further
risk-stratified the patient subgroups, thus demonstrating clinical
incremental value.
Conclusions In a patient population with no evidence of previous coronary artery disease at overall low risk (1.8% hard event rate), myocardial perfusion SPECT adds incremental prognostic information and risk-stratifies patients even after clinical and exercise information is known. It appears that referring physicians use this test in an appropriate manner in selecting patients to be referred to catheterization or revascularization.
Key Words: sestamibi • prognosis • tomography • perfusion
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Coronary artery disease is the leading cause of morbidity and mortality in industrialized societies.1 Because effective treatments can reduce the likelihood of subsequent adverse events, it is important to identify individuals at high risk of future cardiac events in whom medical therapy or revascularization may enhance survival.1
Although the incremental prognostic value of nuclear testing has been demonstrated in a number of studies, these study cohorts have consisted of patients both with and without prior myocardial infarction, revascularization, or catheterization.2 3 4 5 6 7 8 9 In those few studies evaluating the incremental prognostic value of nuclear testing in patients with "suspected coronary disease," the study cohorts included some patients with prior catheterization documenting coronary disease2 or have been limited to those patients who have undergone both nuclear testing and subsequent catheterization.3 4 5 Although some previous studies have looked at purely diagnostic patient populations, they did not assess the incremental value of nuclear testing over prior information.10 11 To the best of our knowledge, the incremental prognostic value of myocardial perfusion scintigraphy in a homogeneous patient cohort without previously documented CAD has not been examined.
The goals of this study were to define the statistical incremental prognostic value of exercise stress myocardial perfusion SPECT in a patient population without previously defined CAD and to define the clinical role of the test in risk stratification of this population. Since effective risk stratification per se does not necessarily imply a subsequent change in patient management, the utility of nuclear testing, as measured by its impact on subsequent patient referral, takes on an important role. Thus, this study also sought to determine the impact of this test on patient management as measured by the post–nuclear testing referral of patients to catheterization and revascularization.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Study Population
We identified 2268 consecutive patients who underwent exercise dual-isotope SPECT between January 1, 1991, and December 1, 1993, who at the time of their nuclear tests had not undergone cardiac catheterization, coronary artery bypass surgery, or percutaneous transluminal coronary angioplasty and had no known history of previous myocardial infarction. Patients who underwent pharmacological dual-isotope SPECT or who were known to have valvular heart disease or primary cardiomyopathy were not included in this study. Of the initial population, 68 patients were lost to follow-up, and the remaining 2200 patients with successful follow-up (97%) were included in this study. At the time of nuclear study, all patients completed a questionnaire detailing the characteristics of their presenting symptomology. All patients were then interviewed by a physician who reviewed their responses prior to the initiation of the treadmill portion of their tests.
We have shown previously that referral to revascularization in the first 60 days after nuclear testing tends to be based on the results of the scan, and referral to revascularization more than 60 days after nuclear testing tends to be based on worsening of the patient's clinical status.10 12 For this reason, the 87 patients in our cohort who were revascularized in the first 60 days after nuclear testing were censored from the prognostic portion of the analyses. Thus, the prognostic data presented here are based on a subset of 2113 patients.
Exercise Myocardial Perfusion Protocol
All patients underwent
exercise dual-isotope myocardial
perfusion imaging as previously described.13 Whenever
possible, ß-blockers and calcium channel antagonists
were discontinued 48 hours before testing, and nitrate compounds were
discontinued at least 6 hours before testing; 105 (4.8%) patients were
under the influence of ß-blockers and 180 (8.2%) were under the
influence of calcium channel blockers at the time of their tests.
Thallium-201 (2.5 to 3.5 mCi) was injected intravenously at
rest, with dose variation based on patient weight. Rest thallium-201
SPECT imaging was initiated 10 minutes after injection of the isotope.
Immediately after imaging, all patients performed a symptom-limited
treadmill exercise test using standard protocols with 12-lead ECG
recording each minute of exercise and continuous monitoring of
leads AVF, V1, and V5. Blood pressure
was measured and recorded at rest, at the end of each exercise
stage, and at peak exercise. Exercise end points included physical
exhaustion, severe angina, sustained ventricular
tachycardia, hemodynamically significant
supraventricular dysrhythmias, or significant
exertional hypotension. Maximal degree of ST-segment change at 80 ms
after the J-point of the ECG was measured and assessed as horizontal,
upsloping, or downsloping.
The ECG response to exercise was categorized as either nonischemic (no significant ECG changes), ischemic (significant ST-segment elevation or depression), equivocal (borderline ECG changes), or nondiagnostic (ECG uninterpretable because of digoxin use, paced rhythm, bundle branch block, and so forth). The clinical response to exercise was also assessed as either nonischemic, ischemic (typical angina pectoris or anginal equivalent during exercise), equivocal, or abnormal (exertional hypotension or inappropriate shortness of breath).
At near-maximal exercise, a 20- to 30-mCi dose of technetium-99m sestamibi was injected (actual dose varied with patient weight), and exercise continued for 1 additional minute after injection. Technetium-99m sestamibi SPECT imaging was begun 30 minutes after isotope injection.
SPECT Acquisition Protocol
SPECT imaging was performed as
previously
described.13 The SPECT studies were performed using a
circular 180° acquisition for 64 projections at 20 seconds per
projection. For thallium-201 imaging, two energy windows were used,
including a 30% window centered on the 68- to 80-keV peak and a 10%
window centered on the 167 keV peak. For technetium-99m
sestamibi SPECT, a 15% window centered on the 140-keV peak was used.
Images were acquired using a 64x64 image matrix and were subject to
quality control measures as previously described.13
Image Interpretation
A semiquantitative visual interpretation
was performed using
short-axis and vertical long-axis myocardial tomograms that
were divided into 20 segments for each study (Fig 1
).
These segments were assigned on six evenly spaced regions in the
apical, midventricular, and basal slices of the
short-axis views and two apical segments on the
midventricular long-axis slice.14 Each
segment was scored by consensus of two experienced observers using a
5-point scoring system (0=normal, 1=equivocal,
2=moderate, 3=severe
reduction of radioisotope uptake, and 4=absence of detectable tracer
uptake in a segment).
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Scintigraphic Indices
We defined three nuclear variables
using the
above-described 20-segment, 5-point scoring system. A summed stress
score (SSS) was obtained by adding the scores of the 20 segments of the
stress sestamibi images. Summed stress scores less than 4 were
considered normal, between 4 and 8 mildly abnormal, and greater than 8
severely abnormal. A summed rest score (SRS) was obtained by similarly
adding the scores of the 20 segments of the rest thallium images (Fig
1
). The sum of the differences between each of the 20 segments
on the
stress and rest images was defined as the summed difference score
(SDS). Each of these variables incorporate both the extent and
severity of perfusion defects, both of which independently add
prognostic information.12 Scans with defects in more than
one region associated with a particular coronary artery were
considered to demonstrate multivessel disease.15 Scans
that appeared to have left ventricular dilation on stress
images but not on rest images were considered to have transient
ischemic dilation.
Patient Follow-up
Patient follow-up was performed by scripted
telephone
interview by individuals blinded to the patient's test results. Events
were defined as either cardiac death (confirmed by review of death
certificate and hospital chart or physician's records) or nonfatal
myocardial infarction (documented by appropriate cardiac enzyme and ECG
changes). When interventions (cardiac catheterization,
coronary artery bypass surgery, or percutaneous
transluminal coronary angioplasty) were identified, these
outcomes were confirmed by hospital records or the physician's
office records. All patients included in this report were followed
for at least 1 year. The mean follow-up interval was 566±142
days.
Likelihood of Coronary Artery Disease
For purposes of
analyzing patients in different risk subsets, we
used analysis of the pre- and post-ETT likelihood of CAD as
aggregate descriptors of proven prognostic importance based on bayesian
analysis of age and calculated with the use of
CADENZA.16 The variables included in the calculations
of pre- and post-ETT likelihoods of CAD are listed in Table 1.
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Statistical Analysis
Comparisons between patient groups were
performed using a
one-way ANOVA (with a Bonferroni correction as appropriate) for
continuous variables and a 2 test for
categorical variables. All continuous variables are described
as mean±SD. A value of P<.05 was considered statistically
significant.
Survival Analysis
To determine the
incremental prognostic value of a test,
it is necessary to include all other information known regarding the
patient prior to that time. With this in mind, the Cox proportional
hazards model (BMDP version 7, program 2L)17 18 was
used
in a stepwise fashion to determine four distinct statistical models:
(1) a clinical model predictive of events, (2) a clinical and exercise
model predictive of events, (3) a nuclear model predictive of events,
and (4) a model to determine the increase in prognostic information
after adding the most predictive nuclear variable(s) (model 3) to a
model that "forces in" the best clinical and exercise
variables (model 2). The dependent variable in the Cox
proportional hazards analysis is the time to an event rather
than the occurrence of the event within a determined time period. The
threshold for entry of variables into all models was
P<.05. A statistically significant increase in the global
2 of the model (as determined by Cox proportional
hazards testing) after the addition of the nuclear variables
defined incremental prognostic value. The value of
2 obtained is proportional to the information
content of the model examined.
In light of the limitation of 39 outcome
events of interest, we avoided
underpowered Cox proportional hazards models19 by using
validated aggregate variables rather than deriving optimal models
based on our raw data. The variables entered into the models
consisted of the pre-ETT likelihood of CAD in the clinical model and
the post-ETT likelihood of CAD and the Duke treadmill score in the
exercise model. In the absence of generally accepted nuclear aggregate
variables, we entered the raw data of the derived nuclear
variables. These included the SSS, the SDS, and the presence of
multivessel abnormalities on the scan. For each model, the global
2 of the model and the proportion of the
information content of the model contained in the leading variable
were both expressed.
ROC Analysis
Incremental value
was also determined by using the same
variables tested in the Cox model to construct logistic models for
clinical, clinical+exercise, and clinical+exercise+nuclear
variables. These logistic regression models were used to calculate
the probability of an event for each patient using each model, and ROC
curves were constructed for each of these models. These curves were
analyzed by comparing the area underneath them, a measure that
reflects the discriminatory power of the test in question independent
of factors such as diagnostic threshold, the baseline event
rate in the study sample, or selection
bias.20 21 22 23 ROC
curves have a potential area that has values ranging from 0 to 1; an
area of 0.5 corresponds to no discriminatory power, while an area of 1
defines perfect discrimination. ROC areas were expressed as the
area±SEM.
Predictors of Post–Nuclear Referral
to
Catheterization or
Revascularization
To determine the most powerful predictors of
referral to
catheterization within 60 days after nuclear testing
(early catheterization) and referral to
revascularization within this same time span (early
revascularization), we performed multiple logistic
regression (BMDP version 7, program LR)18 using the
uncensored patient cohort (n=2200). The temporal restriction of 60 days
was placed to limit the interventions studied (end points of interest)
to those most likely related to the results of the index noninvasive
study. The number of variables entered into the regression model
were limited to 1 per 10 events of interest to prevent overfitting of
the model.19 Global 2 for each final
model and the percent contribution of each covariate to the global
2 were determined.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Initial Patient Population
The 2113 patients included in this study are characterized in Table 2
. Patients who had events on follow-up had
greater pre-ETT likelihood of CAD, more frequent uninterpretable ECG,
and more commonly had cardiac risk factors when compared with patients
who had no events on follow-up. The presenting symptoms and
pre-ETT likelihood of CAD in our population are shown in Table
3. Of those patients with atypical and typical angina at
the time of presentation, virtually all had intermediate or
high pre-ETT likelihood of CAD. Almost half the patients with
nonanginal chest discomfort and the majority of patients with no
symptoms at the time of presentation had a low pre-ETT
likelihood of CAD. Of these 930 patients with low pre-ETT likelihood of
CAD, 320 had more than one cardiac risk factor, 171 had abnormal rest
ECGs, 378 were greater than 60 years of age, and 549 had a positive
ETT, as demonstrated by an increase in likelihood of CAD after
consideration of exercise variables, that is, post-ETT greater than
pre-ETT likelihood of CAD.
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Outcome Events
Among the 2113 patients included in this
study, 39 hard events
occurred. These included 13 cardiac deaths and 26 nonfatal myocardial
infarctions (1.8% hard event rate). In the overall uncensored
population of 2200 patients, 185 catheterizations and
87 revascularizations (44
percutaneous transluminal coronary
angioplasties, 43 coronary artery bypass grafts) occurred in
the first 60 days after nuclear testing. This represents an
early catheterization rate of 8.4% and an early
revascularization rate of 4.0%.
Univariate Analysis
Descriptive patient characteristics,
exercise, and nuclear
variables in patients with and without events on follow-up are
presented in Tables 2, 4, and 5.
In general, patients who had events had lowered exercise tolerance,
more frequent abnormal ECG responses during exercise, greater post-ETT
likelihood of CAD, and lower Duke treadmill scores. With respect to
nuclear variables, patients who had events had more severe,
extensive, and frequent scan abnormalities.
Survival Analysis
The results of the Cox analysis are shown
in Table 6. Significant increases in global
2 occurred both with the addition of the exercise
variables, yielding the clinical+ exercise model, as well as with
the addition of nuclear variables after forcing in the
clinical+exercise model. There was almost a twofold increase in
information content with the addition of exercise variables and a
fivefold gain in incremental information with the addition of nuclear
information (Table 6).
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Incremental Value: ROC Curve Analysis
The area under the ROC
curve for clinical variables
alone was 0.66±0.04. This area increased significantly with the
addition of exercise information (area for clinical+ exercise
variables=0.73±0.04; P=.03). Forcing in the
clinical
and exercise information and adding the nuclear variable
(clinical+exercise+nuclear model) resulted in a further significant
gain in area and, thus, information (area for final
model=0.87±0.03).
The log odds of the areas for these three models were 0.6, 1.0, and
1.9, suggesting a doubling of prognostic information with the addition
of information at each step.
Logistic Analysis of Predictors of
Intervention
The logistic model evaluating referral to
catheterization was powerful (overall
2=511), with 95% of the information provided by
the SDS and further small gains added by presenting symptoms. We
also developed similar logistic models that separately evaluated
predictors of early catheterization in patients with
normal scans and in patients with abnormal scans. The subgroup
analysis focusing on referral to early
catheterization after a normal scan revealed post-ETT
likelihood of CAD to be the best predictor of referral. This suggests
that in the setting of a low-risk scan, clinical and exercise
variables as well as uncertainty regarding the scan results
contributed to the referral to catheterization. In
patients with abnormal scans, the subgroup analysis revealed
the extent and severity of reversible defects present on the scan
(as measured by the SDS) to be the best predictor of referral to early
catheterization, with further information added by the
presence of anginal symptoms. Thus, the predominant information for the
referral to catheterization in the overall cohort, as
well as higher-risk patients (abnormal scans), was provided by the
results of nuclear testing. Only in those patients with low-risk
scans did clinical information play the major role in the referral. See
Table 7.
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Nuclear Threshold for Abnormality Versus Proportion of Hard
Events Detected
Fig 3 demonstrates the proportion of
hard events detected and the
proportion of the total patient population examined with abnormal scans
as a function of the SSS threshold defining a normal scan. The number
of hard events missed (hard events occurring in patients with normal
scans) would be similar at all SSS thresholds less than 5, suggesting
that no gain in patient benefit (increased detection of high-risk
patients) would be achieved by altering this threshold. Increases in
the value of SSS used as a threshold would, however, result in
decreases in the number of patients with abnormal scans and fewer
subsequent referrals to catheterization, at the expense
of increasing numbers of hard events not detected (decreased patient
benefit).
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Events and Subsequent Management Versus Extent and Severity
of Hypoperfusion
The frequency of hard events, early
catheterization, and
revascularization as a function of the scan result
is shown in Table 8. Patients with normal scans had an
exceedingly low hard event rate over the follow-up period (0.3%).
The hard event rate increased significantly with worsening scan
findings. Referral rates to early catheterization and
revascularization paralleled the hard event
rates in all scan categories– very low referral rates in patients with
normal scans and significant increases in referral rates as a function
of worsening scan results.
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The rate of referral to early catheterization was low in normal, probably normal, and equivocal scans but increased dramatically for abnormal and probably abnormal scans. On the other hand, the rate of referral to late catheterization also increased significantly but far less dramatically than for early catheterization. Thus, even though we only assessed early catheterization rates in our population, the vast majority of catheterizations are included in this analysis (>80% of all catheterization).
Events and Subsequent Management Versus Clinical and ETT Factors
and Scan Results
We compared the rate of hard events as a function of
scan result
and the Duke treadmill score,24 a widely used aggregate
prognostic index of exercise variables (Fig 2A). As
expected, a significant increase in hard event rate was noted with
increasing Duke treadmill score. Importantly, in the low and
intermediate Duke score groups, the patients were further stratified by
the scan result into very low risk groups for normal scans and an
increasing event rate in mild and severely abnormal scans. This finding
reveals the incremental clinical information yielded by nuclear
testing. Of interest, significant stratification was achieved in the
low-risk Duke group despite its low (0.9%) overall event rate.
From a clinical standpoint, however, the most pronounced stratification
occurred in the intermediate Duke score group that comprised 55% of
our population (1187 patients). The relatively high event rate in
patients with normal scans in the high-risk Duke score may be
attributable to the small patient size for that group (one event in 28
patients).
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Fig 2B demonstrates the catheterization rate
as a
function of the same classification. The rates of referral to
catheterization and
revascularization paralleled the hard event
rates as a function of the Duke score category and scan result. As
noted with hard events, patients with normal scans were very
infrequently referred to catheterization in all Duke
treadmill score categories. This referral rate increased significantly
as a function of scan result. Similar findings were noted in our cohort
when pre- or post-ETT likelihood of coronary disease was used
in place of the Duke treadmill score in this stratification
analysis (Tables 9 and 10).
Patients with normal scans had low event rates and low referral rates
to catheterization regardless of pre- and post-ETT
likelihood of CAD category. In patients with mildly and severely
abnormal scans, there were significant increases in hard event rates as
a function of worsening scan results but not as a function of pre- or
post-ETT likelihood of CAD. There were, however, significant increases
in referral rates to catheterization and
revascularization as a function of both scan result
and pre- and post-ETT likelihood of CAD.
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Although the results of the
nuclear scan risk-stratified patients
with both anginal and nonanginal presentations (Table 9),
there was a trend toward higher event rates in the patients with
anginal symptoms (P=NS). Interestingly, patients with
anginal presentations were referred to
catheterization twice as often as those patients
without symptoms in all scan categories (Table 9). This
difference was
also noted in the rates of revascularization (Table 10), as
patients with mildly and severely abnormal scans were referred
for revascularization more frequently when the
patient presented with anginal symptoms. Thus, while anginal
symptoms did not confer added risk, they did play a secondary role in
influencing patient management.
Events and Subsequent Management Versus Sex and Age
In both
men and women the hard event rate increased significantly
as a function of SSS (Table 9). Importantly, this increase was
more
dramatic in the women compared with the men, resulting in significantly
greater hard event rates in the women with severely abnormal scans when
compared with the men (P<.01). Interestingly, the rate of
referral to catheterization and
revascularization (Table 10) was virtually
identical in men and women–very low referral rates in normal
scans, significantly greater rates increasing as a function of SSS.
Thus, while no sex-related referral bias was present, relative
undercatheterization was present in women
relative to their risk in the setting of a severely abnormal scan.
With
respect to patient age, there were similar increases in event
rates as a function of the results of nuclear scan, with no differences
between three age groups within scan categories (Table 9).
Similarly,
the rate of referral to catheterization and
revascularization paralleled the scan
findings, with no differences between age groups (Table 9).
Thus, the
age-related effect in this study was that of increasing prevalence
of abnormal scans rather than a change in risk associated with a
particular scan result.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The intent of the current study was twofold: to determine the incremental prognostic value of exercise sestamibi myocardial perfusion SPECT in a population of patients without known CAD and to evaluate the impact on patient management of this test as measured by the rates of referral to catheterization and revascularization early (within 60 days) after nuclear testing. Regarding prognosis, we found that even after the most predictive clinical and exercise variables were forced into the Cox model, the addition of nuclear information provided statistical incremental prognostic value-more than a fivefold increase in prognostic information. The ROC curve also demonstrated a similar incremental value for nuclear variables over clinical and exercise variables. Further, the results of the nuclear scan significantly stratified the patient population examined; those patients with normal scans had a very low event rate (<1%), and those with abnormal scans had increasing event rates with worsening scan result. Even after stratification by clinical and exercise characteristics, such as Duke treadmill score, pre- and post-ETT likelihood of CAD, presenting symptoms, sex, and age, the nuclear scan results further stratified the patient subgroups.
With respect to patient management, referral rates to catheterization and revascularization paralleled patient risk as a function of nuclear variables both in the overall cohort as well as after patient subgrouping by clinical and exercise variables as described above. These results indicate that physicians appropriately used the nuclear scan results-the best predictors of outcome-in referring patients to subsequent intervention. Clinical characteristics, such as anginal symptoms and pre- and post-ETT likelihood of CAD, also appropriately modified referral patterns. Thus, it would appear that in patients without previously known CAD, sestamibi myocardial perfusion SPECT both adds incremental prognostic value to clinical and exercise variables and is used in an appropriate manner by referring physicians.
Comparison to Previous Studies
A number of previous studies
have evaluated the prognostic
implications of exercise thallium myocardial perfusion
scintigraphy in patients with suspected
CAD.2 3 4 5 10 11
The work of Staniloff et al10
in a purely diagnostic population, one of the earliest
studies on prognostic value of thallium imaging, revealed the potential
prognostic power of thallium imaging but did not assess it in an
incremental fashion. The findings of the current study agree with those
of the previous work by Ladenheim et al2 from our
laboratory, which was the first to assess the incremental prognostic
value of nuclear testing. A greater increment in information from the
nuclear test was shown in the present study compared with the
Ladenheim study. This may be due to differences in the patient
population used (the Ladenheim study included patients with previous
catheterization), SPECT versus planar imaging, or
sestamibi versus thallium as the isotope utilized. Three important
studies were reported from Kaul and
colleagues3 4 5 at the
University of Virginia in patients with "suspected CAD"; however,
all three of these studies included patients with known prior
myocardial infarction (43% of the combined
populations3 4 ). The low event rates in the normal
scan
group confirms the observations from previous
studies.7 8 25 26
Nuclear Scan Low-Risk Threshold
As shown in Fig
3, the threshold we have previously
used to define normal scans is appropriate for prognostic purposes. The
proportion of hard events missed using this threshold is not affected
by shifting to a lower SSS value, and more hard events would have been
missed using a higher SSS threshold.
Risk Stratification by Nuclear Testing
Our study goals were
to evaluate nuclear testing in patients in
whom the coronary anatomy was not known and,
importantly, to determine the prognostic value and stratification
utility of nuclear testing prior to referral to
catheterization. The results of our study could be used
to guide the decision process after nuclear testing with respect to
whether to refer to intervention. Our results indicate that the
majority of diagnostic patients referred to our laboratory,
the 1624 patients with normal scans (76% of cohort, 0.4% event rate),
can be safely managed without need for intervention. It can be further
argued that many of these patients did not need nuclear testing and
could have been risk-stratified by clinical and exercise
variables alone. Thus, the 1068 patients with low post-ETT
likelihood of CAD or the 926 patients with low-risk Duke treadmill
score could have been managed without nuclear testing (Fig 2A
and Table 8). The exclusion of these patients, however, does
not alter the
successful stratification of the remaining patients by nuclear scan
results.
The ability of the nuclear scan to further risk-stratify patients after initial clinical stratification is key to understanding its potential clinical role. Although the scan results stratified patients in the low-risk Duke treadmill score group, the cost-effectiveness of this stratification is doubtful, since few high-risk patients would be identified by the scan. On the other hand, nuclear testing in intermediate-risk Duke groups would result in considerable potential savings, since the overall group risk is intermediate, yet more than two thirds of these patients had normal scans, thus not requiring any further evaluation (such as catheterization). Importantly, this group comprised 55% of our study population. This noninvasive approach may also work well even in patients with high-risk Duke scores, but this approach will require further study in larger populations.
Impact of Nuclear Testing on Patient Management
An important
result of the current study is the striking parallel
between event rates and referral to catheterization
after nuclear testing. Patients with normal and equivocal scans had
uniformly low referral rates to catheterization. The
results of this study suggest that referral to
catheterization was based on appropriate criteria and
occurred at an acceptable rate relative to risk or symptoms in patients
with both normal and abnormal scans. These results are similar to those
found in a general population referred to nuclear
testing.27
Limitations
Technical
The scintigraphic studies
used in the current work were assessed
by experienced observers using a standardized, semiquantitative
approach to visual interpretation that we have developed14
and have documented to be highly reproducible.13
Consequently, the reliance on the expertise of the observer limits the
extrapolation of our results to those of other centers. Objective
quantitative methods for analysis of technetium-99m
myocardial perfusion SPECT studies have been developed28
that correlate highly with both visual scan assessment and
coronary angiography.29 At the time of collection
of the SPECT studies in this patient population, we did not have a
quantitative analysis technique in operation on all of our
camera/computer systems. The visual interpretation methods that were
used form the basis for the quantitative analysis programs
developed by Cedars-Sinai Medical Center and Emory
University.28 Therefore, the results of semiquantitative
analysis in this study should correlate strongly with those of
quantitative analysis. Further prognostic studies using
quantitative analysis would be of interest. Finally, since our
patient population had infrequent fixed defects, the preponderance of
the information was derived from the stress scan performed with
sestamibi. We believe that the results of this study are applicable to
any of the high-dose stress sestamibi study
protocols.30
Statistical and Clinical
The patients in this study are those referred to a
university-affiliated community hospital in a major urban area, and
the results of this study should be applicable to this setting. With
respect to the statistical analysis, the use of
multivariate models is limited by the number of events
accumulated during the follow-up period. We limited the number of
variables entered into these models to 1 per 10 outcome events to
prevent overfitting of the model and thus enhance its
accuracy.19 The low loss to follow-up rate, the large
patient group used, and the adequate number of events favor the
likelihood that our multivariate results are
accurate.19 Since we were limited to using four
variables in the Cox proportional hazards analysis, we
chose to use previously derived and validated aggregate variables
(likelihood of CAD and Duke treadmill score) rather than to derive
models consisting of variables specific to our data set. The
disadvantage to this approach was that the nonnuclear models were not
optimized for our population while the nuclear model was (since no
accepted nuclear aggregate variable is accepted). We also performed
an analysis using models specific to our population and found
similar results; thus, the use of optimized nuclear variables and
generalized nonnuclear variables did not significantly alter our
results.
Conclusions
The results of this study reveal that exercise
sestamibi
myocardial perfusion SPECT adds incremental prognostic information when
used in patients who have not undergone previous
catheterization or
revascularization and have not had previous
myocardial infarction and who are at overall low-intermediate risk
(1.8% hard event rate, 1.2% per year of follow-up). Further,
physicians referred patients to catheterization and
revascularization in proportion to the extent and
severity of their scan results and, thus, to their risk of cardiac
events. In light of this, the effect of testing on patient management
appears to be both powerful and appropriate.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by a grant from Dupont-Pharma.
Received August 21, 1995; revision received September 28, 1995; accepted October 4, 1995.
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References |
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R. Hachamovitch, S. W. Hayes, J. D. Friedman, I. Cohen, X. Kang, G. Germano, and D. S. Berman Is there a referral bias againstcatheterization of patients withreduced left ventricular ejection fraction?: Influence of ejection fraction and inducible ischemia onpost-single-photon emission computed tomographymanagement of patients without a history of coronary artery disease J. Am. Coll. Cardiol., October 1, 2003; 42(7): 1286 - 1294. [Abstract] [Full Text] [PDF]
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Committee Members, F. J. Klocke, M. G. Baird, B. H. Lorell, T. M. Bateman, J. V. Messer, D. S. Berman, P. T. O'Gara, B. A. Carabello, R. O. Russell Jr, et al. ACC/AHA/ASNC Guidelines for the Clinical Use of Cardiac Radionuclide Imaging--Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASNC Committee to Revise the 1995 Guidelines for the Clinical Use of Cardiac Radionuclide Imaging) J. Am. Coll. Cardiol., October 1, 2003; 42(7): 1318 - 1333. [Full Text] [PDF]
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S. W. Hayes, A. De Lorenzo, R. Hachamovitch, S. C. Dhar, P. Hsu, I. Cohen, J. D. Friedman, X. Kang, and D. S. Berman Prognostic Implications of Combined Prone and Supine Acquisitions in Patients with Equivocal or Abnormal Supine Myocardial Perfusion SPECT J. Nucl. Med., October 1, 2003; 44(10): 1633 - 1640. [Abstract] [Full Text] [PDF]
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F. J. Klocke, M. G. Baird, B. H. Lorell, T. M. Bateman, J. V. Messer, D. S. Berman, P. T. O'Gara, B. A. Carabello, R. O. Russell Jr, M. D. Cerqueira, et al. ACC/AHA/ASNC Guidelines for the Clinical Use of Cardiac Radionuclide Imaging--Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASNC Committee to Revise the 1995 Guidelines for the Clinical Use of Cardiac Radionuclide Imaging) Circulation, September 16, 2003; 108(11): 1404 - 1418. [Full Text] [PDF]
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A. P. Morise and F. Jalisi Evaluation of pretest and exercise test scores to assess all-cause mortality in unselected patients presenting for exercise testing with symptoms of suspected coronary artery disease J. Am. Coll. Cardiol., September 3, 2003; 42(5): 842 - 850. [Abstract] [Full Text] [PDF]
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R. G. Schwartz, T. A. Pearson, V. G. Kalaria, M. L. Mackin, D. J. Williford, A. Awasthi, A. Shah, A. Rains, and J. J. Guido Prospective serial evaluation of myocardial perfusion and lipids during the first six months of pravastatin therapy: Coronary artery disease regression single photon emission computed tomography monitoring trial J. Am. Coll. Cardiol., August 20, 2003; 42(4): 600 - 610. [Abstract] [Full Text] [PDF]
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M. J. Zellweger, M. Weinbacher, A. W. Zutter, R. V. Jeger, J. Mueller-Brand, C. Kaiser, P. T. Buser, and M. E. Pfisterer Long-term outcome of patients with silent versus symptomatic ischemia six months after percutaneous coronary intervention and stenting J. Am. Coll. Cardiol., July 2, 2003; 42(1): 33 - 40. [Abstract] [Full Text] [PDF]
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L. Spinelli, M. Petretta, W. Acampa, W. He, A. Petretta, D. Bonaduce, and A. Cuocolo Prognostic Value of Combined Assessment of Regional Left Ventricular Function and Myocardial Perfusion by Dobutamine and Rest Gated SPECT in Patients with Uncomplicated Acute Myocardial Infarction J. Nucl. Med., July 1, 2003; 44(7): 1023 - 1029. [Abstract] [Full Text] [PDF]
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R. Hachamovitch, S. W. Hayes, J. D. Friedman, I. Cohen, and D. S. Berman 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, June 17, 2003; 107(23): 2900 - 2907. [Abstract] [Full Text] [PDF]
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R. C. Pasternak, J. Abrams, P. Greenland, L. A. Smaha, P. W. F. Wilson, and N. Houston-Miller Task force #1--identification of coronary heart disease risk: is there a detection gap? J. Am. Coll. Cardiol., June 4, 2003; 41(11): 1863 - 1874. [Full Text] [PDF]
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T.H. Marwick, L. Shaw, C. Case, C. Vasey, and J.D. Thomas Clinical and economic impact of exercise electrocardiography and exercise echocardiography in clinical practice Eur. Heart J., June 2, 2003; 24(12): 1153 - 1163. [Abstract] [Full Text] [PDF]
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 D V. Anand, D. Lipkin, and A. Lahiri Finding the age of the patient's heart BMJ, May 15, 2003; 326(7398): 1045 - 1046. [Full Text] [PDF]
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R. Hachamovitch, S. Hayes, J. D. Friedman, I. Cohen, L. J. Shaw, G. Germano, and D. S. Berman Determinants of risk and its temporal variation in patients with normal stress myocardial perfusion scans: What is the warranty period of a normal scan? J. Am. Coll. Cardiol., April 16, 2003; 41(8): 1329 - 1340. [Abstract] [Full Text] [PDF]
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L. J. Shaw, R. Hendel, S. Borges-Neto, M. S. Lauer, N. Alazraki, J. Burnette, E. Krawczynska, M. Cerqueira, and J. Maddahi Prognostic Value of Normal Exercise and Adenosine 99mTc-Tetrofosmin SPECT Imaging: Results from the Multicenter Registry of 4,728 Patients J. Nucl. Med., February 1, 2003; 44(2): 134 - 139. [Abstract] [Full Text] [PDF]
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Committee Members, R. J. Gibbons, G. J. Balady, J. Timothy Bricker, B. R. Chaitman, G. F. Fletcher, V. F. Froelicher, D. B. Mark, B. D. McCallister, A. N. Mooss, et al. ACC/AHA 2002 guideline update for exercise testing: summary article: A report of the American college of cardiology/American heart association task force on practice guidelines (committee to update the 1997 exercise testing guidelines) J. Am. Coll. Cardiol., October 16, 2002; 40(8): 1531 - 1540. [Full Text] [PDF]
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R. J. Gibbons, G. J. Balady, J. Timothy Bricker, B. R. Chaitman, G. F. Fletcher, V. F. Froelicher, D. B. Mark, B. D. McCallister, A. N. Mooss, M. G. O'Reilly, et al. ACC/AHA 2002 Guideline Update for Exercise Testing: Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines) Circulation, October 1, 2002; 106(14): 1883 - 1892. [Full Text] [PDF]
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 A. F.L. Schinkel, A. Elhendy, R. T. van Domburg, J. J. Bax, E. C. Vourvouri, F. B. Sozzi, R. Valkema, J. R.T.C. Roelandt, and D. Poldermans Prognostic Value of Dobutamine-Atropine Stress Myocardial Perfusion Imaging in Patients With Diabetes Diabetes Care, September 1, 2002; 25(9): 1637 - 1643. [Abstract] [Full Text] [PDF]
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A. F.L. Schinkel, A. Elhendy, R. T. van Domburg, J. J. Bax, J. R.T.C. Roelandt, and D. Poldermans Prognostic Value of Dobutamine-Atropine Stress 99mTc-Tetrofosmin Myocardial Perfusion SPECT in Patients with Known or Suspected Coronary Artery Disease J. Nucl. Med., June 1, 2002; 43(6): 767 - 772. [Abstract] [Full Text] [PDF]
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K.-T. Ho, T. D. Miller, D. O. Hodge, K. R. Bailey, and R. J. Gibbons Use of a Simple Clinical Score to Predict Prognosis of Patients With Normal or Mildly Abnormal Resting Electrocardiographic Findings Undergoing Evaluation for Coronary Artery Disease Mayo Clin. Proc., June 1, 2002; 77(6): 515 - 521. [Abstract] [PDF]
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 T. H. Marwick, C. Case, S. Sawada, C. Vasey, and J. D. Thomas Prediction of Outcomes in Hypertensive Patients With Suspected Coronary Disease Hypertension, June 1, 2002; 39(6): 1113 - 1118. [Abstract] [Full Text] [PDF]
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M. S. Lauer The "exercise" part of exercise echocardiography J. Am. Coll. Cardiol., April 17, 2002; 39(8): 1353 - 1355. [Full Text] [PDF]
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L. Emmett, R. M. Iwanochko, M. R. Freeman, A. Barolet, D. S. Lee, and M. Husain Reversible regional wall motion abnormalities on exercise technetium-99m-gated cardiac single photon emission computed tomography predict high-grade angiographic stenoses J. Am. Coll. Cardiol., March 20, 2002; 39(6): 991 - 998. [Abstract] [Full Text] [PDF]
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P. B. Gibson, D. Demus, R. Noto, W. Hudson, and L. L. Johnson Low event rate for stress-only perfusion imaging in patients evaluated for chest pain J. Am. Coll. Cardiol., March 20, 2002; 39(6): 999 - 1004. [Abstract] [Full Text] [PDF]
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D. D. Miller Coronary flow studies for risk stratification in multivessel disease: A physiologic bridge too far? J. Am. Coll. Cardiol., March 6, 2002; 39(5): 859 - 863. [Full Text] [PDF]
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O. Blagosklonov, A. Sabbah, J. Verdenet, M. Baud, and J.-C. Cardot Poststress Motionlike Artifacts Caused by the Use of a Dual-Head Gamma Camera for 201Tl Myocardial SPECT J. Nucl. Med., March 1, 2002; 43(3): 285 - 291. [Abstract] [Full Text] [PDF]
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 P. G. Danias and J. A. Parker Novel Internet-based Tool for Correcting Apparent Sensitivity and Specificity of Diagnostic Tests to Adjust for Referral (Verification) Bias RadioGraphics, March 1, 2002; 22(2): e4 - e4. [Abstract] [Full Text]
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H. Yamagishi, N. Shirai, M. Yoshiyama, M. Teragaki, K. Akioka, K. Takeuchi, J. Yoshikawa, and H. Ochi Incremental Value of Left Ventricular Ejection Fraction for Detection of Multivessel Coronary Artery Disease in Exercise 201Tl Gated Myocardial Perfusion Imaging J. Nucl. Med., February 1, 2002; 43(2): 131 - 139. [Abstract] [Full Text] [PDF]
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R. Wayhs, A. Zelinger, and P. Raggi High coronary artery calcium scores pose an extremely elevated risk for hard events J. Am. Coll. Cardiol., January 16, 2002; 39(2): 225 - 230. [Abstract] [Full Text] [PDF]
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J. T. Kuvin, A. R. Patel, K. A. Sliney, N. G. Pandian, W. M. Rand, J. E. Udelson, and R. H. Karas Peripheral vascular endothelial function testing as a noninvasive indicator of coronary artery disease J. Am. Coll. Cardiol., December 1, 2001; 38(7): 1843 - 1849. [Abstract] [Full Text] [PDF]
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S. V. Williams, S. D. Fihn, and R. J. Gibbons Guidelines for the Management of Patients with Chronic Stable Angina: Diagnosis and Risk Stratification Ann Intern Med, October 2, 2001; 135(7): 530 - 547. [Abstract] [Full Text] [PDF]
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T. D. Miller, V. L. Roger, D. O. Hodge, M. R. Hopfenspirger, K. R. Bailey, and R. J. Gibbons Gender differences and temporal trends in clinical characteristics, stress test results and use of invasive procedures in patients undergoing evaluation for coronary artery disease J. Am. Coll. Cardiol., September 1, 2001; 38(3): 690 - 697. [Abstract] [Full Text] [PDF]
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L. J. Shaw, A. E. Iskandrian, R. Hachamovitch, G. Germano, H. C. Lewin, T. M. Bateman, and D. S. Berman Evidence-Based Risk Assessment in Noninvasive Imaging J. Nucl. Med., September 1, 2001; 42(9): 1424 - 1436. [Abstract] [Full Text] [PDF]
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 K.C. Allman and L.E.J. Thomson Prognostic value of myocardial perfusion imaging in patients with known or suspected coronary artery disease Eur. Heart J. Suppl., September 1, 2001; 3(suppl_F): F5 - F7. [Abstract] [PDF]
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T. H. Lee and C. A. Boucher Noninvasive Tests in Patients with Stable Coronary Artery Disease N. Engl. J. Med., June 14, 2001; 344(24): 1840 - 1845. [Full Text] [PDF]
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T. Sharir, G. Germano, X. Kang, H. C. Lewin, R. Miranda, I. Cohen, R. D. Agafitei, J. D. Friedman, and D. S. Berman Prediction of Myocardial Infarction Versus Cardiac Death by Gated Myocardial Perfusion SPECT: Risk Stratification by the Amount of Stress-Induced Ischemia and the Poststress Ejection Fraction J. Nucl. Med., June 1, 2001; 42(6): 831 - 837. [Abstract] [Full Text] [PDF]
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S. T. Mast, L. K. Shaw, G. C. Ravizzini, M. Chambless, P. Joski, R. E. Coleman, and S. Borges-Neto Incremental Prognostic Value of RNA Ejection Fraction Measurements During Pharmacologic Stress Testing: A Comparison with Clinical and Perfusion Variables J. Nucl. Med., June 1, 2001; 42(6): 871 - 877. [Abstract] [Full Text] [PDF]
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B Haluska, C Case, L Short, J Anderson, and T H Marwick Effect of power Doppler and digital subtraction techniques on the comparison of myocardial contrast echocardiography with SPECT Heart, May 1, 2001; 85(5): 549 - 555. [Abstract] [Full Text]
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T. H. Marwick, C. Case, S. Sawada, C. Rimmerman, P. Brenneman, R. Kovacs, L. Short, and M. Lauer Prediction of mortality using dobutamine echocardiography J. Am. Coll. Cardiol., March 1, 2001; 37(3): 754 - 760. [Abstract] [Full Text] [PDF]
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 M. E. Tavel Stress Testing in Cardiac Evaluation : Current Concepts With Emphasis on the ECG Chest, March 1, 2001; 119(3): 907 - 925. [Full Text] [PDF]
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 S. Yoder, R. G. Schwartz, and M. S. Lauer Abnormal Heart Rate Recovery and Risk of Death JAMA, February 21, 2001; 285(7): 879 - 880. [Full Text] [PDF]
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D.R. Holdright The role of pharmacological stress echo for evaluating chest pain in women Eur. Heart J., January 2, 2001; 22(2): 107 - 109. [PDF]
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M. J. Zellweger, H. C. Lewin, S. Lai, E. A. Dubois, J. D. Friedman, G. Germano, X. Kang, T. Sharir, and D. S. Berman When to stress patients after coronary artery bypass surgery?: Risk stratification in patients early and late post-CABG using stress myocardial perfusion SPECT: implications of apppropriate clinical strategies J. Am. Coll. Cardiol., January 1, 2001; 37(1): 144 - 152. [Abstract] [Full Text] [PDF]
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E. Verna, L. Ceriani, L. Giovanella, G. Binaghi, and S. Garancini "False-Positive" Myocardial Perfusion Scintigraphy Findings in Patients with Angiographically Normal Coronary Arteries: Insights from Intravascular Sonography Studies J. Nucl. Med., December 1, 2000; 41(12): 1935 - 1940. [Abstract] [Full Text] [PDF]
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