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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 Downloaded from http://circimaging.ahajournals.org/ by guest on May 13, 2017 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 Downloaded from http://circimaging.ahajournals.org/ by guest on May 13, 2017 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 Downloaded from http://circimaging.ahajournals.org/ by guest on May 13, 2017 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 (%) Downloaded from http://circimaging.ahajournals.org/ by guest on May 13, 2017 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, % Downloaded from http://circimaging.ahajournals.org/ by guest on May 13, 2017 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. Downloaded from http://circimaging.ahajournals.org/ by guest on May 13, 2017 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 Downloaded from http://circimaging.ahajournals.org/ by guest on May 13, 2017 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 Downloaded from http://circimaging.ahajournals.org/ by guest on May 13, 2017 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. References 1. MedAxiom. Cardiologists performing fewer advanced tests on patients as tighter rules, financial factors take hold [press release]. September 4, 2012. 2.Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood JE. Exercise capacity and mortality among men referred for exercise testing. N Engl J Med. 2002;346:793–801. 3. Goraya TY, Jacobsen SJ, Pellikka PA, Miller TD, Khan A, Weston SA, Gersh BJ, Roger VL. Prognostic value of treadmill exercise testing in elderly persons. Ann Intern Med. 2000;132:862–870. 4. Morris CK, Ueshima K, Kawaguchi T, Hideg A, Froelicher VF. The prognostic value of exercise capacity: a review of the literature. Am Heart J. 1991;122:1423–1431. 5. Bourque JM, Holland BH, Watson DD, Beller GA. 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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 Circulation: Cardiovascular Imaging is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2013 American Heart Association, Inc. All rights reserved. Print ISSN: 1941-9651. 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