Download Value of an Exercise Workload ≥10 Metabolic Equivalents

Coronary Artery Disease
Value of an Exercise Workload ≥10 Metabolic Equivalents
for Predicting Inducible Myocardial Ischemia
Jesús Peteiro, MD, PhD; Alberto Bouzas-Mosquera, MD, PhD; Francisco Broullón, MS;
Dolores Martinez, MD; Juan Yañez, MD; Alfonso Castro-Beiras, MD, PhD
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Background—We sought to identify extensive ischemia on exercise echocardiography (ExE) relative to workload in patients
without known coronary artery disease and to investigate whether ExE is useful in predicting outcomes in those with high
exercise capacity (≥10 metabolic equivalents [METs]) plus a maximal test (≥85% of their maximal age-predicted heart
rate [MAPHR]).
Methods and Results—The analysis was performed on 4269 patients who underwent ExE, of whom 3995 achieved ≥85%
of their MAPHR. These patients were divided according to the reached workload (<7, 7–9, or ≥10 METs) and compared
for ExE results. Outcomes in the group achieving ≥10 METs plus ≥85% of their MAPHR (n=2221) were specifically
assessed. Ischemia was defined as new/worsening wall motion abnormalities with exercise. ExE results were different
between groups because the METs were lower. Still, among patients achieving ≥10 METs plus ≥85% of their MAPHR,
9.3% had extensive ischemia and 6% multiterritory disease. During follow-up in this subgroup, 108 patients died and 42
had a major cardiac event. Annualized mortality and major cardiac event rates were 0.84% and 0.32% in patients without
ischemia versus 2.26% and 0.84% in those with ischemia, respectively (P<0.001 and P=0.002, respectively). Ischemia
was an independent predictor of mortality (hazard ratio, 1.88; 95% confidence interval, 1.23–2.89; P=0.004) and major
cardiac event (hazard ratio, 2.39; 95% confidence interval, 1.22–4.71; P=0.01).
Conclusions—Patients without known coronary artery disease achieving ≥10 METs plus ≥85% of their MAPHR may still
have ischemia. However, the low event rates even in those with ischemia limit the usefulness of imaging for assessing
outcomes in this group. (Circ Cardiovasc Imaging. 2013;6:899-907.)
Key Words: echocardiography ◼ exercise
A
ssessment of functional capacity and myocardial ischemia has become a mandatory step in the evaluation
of patients with known or suspected coronary artery disease
(CAD). Functional tests such as exercise echocardiography
(ExE) and exercise myocardial perfusion imaging are commonly used for this purpose. For the first time, the number
of ExE studies ordered by cardiologists in the United States
has increased, whereas the number of myocardial perfusion
imaging studies has decreased.1 One possible explanation for
this finding is concern about radiation. Although ExE may
evaluate functional capacity and ischemia in a single test, the
relationship between these 2 variables is controversial because
functional capacity depends on several factors beyond those
imposed by the presence of CAD. Previous work has shown
that good exercise capacity measured in metabolic equivalents
(METs) confers a good prognosis and an extremely low risk of
inducible ischemia.2–5 However, we have observed that even in
patients expected to have a good outcome such as those with
normal ECG exercise test, imaging by echocardiography identified ischemia in ≤16% of patients and these patients were at a
higher risk of adverse events.6 Therefore, we hypothesize that
individuals without known CAD who achieve a high exercise
workload (≥10 METs) and a maximal test (≥85% of the maximal age-predicted heart rate [MAPHR]) may still have significant ischemia, and this finding may influence outcome. Also,
we aimed to investigate whether patients achieving a high
functional capacity (≥10 METs) may have different ischemic
burden depending on the percentage of MAPHR achieved.
Clinical Perspective on p 907
Methods
Prospectively collected data from the University of A Coruña stress
echocardiography laboratory data bank were retrospectively analyzed.
Patients
A total of 8088 consecutive patients having a first ExE performed
at our institution between March 1995 and December 2007 were
considered. Patients with significant aortic or mitral valve disease,
patients with known CAD based on clinical history of prior myocardial infarction (MI) or revascularization procedures, and patients
who achieved <10 METs and <85% of their MAPHR were excluded.
Patients with known CAD and patients who achieved <10 METs
Received March 6, 2013; accepted September 3, 2013.
From the Laboratory of Stress Echocardiography (J.P., A.B.-M., D.M., J.Y.), Department of Information Technology (F.B.), and Department of
Cardiology (A.C.-B.), Complejo Hospitalario Universitario de A Coruña (CHUAC), University of A Coruña, A Coruña, Spain.
Correspondence to Jesús Peteiro, MD, PhD, Laboratory of Stress Echocardiography, Department of Cardiology, Complejo Hospitalario Universitario de
A Coruña (CHUAC), As Xubias, 84. 15006, A Coruña. Spain. E-mail [email protected]
© 2013 American Heart Association, Inc.
Circ Cardiovasc Imaging is available at http://circimaging.ahajournals.org
899
DOI: 10.1161/CIRCIMAGING.113.000413
900 Circ Cardiovasc Imaging November 2013
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and <85% of their MAPHR were excluded because these individuals
are at higher risk of events and imaging has previously demonstrated
its usefulness in these patients.7–9 Therefore, the final study population included 4269 patients (Figure 1).
Patients achieving ≥85% of their MAPHR (n=3995) were subdivided into 3 groups (<7 METs [n=520], 7–9 METs [n=1254], and ≥10
METs [n=2221]. Patients who achieved ≥10 METs were stratified
according to the percentage of MAPHR (≥85% [n=2221], <85%
[n=274]) for a secondary analysis. Finally, patients who achieved ≥10
METs plus ≥85% of their MAPHR (n=2221) were studied separately
to define the value of ExE to predict outcome.
Demographic and clinical data, as well as stress testing results,
were entered in our database at the time of the procedures. The pretest probability of CAD was assessed according to the American
College of Cardiology/American Heart Association guidelines on
exercise testing.10
Whenever possible, β-blocker therapy was discontinued for ≥48
hours before testing. However, 4.1% of the patients were still under
the influence of β-blockers at the time of their tests.
ExE data were acquired and analyzed by cardiologists not involved
in patient care. The investigator coding the events was blinded to all
the ExE data.
Exercise ECG Testing
Heart rate, blood pressure, and ECG were obtained at baseline and at
each stage of exercise. Patients were encouraged to perform a treadmill exercise test (Bruce protocol, 87.7%; other protocols, 12.3%).
Exercise end points included physical exhaustion, significant arrhythmia, severe hypertension (systolic blood pressure >240 mm Hg or
diastolic blood pressure >110 mm Hg), severe hypotensive response
(decrease >20 mm Hg), or symptoms during exercise. Ischemic ECG
was defined as the development of ST-segment deviation of ≥1 mm
which was horizontal or downsloping away from the isoelectric line
80 ms after the J point, in patients with normal baseline ST segments.
The ECG was considered nondiagnostic in the presence of left bundle-branch block, pre-excitation, paced rhythm, repolarization abnormalities, or treatment with digoxin. Positive exercise testing was
defined as chest pain during the test or ischemic ECG abnormalities
in patients with diagnostic ECG. A maximal test was defined as the
achievement of ≥85% of the MAPHR, otherwise the test was considered submaximal. The study was approved by our institutional review
committee, and all patients gave informed consent.
ExE and Echocardiographic Analysis
Echocardiography was performed in 3 apical views (long-axis, 4-,
and 2-chamber) and 2 parasternal views (long- and short-axis) at
baseline, peak exercise,11,12 and in the immediate postexercise period.
Peak imaging was performed with the patient still exercising, when
signs of exhaustion were present or an end point was achieved.
Feasibility of peak treadmill exercise imaging has been previously
assessed by our group.11,12 In 1 study, the feasibility was 99% and the
percentage of patients in whom ≤13 segments were adequately visualized was 3%.11 Previously reported intra- and interobserver agreement by our group was 100% (κ=1.0±0) and 96% (κ=0.90±0.09),
respectively, for resting wall motion abnormalities (WMAs), and
92% (κ=0.83±0.16) and 96% (κ=0.91±0.09), respectively, for exercise-induced WMAs.12
Regional WMAs were evaluated with a 16-segment model of the
left ventricle.13 Each segment was graded on a 4-point scale, with
normal wall motion scoring=1, hypokinetic=2, akinetic=3, dyskinetic=4, and nonvisualized=0. However, isolated hypokinesia of
the basal inferior or inferoseptal segments was not considered abnormal.14 Wall motion score index (WMSI) and visually estimated
left ventricular (LV) ejection fraction15 were calculated at rest, peak,
and postexercise. WMSI was calculated as the sum of scores divided
by the number of visualized segments. The worst WMSI and LV
ejection fraction obtained at peak or postexercise imaging were
considered. The change in WMSI from rest to exercise (ΔWMSI)
was calculated. Ischemia was defined as the development of new or
worsening WMA with exercise. Extensive ischemia was defined as
new or worsening WMA involving ≥3 segments in the same or different coronary artery distribution territories. Multiterritory involvement was defined as exercise WMA in >1 territory. WMAs in the
apex, anteroseptal, septal, and anterior walls were ascribed to the left
anterior descending coronary artery distribution territory, whereas
WMAs in other walls of the LV were assigned to the right and left
circumflex coronary arteries distribution territories. Contrast agents
were not routinely administered. They were only used in 5 patients
with poor acoustic windows.
Follow-up and End Points
Follow-up in the entire study cohort of 4269 was obtained by review
of hospital databases, medical records, and death certificates, as well
as by telephone interviews when necessary.
End points were all-cause mortality and major cardiac events
(MACEs), that is, cardiac death and nonfatal MI. Cardiac death was
defined as death caused by acute MI, congestive heart failure, lifethreatening arrhythmias, or documented cardiac arrest; unexpected,
otherwise unexplained sudden death was also considered cardiac
death. MI was defined as the appearance of new symptoms of myocardial ischemia or ischemic ECG changes accompanied by increases
in markers of myocardial necrosis. Revascularization procedures during follow-up were not considered events because ExE results might
have influenced patient management.
Figure 1. Flowchart depicting patients excluded
and patients included for primary and secondary
analysis and for comprehensive outcome assessment. CAD indicates coronary artery disease;
ExE, exercise echocardiography; MAPHR, mean
age-predicted heart rate; and MET, metabolic
equivalent.
Peteiro et al High Exercise Workload and Ischemia 901
Statistical Analysis
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Categorical variables were reported as % and comparison between
groups based on the χ2 test. Continuous variables were reported as
mean±1 SD, and intergroup differences were assessed using the
ANOVA test.
Univariable logistic regression analysis of possible predictors of
extensive ischemia (≥3 segments with exercise-induced ischemia)
in all patients who reached ≥85% of their MAPHR was performed.
Variables with P<0.05 were entered in a multivariable logistic regression model predicting ≥3 myocardial ischemic segments. The
C-statistic of the predictive model was assessed. A value of 1.0 represents perfect prediction of the model.
Survival free of the end point of interest was estimated by the
Kaplan–Meier method, and survival curves were compared with the
log-rank test. Patients were censored at the time of a coronary revascularization procedure or noncardiac death for the MACE analysis,
but not for analysis of the overall mortality to avoid misclassification
of the cause of death.16 Annualized event rates were calculated by
dividing the number of events by the total number of person-years
at risk.
Univariable and multivariable associations of the different variables with outcome in the specific group of 2221 patients who
achieved ≥10 METs plus ≥85% of their MAPHR were assessed with
Cox proportional hazard model. Variables were selected in a stepwise
forward selection manner, with entry and retention set at P=0.05.
Hazard ratios with 95% confidence intervals were estimated.
The incremental value of ExE results over clinical, resting echocardiographic, and exercise treadmill testing variables was assessed
in 4 steps. The first step was based on clinical data. Resting echocardiographic data were then added in the following step. The third step
consisted of data obtained during exercise. In the final step, the ExE
data were added. The χ2 value of each model and the incremental
value of adding the different variables were estimated. A statistically
significant increase in the global χ2 defined incremental prognostic
value.17 Statistical analysis was performed using SPSS software, version 15.0 (SPSS, Chicago, IL).
Results
Baseline Clinical Characteristics and ExE
Results in Patients Achieving a Maximal
Response to Exercise
Baseline clinical characteristics, exercise testing, and
ExE results of the 3995 patients achieving ≥85% of their
MAPHR according to exercise workload are summarized in
Tables 1 to 3. The clinical, exercise testing, and ExE risk
profiles were significantly lower because higher workload
was attained. Among ischemic patients, hypertension was
less frequent because exercise workload was higher (<7
METs, 73%; 7–9 METs, 62%; ≥10 METs, 47%; P<0.001),
and the same trend was observed with the percentage of
patients with left bundle-branch block (<7 METs, 19%;
7–9 METs, 12%; ≥10 METs, 9%; P=0.009), whereas the
percentage of patients with LV hypertrophy was not statistically different between the 3 groups (<7 METs, 68%;
7–9 METs, 61%; ≥10 METs, 58%). The annualized revascularization, MACE, and mortality rates in the 3 groups of
patients are depicted in Table 3.
Table 1. Clinical Baseline Characteristics in Patients Achieving ≥85% of Their MAPHR According to
Exercise Workload
Male, n (%)
<7 METs (n=520)
7–9 METs (n=1254)
≥10 METs (n=2221)
P Value
193 (36)
469 (37)
1387 (62)
<0.001
Age, y
68±9
65±11
57±13
<0.001
Current smokers, n (%)
87 (17)
225 (18)
539 (24)
<0.001
Diabetes mellitus, n (%)
134 (26)
243 (19)
228 (19)
<0.001
Hypertension, n (%)
349 (67)
746 (60)
973 (44)
<0.001
Hypercholesterolemia, n (%)
230 (44)
572 (46)
883 (40)
<0.001
40 (8)
70 (6)
82 (4)
<0.001
Atypical/probable angina, n (%)
199 (38)
521 (42)
1129 (51)
Nonanginal chest pain, n (%)
281 (54)
663 (53)
1010 (46)
87 (17)
116 (9)
72 (3)
<0.001
196 (38)
391 (31)
477 (22)
<0.001
Chest pain, n (%)
Typical angina, n (%)
Atrial fibrillation, n (%)
Abnormal resting ECG, n (%)
Medications
β-Blocker use the day of the ExE, n (%)
24 (5)
24 (2)
80 (4)
0.004
Nitrates, n (%)
209 (4)
399 (32)
480 (39)
<0.001
Calcium channel blockers, n (%)
154 (30)
289 (23)
361 (30)
<0.001
ACEIs/ARAs, n (%)
70 (13)
149 (12)
192 (16)
<0.001
Digoxin, n (%)
45 (9)
68 (5)
63 (5)
<0.001
Diuretics, n (%)
93 (18)
155 (12)
131 (11)
<0.001
<0.001
Pretest probability of CAD
Low or extremely low, n (%)
Intermediate, n (%)
High, n (%)
34 (7)
164 (13)
427 (19)
448 (86)
1024 (82)
1718 (77)
38 (7)
66 (5)
76 (3)
ACEIs indicates angiotensin-converting enzyme inhibitors; ARAs, angiotensin receptor antagonists; CAD, coronary artery
disease; ExE, exercise echocardiography; MAPHR, maximal age-predicted heart rate; and METs, metabolic equivalents.
902 Circ Cardiovasc Imaging November 2013
Table 2. Exercise Testing Variables in Patients Achieving ≥85% of Their MAPHR According to
Exercise Workload
<7 METs (n=520)
7–9 METs (n=1254)
≥10 METs (n=2221)
P Value
Systolic blood pressure, mm Hg
Rest
140±23
138±21
134±18
<0.001
Peak
163±35
172±31
177±26
<0.001
Rest
88±17
84±14
78±14
<0.001
Peak
149±18
153±16
160±16
<0.001
Heart rate, beats/min
Rate-pressure product, 1000 mm Hg×beats/min
Rest
12.3±3.1
11.6±2.6
10.5±2.4
<0.001
Peak
24.2±5.6
26.3±5.5
28.4±5.1
<0.001
<0.001
Angina during the test, n (%)
56 (11)
102 (8)
98 (4)
Positive ECG, n (%)
67 (13)
150 (12)
251 (11)
0.57
105 (20)
206 (16)
317 (14)
0.003
Positive exercise ECG, n (%)
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MAPHR indicates maximal age-predicted heart rate; and METs, metabolic equivalents.
ExE Results, Revascularizations, and Outcome in
Patients Achieving ≥10 METs
Table 4 shows the ExE results, number and annualized
revascularization, MACE, and mortality rates in patients
achieving ≥10 METs and having or not having achieved an
MAPHR ≥85%. Patients with maximal tests had less frequently ischemia than those with submaximal tests. Accordingly, the percentage of revascularization procedures was
also lower in the former. Among patients achieving ≥10
METs plus an MAPHR ≥85%, 39 underwent revascularization procedures. Thirty-three of them had multivessel CAD
(85%), and the rest had 1-vessel CAD (6; 15%). Left main
CAD was present in 9 (23%), CAD involving the left anterior descending coronary artery in 36 (92%), involving the
right coronary artery in 25 (64%), and involving the left circumflex coronary artery in 29 (74%).
Prediction of Extensive Ischemia
Table 5 shows the multivariable logistic regression analysis for
predicting ischemia in ≥3 myocardial segments. The C-statistic
of this model was 0.80 (95% confidence interval, 0.78–0.82).
Positive exercise testing (C-statistic=0.68), age (C-statistic=0.64), and METs (C-statistic=0.62) gave the largest odds
of ischemia in ≥3 segments. Figure 2 shows the relationship of
exercise ECG testing and METs achieved to the percentages of
LV ischemia and multiterritory disease. Significant ischemia
was still observed in a percentage of patients who achieved ≥10
METs plus ≥85% of their MAPHR, even though exercise ECG
was negative. Half of the patients who had extensive ischemia
also had multiterritory involvement (239/523; 46%). However,
these percentages were significantly different between groups
according to exercise workload: <7 METs, 64%; 7 to 9 METs,
51%; ≥10 METs, 29% (P<0.001).
Table 3. Exercise Echocardiography Results and Annualized Revascularization, MACE, and Mortality
Rates in Patients Achieving ≥85% of Their MAPHR According to Exercise Workload
≥10 METs (n=2221)
<7 METs (n=520)
7–9 METs (n=1254)
102 (30)
157 (13)
153 (7)
<0.001
48 (9)
63 (5)
51 (2)
<0.001
Ischemia, n (%)
140 (27)
241 (19)
300 (14)
<0.001
Extensive ischemia, n (%)
125 (24)
191 (15)
207 (9.3)
<0.001
Multiterritory involvement, n (%)
123 (24)
172 (14)
134 (6)
<0.001
Rest
1.14±0.32
1.08±0.25
1.04±0.19
<0.001
Peak
1.25±0.40
1.15±0.32
1.08±0.21
<0.001
Rest
56±12
58±10
60±7
<0.001
Peak exercise
58±15
63±13
67±10
<0.001
Annualized revascularization rate, %
1.9
1.4
0.4
<0.001
Annualized MACE rate, %
1.9
1
0.4
<0.001
Annualized mortality rate, %
4.4
2.2
1.0
<0.001
Resting WMAs, n (%)
Mixed WMAs and ischemia, n (%)
P Value
Wall motion score index
Left ventricular ejection fraction, %
MACE indicates major cardiac event; MAPHR, maximal age-predicted heart rate; METs, metabolic equivalents; and WMAs, wall
motion abnormalities.
Peteiro et al High Exercise Workload and Ischemia 903
Table 4. Exercise Echocardiography Results and Annualized Revascularization, MACE, and Mortality
Rates in Patients Exercising ≥10 METs
<85% MAPHR (n=274)
≥85% MAPHR (n=2221)
P Value
Resting WMAs, n (%)
24 (8.8)
153 (6.9)
0.26
Mixed WMAs and ischemia, n (%)
11 (4)
51 (2)
0.09
Ischemia, n (%)
54 (19.7)
300 (13.5)
0.006
Extensive ischemia, n (%)
36 (13.1)
207 (9.3)
0.04
Multiterritory involvement, n (%)
20 (7.3)
134 (6)
0.41
Rest
1.05±0.20
1.04±0.19
0.41
Peak
1.10±0.25
1.08±0.21
0.13
Rest
60±8
60±70
0.79
Peak exercise
66±10
67±10
0.11
Annualized revascularization rate, %
1.8
0.4
<0.001
Annualized MACE rate, %
0.7
0.4
0.20
Annualized mortality rate, %
1.6
1.0
0.01
Wall motion score index
Left ventricular ejection fraction, %
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MACE indicates major cardiac event; MAPHR, maximal age-predicted heart rate; METs, metabolic equivalents; and WMAs, wall
motion abnormalities.
Predictors of Outcome in Patients Who
Achieved ≥10 METs and ≥85% of Their MAPHR
The mean follow-up in the 2221 patients who achieved
both ≥10 METs and ≥85% of their MAPHR was 4.3±3.4 years.
During follow-up, 108 deaths occurred and 42 patients had an
MACE before any revascularization procedure, including 32
cardiac deaths and 10 nonfatal MI. The annualized mortality
and MACE rates were 0.84% and 0.32% in patients without
ischemia versus 2.26% and 0.84% in those with ischemia,
respectively (Figure 3). Extensive ischemia was observed in
19.4% of patients who died versus 8.8% of those who did not
and multiterritory involvement in 15.7% versus 5.5%. Also,
extensive ischemia was observed in 21.4% of patients who
had an MACE versus 9% of those who did not and multiterritory involvement in 28.6% versus 5.6%.
Tables 6 and 7 show the predictors of MACE and mortality.
In the multivariable analysis, ischemia remained an independent predictor of both total mortality and MACE.
The χ2 of the clinical model for the prediction of overall mortality was 93.4 (P<0.001), and after the addition
of resting echocardiography, the χ2 increased to 121.8
(P=0.001). Further inclusion of the exercise testing variables (METs) increased the χ2 of the model to 131.2
(P=0.001). The addition of ExE (ischemia) to the clinical,
resting echocardiographic, and treadmill exercise data also
increased the χ2 of the model for predicting overall mortality to 141.7 (P=0.006).
The χ2 of the clinical model for the prediction of MACE
was 39.3 (P<0.001), and after the addition of resting echocardiography, the χ2 increased to 89.7 (P<0.001). No exercise
testing variables increased further the χ2 of the model. Finally,
the addition of ExE (ischemia) increased the χ2 of the model
for predicting MACE to 95.8 (P=0.018).
Table 5. Clinical, Resting Echocardiography, and Exercise
Testing Predictors of Extensive Ischemia (≥3 Myocardial
Segments) in the 3995 Patients Who Reached a Maximal
Exercise Testing
Wald χ2
OR
95% CI
P Value
Age
36.8
1.03
1.02–1.05
<0.001
Male
57.4
2.36
1.89–2.95
<0.001
Abnormal
resting ECG
12.5
1.57
1.23–1.99
<0.001
Typical angina
22.4
2.38
1.66–3.40
<0.001
Resting WMA
17.4
1.82
1.37–2.42
<0.001
Positive
exercise ECG
252.6
6.45
5.12–8.11
<0.001
30.4
0.90
0.86–0.93
<0.001
METs
CI indicates confidence interval; METs, metabolic equivalents; OR, odds ratio;
and WMA, wall motion abnormality.
Figure 2. Relationship of exercise ECG testing and metabolic
equivalents (METs) achieved to the percentages of left ventricular ischemia and multiterritory disease. The 3995 patients
who achieved ≥85 of their maximum age-predicted heart rate
were divided by the number of METs attained (<10 METs or
≥10 METs) and the presence of positive, negative, or nondiagnostic exercise ECG testing. Positive exercise testing was
defined as the development of symptoms and ST-segment
change during exercise.
904 Circ Cardiovasc Imaging November 2013
Figure 3. All-cause mortality and major
cardiac events curves in the 2221
patients who achieved a workload of ≥10
metabolic equivalents and a maximal
exercise testing (≥85% of their maximal
age-predicted heart rate) according to the
presence or absence of ischemia.
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Discussion
The main findings of this study may be summarized as follows. First, in patients without known CAD and with a theoretically good outcome as those who attain 10 METs of an
exercise testing protocol and achieve a maximal response
(>85% of their MAPHR), ExE was able to detect a significant
number of subjects with ischemia. Furthermore, extensive
ischemia was detected in ≤9.3% of these patients and multiterritory disease in ≤6%. Second, ischemia during ExE was an
independent predictor of outcome, either for overall mortality or MACEs. Other clinical, ECG, and echocardiographic
predictors were identified, including age, sex, resting ECG
abnormalities, resting WMAs, and exercise workload. Third,
although these findings might be valuable for patients without
Table 6. Predictors of Major Cardiac Events in Patients Achieving ≥10 METs and ≥85% of Their
MAPHR
Univariable
Multivariable
HR
95% CI
P Value
HR
95% CI
P Value
3.09
1.42–6.68
0.004
2.24
1.02–4.90
0.04
3.11
1.62–5.97
0.001
5.32
2.58–10.97
<0.001
2.39
1.22–4.71
0.01
Clinical variables
Male
Age, per year
1.03
1.00–1.06
0.04
Atrial fibrillation
4.88
1.89–12.23
0.001
Abnormal resting
ECG
4.88
2.66–8.96
<0.001
Diuretics
3.14
1.40–7.09
0.006
ACEIs/ARAs
2.60
1.36–4.96
0.004
Digoxin
6.90
3.06–15.54
<0.001
Resting WMA
6.7
3.53–12.73
<0.001
Resting WMSI
10.21
5.29–19.71
<0.001
Resting LVEF
0.94
0.92–0.96
<0.001
Resting
echocardiography
Peak exercise
echocardiography
Peak LVEF
0.94
0.93–0.96
<0.001
ΔLVEF
0.93
0.90–0.96
<0.001
11.62
6.02–22.47
<0.001
2.82
1.44–5.50
0.002
Peak WMSI
Ischemia
ACEIs indicates angiotensin-converting enzyme inhibitors; ARAs, angiotensin receptor antagonists; CI, confidence interval; HR,
hazard ratio; LVEF, left ventricular ejection fraction; MAPHR, maximal age-predicted heart rate; METs, metabolic equivalents;
WMA, wall motion abnormality; and WMSI, wall motion score index.
Other nonsignificant analyzed variables were hypertension, hypercholesterolemia, diabetes mellitus, current smokers, family
history of coronary artery disease, treatment with β-blockers at the time of the exercise testing, treatment with calcium channel
blockers, treatment with nitrates, typical angina, angina during exercise testing, positive exercise ECG testing, % achieved of the
MAPHR, achieved METs, peak double product, and increase in double product with exercise.
Peteiro et al High Exercise Workload and Ischemia 905
Table 7. Predictors of Mortality in Patients Achieving ≥10 METs and ≥85% of Their MAPHR
Univariable
Multivariable
HR
95% CI
P Value
HR
95% CI
P Value
Male
2.55
1.62–4.01
<0.001
2.76
1.71–4.46
<0.001
Age, per year
1.08
1.06–1.10
<0.001
1.06
1.04–1.08
<0.001
Typical angina
2.98
1.50–5.89
0.002
Atrial fibrillation
3.84
2.00–7.37
<0.001
Abnormal resting ECG
2.57
1.74–3.78
<0.001
ACEIs/ARAs
2.05
1.33–3.15
0.001
Diuretics
3.29
1.98–5.46
<0.001
2.14
1.22–3.74
0.008
Digoxin
4.39
2.41–8.00
<0.001
Resting WMA
3.45
2.16–5.51
<0.001
Resting WMSI
5.20
3.10–8.72
<0.001
2.68
1.50–4.79
0.001
Resting LVEF
0.96
0.94–0.97
<0.001
Peak RPP, per 103 U
0.95
0.91–0.99
0.006
ΔRPP, per 103 U
0.93
0.89–0.97
0.001
METs
0.72
0.62–0.84
<0.001
0.78
0.66–0.92
0.003
Positive ECG
2.11
1.27–3.50
0.004
Positive exercise ECG testing
1.91
1.21–2.99
0.005
Peak LVEF
0.96
0.95–0.98
<0.001
ΔLVEF
0.96
0.94–0.99
0.002
Peak WMSI
5.31
3.20–8.80
<0.001
Ischemia
2.67
1.76–4.06
<0.001
1.88
1.23–2.89
0.004
Clinical variables
Resting echocardiography
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Exercise testing
Peak exercise echocardiography
ACEIs indicates angiotensin-converting enzyme inhibitors; ARAs, angiotensin receptor antagonists; CI, confidence interval;
HR, hazard ratio; LVEF, left ventricular ejection fraction; MAPHR, maximal age-predicted heart rate; METs, metabolic equivalents;
RPP, rate-pressure product; WMA, wall motion abnormality; and WMSI, wall motion score index.
Other nonsignificant analyzed variables were hypertension, hypercholesterolemia, diabetes mellitus, current smokers, family
history of coronary artery disease, treatment with β-blockers at the time of the exercise testing, treatment with calcium channel
blockers, treatment with nitrates, and % achieved of the MAPHR.
a previous diagnosis of CAD, the low MACE and mortality
rates of 0.84% and 2.26% make the presence of ischemia not
prognostically important in patients who exercise maximally
and achieve a good exercise capacity.
We wanted to select a group of patients with a theoretically
good prognosis according to exercise testing, such as those
demonstrating a high functional capacity. Also, the selection of those who achieved ≥85% of their MAPHR excludes
patients whose ExE results would be considered nondiagnostic or prone to represent false-negative results.18 A false-negative result of an imaging technique (namely, lack of ischemia)
may not be as important in patients with known CAD because
it might be in patients without demonstrated CAD. We have
chosen a cutoff value of 3 ischemic segments to define extensive ischemia because this number is proportional to the 10%
ischemic myocardium that has been considered for referring
patients to revascularization to improve outcome.19
Although we in the present work and others previously5,6,9
have clearly demonstrated that patients achieving higher exercise workload have better clinical, exercise testing, and ExE
results, there are still a significant number of subjects within
this group in whom ischemia can be demonstrated. However,
the low event rates in ischemic patients limit the usefulness
of imaging for predicting outcome. Moreover, an imaging
approach would require a large number of tests to find a highrisk individual. For example, the number of tests necessary to
detect a patient with multiterritory disease was 16.6 and the
number of tests necessary to detect a patient with extensive
ischemia was 10.7 in our study. Also, our study raises concerns
about the usefulness of classical ECG markers because not a
single exercise ECG variable was a predictor of MACEs in
patients who achieved ≥10 METs plus ≥85% of their MAPHR.
The low overall annualized mortality and MACE rates of
1% and 0.4% in our patients who attained 10 METs of an
exercise testing protocol and achieved a maximal response
are consistent with previous studies in patients achieving high
functional capacity3,20 and are identical to figures reported for
patients with a negative stress echocardiogram.21 Bourque et
al5 have recently studied a similar population to ours in which
myocardial perfusion imaging was used to assess ischemia in
patients who achieved ≥10 METs plus ≥85% of their MAPHR.
Despite similar exercise testing results between their patients
906 Circ Cardiovasc Imaging November 2013
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and ours, they found significant ischemia in a small percentage of their cohort. A 10% of the myocardium perfusion defect
was observed in only 0.4% of the subjects and in no patients
with normal exercise ECG. Given that myocardial perfusion
imaging is considered to have a slightly higher sensitivity than
stress echocardiography for the detection of CAD,22 explanations for these dissimilar results regarding ischemia detection should be sought in the pretest probability of CAD and
baseline patient characteristics. For example, in their cohort,
age and prevalence of patients with diabetes mellitus and resting ECG abnormalities were lower than in our study. Another
analysis of 509 patients who achieved ≥10 METs found an
extremely low prevalence of cardiac mortality, nonfatal MI,
and late revascularizations (<1% for each) during a follow-up
period of 2.2±0.5 years.23 These authors, therefore, also concluded that functional imaging was not worthwhile to study a
population with these characteristics.
McCully et al24 have considered a good exercise capacity
the achievement of ≥7 METs in men and 5 METs in women.
Although the usefulness of ExE for further stratification in
their population, which included one third of patients with
a history of CAD, was clearly demonstrated, in our view
these patients should be considered as having a moderate
exercise capacity.
There have been concerns about the usefulness of detecting ischemia to modify prognosis, given that it was a common belief that patients at risk of acute coronary syndromes
were mainly those with nonsignificant stenoses.25 However,
it has been lately suggested that most of the acute coronary
syndromes are related to angiographically significant stenotic lesions,26,27 rather than to lesions unlikely to provoke
an ischemic burden. On the contrary, the role of revascularization to improve prognosis in patients with stable angina is
not clear.28,29 In this regard, there was some disparity between
the number of subjects with extensive ischemia in the current
study and the number of subjects who were ultimately referred
to revascularization. Whether medical treatment alone modified favorably the outcome of these patients leading to low
event rates could not be discerned from the present study.
Cost Implications
Patients reaching an exercise workload of 10 METs may represent up to half of the patients considered for exercise testing.
In our cohort, 56% of the patients who achieved a maximal
test also achieved 10 METs. Therefore, functional imaging
instead of exercise ECG testing in these patients certainly has
cost implications. In this regard, it should be pointed out that
predicted costs in patients without CAD and low post-test risk
were lower when an ExE instead of an exercise ECG strategy
was used in 1 study.30
Limitations
Our results should be considered in the light of several potential limitations. First, a type I error cannot be entirely excluded
attributable to the relatively limited number of MACE in
patients who achieved ≥10 METs and ≥85% MAPHR.
Second, patients with ischemic results were more likely
to undergo revascularization procedures, and thus, the actual
prognostic value of ExE may have been underestimated.
Nevertheless, despite the frequency of extensive ischemia and
evidence of multivessel disease, revascularization rates were
relatively low in this cohort, likely attributable to uncountable
morbidities such as chronic pulmonary obstructive disease,
chronic kidney disease, and malignancies.
Third, we have used peak treadmill imaging acquisition
because we have previously demonstrated similar feasibility
but higher sensitivity and prognostic value with this technique
as compared with postexercise imaging.11,12 Therefore, the
results could have been different if the classical approach had
been used.
Finally, our subgroup of patients who achieved ≥10 METs
had an intermediate pretest probability of CAD. Our ExE
results and the value of ExE for predicting outcome could also
have been different if a population with different pretest probability had been studied.
Conclusions
Patients with a theoretically good prognosis by exercise testing, such as those without known CAD achieving ≥10 METs
plus ≥85% of their MAPHR, may still have significant ischemia. Extensive ischemia was found in 9.3% of these patients
by ExE and multiterritory involvement in 6%. Ischemia was
an independent predictor of events, along with other important
variables, including age, sex, resting ECG abnormalities, resting WMAs, and exercise workload. However, the low event
rate may limit the usefulness of an imaging approach in these
subjects. Even in those with ischemia, the MACE and mortality rates of 0.84% and 2.26% make the presence of ischemia
not prognostically important in the context of good exercise
tolerance. Further prospective studies are warranted to evaluate the cost-effectiveness of an ExE strategy in these patients.
Sources of Funding
This study was partially funded by the Spanish Network of
Cardiovascular Studies (RECAVA).
Disclosures
None.
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CLINICAL PERSPECTIVE
It has long been thought that patients who exercise maximally during a negative exercise ECG and achieve an exercise workload of 10 metabolic equivalents have low probability of having ischemia and therefore a low chance of suffering events. In
this study of >3995 patients without known coronary artery disease who exercised maximally, we found that patients who
achieved <10 metabolic equivalents have worse clinical and exercise echocardiography characteristics and outcomes than
those who achieved 10 metabolic equivalents, including higher prevalence of extensive ischemia. However, even in patients
achieving 10 metabolic equivalents, a significant percentage had extensive ischemia (9.3%) and up to 6% had multiterritory
involvement. These patients were at a higher risk of overall mortality and major cardiac events during a follow-up of 4.3
years because ischemia was an independent predictor of events, along with other important variables, including age, sex,
resting ECG abnormalities, resting wall motion abnormalities, and exercise workload. The annualized mortality and major
cardiac event rates were 0.84% and 0.32% in patients without ischemia versus 2.26% and 0.84% in those with ischemia,
respectively (P<0.001 and P=0.002, respectively). Although these findings are of interest for patients without a previous
diagnosis of coronary artery disease, the imaging approach necessitated a large number of tests to find a high-risk individual
(ie, 16.6 to detect a patient with multiterritory disease; 10 to detect a patient with extensive ischemia). Also, the low major
cardiac event and mortality rates even in patients with ischemia and good exercise tolerance make the presence of ischemia
not prognostically important in this group.
Value of an Exercise Workload ≥10 Metabolic Equivalents for Predicting Inducible
Myocardial Ischemia
Jesús Peteiro, Alberto Bouzas-Mosquera, Francisco Broullón, Dolores Martinez, Juan Yañez
and Alfonso Castro-Beiras
Downloaded from http://circimaging.ahajournals.org/ by guest on May 13, 2017
Circ Cardiovasc Imaging. 2013;6:899-907; originally published online September 13, 2013;
doi: 10.1161/CIRCIMAGING.113.000413
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