Kwon et.al

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Background
With the advent of effective medical therapy and sophisticated
percutaneous and surgical coronary revascularization
techniques, life expectancy of patients with coronary artery
disease (CAD) has dramatically improved (1). Consequently,
more Medicare patients are being referred for ECG gated
single photon emission computed tomography myocardial
perfusion imaging (MPI) studies using exercise (eMPI) and
pharmacologic (pMPI) stress to evaluate the presence and
extent of underlying atherosclerotic CAD.
In the United States, the proportion of the population
over the age of 65 years is projected to increase from 12.4%
in 2000 to 19.6% in 2030 (2). Although the elderly represent
only 13% of the population, they consume approximately
36% of health care expenditures (3). Despite being major
consumers of the health care dollar, the Medicare population
has been under-represented in clinical trials assessing the
utility of interventional and diagnostic strategies (4).
In this age of increasing Medicare costs, the role of
non-invasive stress testing remains poorly defined in
the elderly. A previous study demonstrated that exercise
stress testing provides different prognostic information in
Original Article
Predictive value of exercise myocardial perfusion imaging in the
Medicare population: the impact of the ability to exercise
Deborah H. Kwon, Venu Menon, Penny Houghtaling, Elizabeth Lieber, Richard C. Brunken, Manuel D.
Cerqueira, Wael A. Jaber
Cleveland Clinic, Department of Cardiovascular Medicine, Cleveland, OH 44195, USA
Corresponding to: Deborah H. Kwon, MD. Cleveland Clinic, Department of Cardiovascular Medicine, 9500 Euclid Avenue, J1-5, Cleveland, OH
44195, USA. Email: kwond@ccf.org.
Background: Although the prognostic value of quantitative single photon emission computed tomography
myocardial perfusion imaging (MPI) with exercise and pharmacologic stress is well established, the
prognostic and management value in the Medicare age population is less clear.
Methods: The prospectively populated Cleveland Clinic nuclear cardiology database was used to identify
5,994 consecutive pateints, age >65 years [1,664 (28%) exercise MPI, mean age 72.4±5.1, 74% male], who
underwent MPI between January 2004 and January 2008. Clinical baseline variables, post test 90 days
revascularization and MPI variables were analyzed. Overall and stratified nonparametric survival estimates
were obtained by Kaplan-Meier method. Median follow-up time was 2.4 years. Parametric hazard modeling
with bootstrap bagging methods was used to determine prognostic variables predicting mortality.
Results: There was no difference in mortality in patients with an abnormal MPI vs. those with normal MPI.
Amongst the patients who underwent exercise MPI, there were 103 (6%) deaths and 121 (8.2%) revascularizations.
Only lower exercise capacity (<7 METs) and higher end systolic volume (ESV) predicted mortality. Although
a larger amount of ischemia influenced down stream revascularization ischemia, revascularization of patients
with an abnormal exercise MPI did not offer a survival benefit (log rank P value=0.01).
Conclusions: In the a Medicare age population, exercise MPI perfusion variables influenced rates of
revascularization but failed to provide incremental significant risk-stratification beyond exercise capacity.
Maximum METs achieved appears to be a better predictor of survival.
Keywords: Cardiovascular outcomes; exercise testing; prognosis; single-photon emission computed tomography;
revascularization
Submitted Nov 22, 2013. Accepted for publication Feb 15, 2014.
doi: 10.3978/j.issn.2223-3652.2014.02.09
Scan to your mobile device or view this article at: http://www.thecdt.org/article/view/3365/4203

6 Kwon et al. Prognostic value of MPI in the Medicare population
middle aged vs. elderly men over the age of 75 years (5),
and elderly patients are often unable to exercise or have
contraindications to exercise stress testing (6-8). Several
recent studies have combined both eMPI and pMPI test
types in their outcomes evaluation in elderly patients (9-17);
However, end systolic volume (ESV), stress ejection fraction
(EF), functional capacity, and the impact of downstream
revascularization were not consistently measured and
analyzed. Therefore, it is unknown how functional capacity,
EF, ESV, and the presence of ischemia interact to predict
risk in elderly patients. We sought to determine the value of
exercise MPI and clinical variables in predicting mortality
in a large, diverse elderly patient population who underwent
gated eMPI. Furthermore, we sought to assess the rate of
downstream revascularization and outcomes in this large
cohort.
Methods
Our institution’s IRB approved nuclear cardiology database
prospectively records variables on all patients referred for
MPI. A 17-segment model is used to semiquantitatively
score rest and stress perfusion, EF, wall motion score and
the subjective presence of left and right ventricular (RV)
dilation are recorded (18).
A retrospective analysis of this database was performed
to identify all patients who underwent adenosine
pharmacological and exercise gated MPI between October
2004 and January 2008. The choice of MPI testing was
made by the referring physician.
Clinical variables [age, gender, smoking history, diabetes,
insulin use, hypertension, and history of coronary artery
bypass grafting (CABG)], nuclear variables [stress EF,
summed difference score (SDS), summed rest score (SRS),
stress ESV, RV dilation, and the overall physician’s result of
the test (abnormal, equivocal, or normal)] were recorded.
All revascularization procedures [percutaneous intervention
(PCI) or CABG] found within 90 days of the index MPI
study were analyzed.
Gated MPI stress protocol
Patients undergoing eMPI were subjected to an appropriate
exercise protocol guided by the individual patient’s
functional capacity. Heart rate, blood pressure, and ECG
were continuously monitored throughout both study types.
All protocols, acquisition, processing, and display were
performed in accordance with the Imaging Guidelines of
the American Society of Nuclear Cardiology (19).
Stress and rest perfusion images were semi-quantitatively
scored using a 17-segment model of the left ventricle using
4DMMPI software (Invia, Ann Arbor, Michigan) (18).
Global summed stress score (SSS) and SRS were calculated
by adding the scores of the 17 segments in the stress and
resting images, respectively. Each segment was scored by an
experienced physician certified by the Certification Board
of Nuclear Cardiology or the American Board of Nuclear
Medicine using a 5-point scoring system (0, normal; 1,
equivocal; 2, moderate reduction of isotope uptake; 3,
severe reduction of uptake; and 4, absence of detectable
tracer uptake in a segment). On the basis of the number and
severity of segments with scores >2, the observers judged
the study results as normal, abnormal, or equivocal/non-
diagnostic (20). Studies were deemed non-diagnostic due
to poor study quality despite re-scanning and/or multiple
reiterations due to severe attenuation artifacts, poor count
statistics, significant adjacent gastro-intestinal activity, or
motion artifacts causing image degradation.
Statistical analysis
The primary end-point was all-cause mortality (21).
Continuous data are expressed as means ± standard deviation.
Wilcoxon rank sum tests were used to analyze group
differences for the continuous data. Categorical data are
displayed as frequencies and percentages, and comparisons are
made using Chi-square tests (Fisher exact tests if appropriate).
Results were analyzed in three groups (normal, abnormal and
equivocal). Transformations of the continuous measures (i.e.,
logarithmic, inverse, exponential) were assessed for proper
calibration of risk factors with respect to outcome.
Overall and stratified nonparametric survival estimates were
obtained by the Kaplan-Meier method. A parametric method
was used to resolve the number of phases of instantaneous
risk for death (hazard function) and to estimate the shaping
parameters. Due to the quite constant phase of events
following MPI, final multivariable models were created and
presented using Cox proportional hazard models. In the
mortality analyses, interactions of ESV with gender, age, and
test result were all tested to assess any subgroup differences.
Bootstrap bagging with automated re-sampling and
stepwise selection was used to determine reliable risk
factors of mortality (22). Factors occurring in 50% or
more of the bootstrap models were retained to form a
final multivariable risk factor model. All variables were
considered for the initial mortality analysis using 200

7Cardiovascular Diagnosis and Therapy, Vol 4, No 1 February 2014
bootstrap runs. Mean imputation was used for missing data
values. A second bootstrap analysis was done (200 additional
runs) after excluding the individual segment scores to
avoid confounding and focus on the summary scores for
prediction. Statistical analyses were performed using SAS®
version 9.1.
Follow-up
The average follow-up was 2.4±0.9 years (median 2.4 years).
We searched the Social Security Death Index to identify
deaths that occurred after the index MPI study during
follow-up. All-cause mortality has been shown to be a more
objective and unbiased endpoint than “cardiac mortality” (21).
Furthermore, competing non-cardiovascular mortality risk in
this elderly population is important. We also looked at 90-day
percutaneous or surgical revascularization for the whole group.
Results
The clinical and MPI findings and characteristics for the
overall study population are listed in Tables 1 and 2. There
were 1,644 patients in our study population that underwent
eMPI (74% male and a mean age of 72.4±5.1 years).
Amongst the patients that underwent exercise MPI, there
were 103 deaths during the follow-up time (See Table 1).
There were 573 (34%) total abnormal exercise MPI
studies, and 48 (3%) equivocal studies. Subsequent
revascularization was performed on 121/573 (21%) patients
with abnormal exercise MPI and 15/1,043 (1%) in the
normal exercise MPI group within 90 days (Figure 1).
The rates of revascularization based on reported SSS
and SDS is summarized in Tables 3 and 4. It is clear that
the size of the perfusion defect as assessed by SDS and SSS
influenced down stream revascularization.
There was no difference in mortality in patients with
abnormal MPI vs. those with normal perfusion studies
(Figure 2). The standard MPI variables, except for ESV,
failed to risk-stratify elderly patients who were able to
exercise. The maximum METs ranged from 2.4 to 14.5
(25% of the patients achieved <6.3 METs, and 25%
achieved >8.7 METs), with a mean of 7.4±1.8 METs in this
population.
The maximum METs achieved was the most powerful
predictor of death amongst patients who were able to
exercise. Patients who were able to exercise ≤7 METs
(n=758) had significantly worse survival compared those
who were able to exercise >7 METs (n=906) (log-rank
Table 1 Baseline demographics
Patient characteristics Total population, N=5,944 pMPI, N=4,280 eMPI, N=1,664 P-value
Age, year 74.5±5.95 75.3±6.08 72.4±5.06 <0.0001
Male 3,560 (60%) 2,330 (54%) 1,230 (74%) <0.0001
BMI 28.7±8.32 29±8.4 27.9±8.07 <0.0001
Death on follow-up 701 (12%) 629 (15%) 72 (4%) <0.0001
Non-insulin dependent DM 1,196 (20%) 949 (22%) 247 (15%) <0.0001
Insulin dependent DM 500 (8.4%) 442 (10%) 58 (3.5%) <0.0001
Hypertension 5,027 (90%) 3,727 (87%) 1,300 (78%) <0.0001
Known CAD 3,034 (51%) 2,097 (49%) 937 (56%) <0.0001
History of_CABG 1,680 (28%) 1,189 (28%) 491 (30%) 0.22
History of_PCI 1,769 (30%) 1,162 (27%) 607 (36%) <0.0001
Betablocker use 3,569 (60%) 2,710 (64%) 859 (52%) <0.0001
Ace-inhibitor use 2,381 (40%) 1,749 (41%) 632 (38%) 0.03
Statin use 3,752 (63%) 2,614 (61%) 1,138 (68%) <0.0001
Current tobacco use 372 (6.3%) 301 (7.1%) 71 (4.3%) <0.0001
Resting systolic blood pressure 139.67±20.35 138±19 140±20 0.005
Resting diastolic blood pressure 81.13±15.25 82±11 81±15 0.54
pMPI, pharmacologic myocardial perfusion imaging; eMPI, exercise myocardial perfusion imaging; CAD, coronary artery disease;
CABG, coronary artery bypass grafting; PCI, percutaneous intervention.

P<0.0001) (Figure 2). Patients with abnormal scans who
underwent subsequent revascularization had worse survival
compared to those who had abnormal scans but were not
revascularized at 2.4 years of follow-up (Figure 3; log rank
P-value =0.01). The independent predictors of survival
for patients undergoing MPI are listed in Table 5. A high
ESV, male gender, diabetes, and older age were also
independently associated with worse survival. No other
nuclear variables were independent predictors of mortality.
Table 6 lists the MPI variables in Cox proportional hazard
model for death, which were not significantly associated
with mortality in our study.
Discussion
In this study, we evaluated the prognostic value of clinical
and MPI variables in elderly patients undergoing MPI as well
as the rates and outcomes of subsequent revascularization.
Our study is the a large observational study in the modern
era of medical therapy that shows that elderly patients (mean
age 75) who are able to exercise have excellent prognosis,
despite an abnormal MPI test result. The only MPI variable
that predicted mortality in this group was a higher ESV.
Furthermore, patients who achieved greater than seven
METs had significantly improved outcomes compared to
those who achieved ≤7 METs. However, the overall MPI
test result when dichotomized into normal vs. abnormal did
not provide any further risk stratification in those with less
functional capacity.
Our study also demonstrated that as expected when
patients have a larger perfusion defect, a higher rate of
revascularization was seen. For instance patients with limited
Table 2 Nuclear MPI variables
Nuclear variables Total population, N=5,944 pMPI, N=4,280 eMPI, N=1,664 P-value
Abnormal stress test 2,294 (39%) 1,721 (40%) 573 (34%) <0.0001
Equivocal stress test 192 (3.2%) 144 (3.4%) 48 (2.9%) 0.32
Normal stress test 3,458 (58%) 2,415 (56%) 901 (54%) 0.22
Stress ESV 35.1±33.5 37.6±36 28.7±25.1 <0.0001
SRS 2.68±5.72 2.84±5.91 2.26±5.17 0.0001
SSS 4.8±7.3 5.02±7.4 4.24±7 <0.0001
Stress EF 62.8±14.2 61.4±14.6 66.5±12.3 <0.0001
Stress EDV 79.8±43.2 81.9±45.4 74.4±36.6 <0.0001
SDS 2.12±4.37 2.18±4.37 1.98±4.34 0.0042
pMPI, pharmacologic myocardial perfusion imaging; eMPI, exercise myocardial perfusion imaging; EF, ejection fraction; ESV, end-
systolic volume; SDS, summed difference score; SRS, summed rest score; SSS, summed stress score.
Figure 1 Flow chart of patients based on type of myocardial
perfusion imaging (MPI), test result, and revascularization.
Table 3 Revascularization rates stratified by summed stress score
Total # abnormal
MPI N=573
Rate of 90 day
revascularization [%]
SSS =0-2 39 1 [2.6]
SSS =3-4 88 11 [12]
SSS >4 446 109 [24]*
*, Chi-square with two degrees of freedom =14.94, P=0.0006.
#, number of patients.
Table 4 Revascularization rates stratified by summed difference score
Total # abnormal
MPI N=573
Rate of 90 day
revascularization [%]
SDS =0-2 202 10 [5.0]
SDS =3-4 98 13 [13]
SDS ≥4 273 98 [36]*
*, Chi-Square with two degrees of freedom =71.12, P=0.0001.
#, number of patients.

or no ischemia had only 5% chance of revascularization at
90 days versus a 36% chance when the amount of
ischemia was large (Table 4). However, a limited impact of
revascularization on short-term mortality was observed,
particularly in patients who can exercise. In fact, patients
with abnormal exercise MPI who subsequently underwent
revascularization had worse outcomes than those who did
not, suggesting that the early procedural hazard was not
associated with downstream survival benefit at the time of
follow up.
MPI in the middle-aged population has been shown to
provide incremental prognostic value for predicting cardiac
events and death in patients with known or suspected CAD.
One meta-analysis demonstrated that both age and the
inability to complete an exercise test are independent and
negative prognostic indicators in patients with CAD (23).
These data cannot be translated to the Medicare population
given the co-morbidities present as well as the competing
mortality risk from other disease processes. A recent study
of elderly patients undergoing MPI demonstrated the utility
of MPI in elderly patients over the age of 75 years (13).
However, this retrospective study analyzed patients who
underwent MPI between 1991 and 1999, and it is unclear
if these patients were treated with modern medical therapy.
Furthermore, the study population had relatively mild
perfusion defects, and the study did not distinguish between
differences in outcomes after subsequent revascularization
based on the type of stress testing (exercise vs. pharmacologic),
or functional capacity. Several smaller studies have also
examined the prognostic value of MPI in the elderly
(9-12,15,16,24,25); however, our study is novel in that it
demonstrates the neutralizing effect of the ability to exercise in
patients with abnormal MPI in an older patient population.
We also demonstrated that maximum METs achieved
was the most powerful independent predictor of mortality,
even more powerful than age and abnormal MPI findings,
in this patient population. This finding contradicts previous
smaller studies and conventional thinking that MPI findings
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
YearsYears
Abnormal 573 572 569 51 429 326 206 60
Normal 1,043 1,042 1,027 871 687 512 335 105
Abnormal
Normal
P=0.67
>7 METs 906 906 903 792 648 495 232 100
≤7 METs 758 755 741 636 514 377 240 69
>7 METs
≤7 METs
Survival(%)
Survival(%)
100
90
80
70
60
50
100
90
80
70
60
50
Survival based on study impression Survival based on maximum METs achieved
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
P<0.001
Figure 2 Exercise group only-survival analysis.
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Years (after exercise test)
Survival(%)
100
90
80
70
60
50
P-value=0.01*
Normal exercise MPI
Abnormal exercise MPI-revascularization
Abnormal exercise MPI-no revascularization
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Normal 1,043 1,042 1,027 871 687 513 335 105
Abnormal (–revasc) 452 452 449 413 344 267 167 54
Abnormal (+revasc) 121 121 120 100 86 59 40 7
Figure 3 Exercise only group—Unadjusted survival of patients
with abnormal myocardial perfusion imaging (MPI) based on
revascularization. *, assuming that >90% of patients underwent
subsequent percutaneous intervention (PCI) at our institution.

should provide incremental information over functional
capacity in this patient population (9,11,23,25). However,
our findings are supported by three other studies. The first
examined the utility of MPI as well as exercise treadmill
testing (ETT) in 626 outpatients age 65 and older, mean
age 70.7 years. This study found that age, gender, exercise
tolerance, and ischemia were independent predictors
of death (25). ROC curve analysis in this study for the
prediction of future events demonstrated the area under
the curve to be 0.659 for patient age and sex; 0.715 for age,
sex, and treadmill time (P=0.048 vs. age and sex); and 0.721
for age, sex, treadmill time, and MPI ischemia (P=0.027
vs. age and sex but P=NS vs. age, sex, and treadmill time).
Therefore, this suggests that after age, sex, and exercise
tolerance were determined, the addition of ischemia of
assessment by MPI offered relatively small incremental
value. The other evaluated 514 elderly patients (≥65 yrs)
who underwent ETT and demonstrated that workload
alone was the only ETT variable that was independently
associated with outcomes (26). Furthermore, Sui et al.
evaluated a cohort of 2,603 patients over the age of 60 years
and found that poor cardiorespiratory fitness was a powerful
predictor of mortality (27).
Our study demonstrates that traditionally accepted
prognostic nuclear variables are not as useful in the
Medicare population undergoing MPI. Clinical variables,
ESV, and functional capacity provided the most prognostic
information in terms of all-cause mortality. It is important
to note that ESV was the only MPI variable that was
predictive of survival, which was also recently demonstrated
in a recent study by Doyle et al. (28).
Older patients with stable CAD who undergo
interventions represent a substantial expenditure without
proof of benefit (29). As the population continues to age,
the potential financial burden of increasing nuclear imaging
studies and possible subsequent interventions may be
significant. Therefore, the prognostic benefit needs to be
closely scrutinized. Our study again raises the question of
prognostic benefit of such procedures, particularly in older
patients who can exercise. With recent studies such as the
COURAGE trial (30), the there is little justification for
spending resources on stress imaging to guide subsequent
revascularizations in elderly patients with stable CAD.
The randomized Trial of Invasive versus Medical therapy
in Elderly patients (TIME) trial demonstrated only a
significant reduction in anginal symptoms and subsequent
hospitalizations, but no significant improvement in
mortality, in patients who were revascularized versus those
who were treated medically (31). Therefore, in older
patients without symptoms, stress imaging and subsequent
revascularization for abnormal findings may not provide
any prognostic benefit. Furthermore, in patients who are
able to exercise, an abnormal MPI does not appear to
impact survival or provide any further risk stratification.
In an era of increasing Medicare and budgetary financial
constraints and with the explosion of proven pharmaceutical
therapeutic primary and secondary prevention tools (Asprin,
betablockers, ACE inhibitors, Clopidogrel and statins),
the utility of non-invasive stress testing in the Medicare
population needs to be further scrutinized.
Table 5 Multivariable Cox proportional hazard model for death
Risk factor Estimate ± SE Chi-square statistic P-value HR (95% CI) Reliability (%)
Max METs –0.38±0.082 21.9 <0.0001 0.68 (0.58-0.80) 59
ESVa
1.7E-7±4.9E-8 11.8 0.0006 NA 62
Male 070±0.31 5.1 0.0200 2.0 (1.1-3.7) 50
Diabetes 0.59±0.26 5.1 0.0200 1.8 (1.08-3.0) 50
Older ageb
0.54±0.24 4.9 0.0300 NA 50
a
, cubic transformation, ESV3
; b
, exponential transformation exp (age/50). ESV, end systolic volume; HR, hazard ratio.
Table 6 MPI variables in Cox proportional hazard model for death
Exercise
group
Univariable Multivariable*
HR (95% CI) P-value HR (95% CI) P-value
SSS 1.018
(0.989-1.047)
0.23 0.993
(0.960-1.030)
0.68
SRS 1.001
(0.957-1.046)
0.97 0.971
(0.921-1.023)
0.27
SDS 1.039
(0.997-1.083)
0.07 1.014
(0.971-1.058)
0.54
*, Includes the five variables from Table 5 with the single
nuclear variable added; HR, hazard ratio.

Limitations
Selection bias may be a significant limitation in our study.
Our patients were referred for MPI at a tertiary-care
medical center, and may have more co-morbidities than
the typical patient of similar age, however we included all
patients (both ambulatory and hospitalized patients) who
presented for evaluation. Subsequent myocardial infarction
and cardiac hospitalization were not recorded in this study.
Another limitation is that 90-day revascularization status
was based upon knowledge of CABG and PCI performed
at our institution. Active follow-up was not used in the
analysis of revascularization; however, from our clinical
practice patterns, we assume that >90% of this patient
cohort would have returned here for care and only a few
early interventions would have been missed. Statistical
comparisons and long-term evaluation of the effect of
revascularization would need active follow-up and a more
appropriate competing risk analysis.
Conclusions
In our study population, perfusion defects on MPI lacked
the ability to provide incremental risk stratification. The
ability to exercise and the number of METs achieved seem
to neutralize the impact of MPI results on mortality. In
this setting, patients who are able to exercise have excellent
outcomes, despite abnormal MPI findings. As expected,
the results of MPI influenced the rate of revascularization.
However, revascularization in patients who can exercise
even when faced with an abnormal MPI failed to be
protective. The assumption that MPI in older patients can
be further risk stratify patients beyond exercise capacity in
the modern era needs to be tested in a prospective trial.
Acknowledgements
DHK, PH, and WAJ had full access to all of the data in the
study and take responsibility for the integrity of the data
and the accuracy of the data analysis.
Disclosure: Dr. Kwon is a consultant for Astellas. Dr. Manuel
Cerqueira is on the Scientific Advisory Board and Speakers
Bureau for Astellas Pharma USA. None of the other authors
have conflicts of interests that would bias the analysis of our
study.
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Cite this article as: Kwon DH, Menon V, Houghtaling P,
Lieber E, Brunken RC, Cerqueira MD, Jaber WA. Predictive
value of exercise myocardial perfusion imaging in the
Medicare population: the impact of the ability to exercise.
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j.issn.2223-3652.2014.02.09
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